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出境医 / 临床实验 / Effect of GSK3640254 on the Pharmacokinetics of a Combination Oral Contraceptive

Effect of GSK3640254 on the Pharmacokinetics of a Combination Oral Contraceptive

Study Description
Brief Summary:
This is an open-label, single-sequence, 1-way drug-drug interaction study to investigate the effect of GSK3640254 on the pharmacokinetics of a combination oral contraceptive containing ethinyl estradiol (EE) and levonorgestrel (LNG). Effective contraception for women infected with human immunodeficiency virus (HIV) is important in the prevention of unplanned pregnancies. The study will consist of a screening period of 28 days, check-in (Day -4), a run-in period and a treatment period. During the run-in period, subjects will be administered Portia® (0.03 milligrams [mg] EE/0.15 mg LNG) once daily on Days -3 to -1. Subjects will then be administered Portia once daily on Days 1 to 10 of treatment period A followed by administration of Portia once daily along with GSK3640254 200 mg on Days 11 to 21 of treatment period B. The duration of the study is approximately 8 weeks, including Screening and Run-in. Portia is a registered trademark of Teva Pharmaceuticals USA.

Condition or disease Intervention/treatment Phase
HIV Infections Drug: GSK3640254 Drug: Portia Phase 1

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Effect of Coadministration of GSK3640254 on the Pharmacokinetics of a Combined Oral Contraceptive Containing Ethinyl Estradiol and Levonorgestrel in Healthy Female Subjects
Actual Study Start Date : June 13, 2019
Actual Primary Completion Date : August 16, 2019
Actual Study Completion Date : August 16, 2019
Arms and Interventions
Arm Intervention/treatment
Experimental: Portia followed by Portia co-administered with GSK3640254
Subjects will be administered Portia (0.03 mg EE/0.15 mg LNG) once daily on Days -3 to -1 during run-in period and on Days 1 to 10 in treatment period A. Subjects will then receive Portia (0.03 mg EE/0.15 mg LNG) co-administered with GSK3640254 200 mg once daily on Days 11 to 21 in treatment period B.
 Drug: GSK3640254
GSK3640254 will be available as a 100 mg capsule. Subjects will be administered 200 mg GSK3640254 once daily via the oral route on Days 11 to 21.

Drug: Portia
Portia will be available in the form of tablets containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel.
Outcome Measures
Primary Outcome Measures :
  1. Period 1: Area Under the Plasma Concentration-time Curve From Time 0 to the End of the Dosing Interval at Steady State (AUC [0-tau]) of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of EE. PK parameters were calculated by standard non-compartmental analysis. The PK population included all participants who underwent plasma PK sampling and had evaluable PK parameters estimated.

  2. Period 2: AUC (0-tau) of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of EE. PK parameters were calculated by standard non-compartmental analysis.

  3. Period 1:AUC (0-tau) of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of LNG. PK parameters were calculated by standard non-compartmental analysis.

  4. Period 2: AUC (0-tau) of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of LNG. PK parameters were calculated by standard non-compartmental analysis.

  5. Period 1: Maximum Observed Concentration (Cmax) and Plasma Concentration at the End of the Dosing Interval (Ctau) of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of EE. PK parameters were calculated by standard non-compartmental analysis.

  6. Period 2: Cmax and Ctau of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of EE. PK parameters were calculated by standard non-compartmental analysis.

  7. Period 1:Cmax and Ctau of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of LNG. PK parameters were calculated by standard non-compartmental analysis.

  8. Period 2: Cmax and Ctau of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of LNG. PK parameters were calculated by standard non-compartmental analysis.


Secondary Outcome Measures :
  1. Period 1: Effect of GSK3640254 on PD of EE/LNG- Serum Progesterone Level [ Time Frame: At Day 1 and Day 10 ]
    Serum samples were collected for the analysis of progesterone concentration levels when GSK3640254 is co-administered with EE/LNG. PD concentration Population comprised of all participants who underwent plasma PD sampling and had evaluable PD assay results.

  2. Period 2: Effect of GSK3640254 on PD of EE/LNG- Serum Progesterone Level [ Time Frame: At Days 11, 21 and 22 ]
    Serum samples were collected for the analysis progesterone concentration levels when GSK3640254 is co-administered with EE/LNG.

  3. Period 1: Absolute Values of Effect of GSK3640254 on Luteinizing Hormone (LH) and Follicle-stimulating Hormone (FSH) [ Time Frame: At Day 1 and Day 10 ]
    Serum samples were collected for the analysis of effect of GSK3640254 on LH and FSH.

  4. Period 2: Absolute Values of Effect of GSK3640254 on LH and FSH [ Time Frame: At Days 11, 21 and 22 ]
    Serum samples were collected for the analysis of effect of GSK3640254 on LH and FSH.

  5. Period 2: AUC (0-tau) of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.

  6. Period 2: Cmax and Ctau of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.

  7. Period 2: Apparent Terminal Phase Half-life (t1/2) of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 hours; Day 22: 24 hours; Day 23: 48 hours; Day 24: 72 hours and Day 25: 96 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.

  8. Period 2: Time of Maximum Observed Concentration (Tmax) of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of Tmax of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.

  9. Period 1: t1/2 of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of EE. PK parameters were calculated by standard non-compartmental analysis.

  10. Period 2: t1/2 of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of EE. PK parameters were calculated by standard non-compartmental analysis.

  11. Period 1: Tmax of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of EE. PK parameters were calculated by standard non-compartmental analysis.

  12. Period 2: Tmax of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of EE. PK parameters were calculated by standard non-compartmental analysis.

  13. Period 1: t1/2 of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of LNG. PK parameters were calculated by standard non-compartmental analysis.

  14. Period 2: t1/2 of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours; Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of LNG. PK parameters were calculated by standard non-compartmental analysis.

  15. Period 1: Tmax of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of LNG. PK parameters were calculated by standard non-compartmental analysis.

  16. Period 2: Tmax of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours; Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of LNG. PK parameters were calculated by standard non-compartmental analysis.

  17. Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAE) (Treatment Period) [ Time Frame: Up to Day 25 ]
    An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. Safety Population comprised of all participants who received at least one dose of study medication.

  18. Number of Participants With Non-SAEs and SAE (Run-in Period) [ Time Frame: From Day -3 to Day -1 ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before.

  19. Period 1: Change From Baseline in Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and Blood Urea Nitrogen (BUN) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  20. Period 2: Change From Baseline in Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and BUN [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  21. Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  22. Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  23. Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  24. Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  25. Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Creatine Kinase, Lactate Dehydrogenase, Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  26. Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST and GGT [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  27. Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  28. Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  29. Period 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  30. Period 2: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  31. Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  32. Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  33. Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  34. Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  35. Period 1: Change From Baseline in Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  36. Period 2: Change From Baseline in Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  37. Period 1: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  38. Period 2: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  39. Period 1: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  40. Period 2: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  41. Period 1: Change From Baseline in Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  42. Period 2: Change From Baseline in Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  43. Period 1: Change From Baseline in Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  44. Period 2: Change From Baseline in Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  45. Period 1: Change From Baseline in Urine Concentration: Urine Potential of Hydrogen (pH) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  46. Period 2: Change From Baseline in Urine Concentration: Urine pH [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  47. Period 1: Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  48. Period 2: Change From Baseline in ECG Mean Heart Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11: 2, 4, 6 hours, Day 15: 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the average of the triplicate predose assessments on Day 11. Change from Baseline was defined as post-dose visit value minus Baseline value.

  49. Period 1: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, Fridericia QT Correction Formula (QTcF) Interval, and Bazett QT Correction Formula (QTcB) Interval [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure PR interval, QRS duration, QT Interval, QTcF Interval and QTcB interval. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  50. Period 2: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF and QTcB Interval [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11: 2, 4, 6 hours, Day 15: 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the average of the triplicate predose assessments on Day 11. Change from Baseline was defined as post-dose visit value minus Baseline value.

  51. Period 1: Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate pre-dose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.

  52. Period 2: Change From Baseline in Vital Signs: SBP and DBP [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as as the average of the triplicate pre-dose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.

  53. Period 1: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate predose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.

  54. Period 2: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate predose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.

  55. Period 1: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Respiratory rate was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  56. Period 2: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Respiratory rate was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  57. Period 1: Change From Baseline in Temperature [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  58. Period 2: Change From Baseline in Temperature [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.

  59. Period 1: Absolute Values of Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and BUN [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  60. Period 2: Absolute Values of Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and BUN [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  61. Period 1: Absolute Values of Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  62. Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  63. Period 1: Absolute Values of Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  64. Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  65. Period 1: Absolute Values of Clinical Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST and GGT [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  66. Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST and GGT [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  67. Period 1: Absolute Values of Clinical Chemistry Parameters: Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  68. Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  69. Period 1: Absolute Values of Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  70. Period 2: Absolute Values of Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  71. Period 1: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  72. Period 2: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  73. Period 1: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  74. Period 2: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  75. Period 1: Absolute Values of Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  76. Period 2: Absolute Values of Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  77. Period 1: Absolute Values of Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  78. Period 2: Absolute Values of Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  79. Period 1: Absolute Values of Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  80. Period 2: Absolute Values of Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  81. Period 1: Absolute Values of Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  82. Period 2: Absolute Values of Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  83. Period 1: Absolute Values of Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  84. Period 2: Absolute Values of Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  85. Period 1: Absolute Values of Urine Concentration: Urine pH [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  86. Period 2: Absolute Values of Urine Concentration: Urine pH [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  87. Period 1: Number of Participants With Abnormal Urinalysis Parameters Using Dipstick Method. [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    The dipstick test gives results in a semi-quantitative manner and results for urinalysis parameters (ketones, glucose, bilirubin, occult blood, nitrite and blood protein) can be read as positive, trace, 1+, 2+, 3+ and 4+ indicating proportional concentrations in the urine sample. Only participants with abnormal findings for urinalysis at any visit has been presented.

  88. Period 2: Number of Participants With Abnormal Urinalysis Parameters Using Dipstick Method. [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    The dipstick test gives results in a semi-quantitative manner and results for urinalysis parameters (ketones, glucose, bilirubin, occult blood, nitrite and blood protein) can be read as positive, trace, 1+, 2+, 3+ and 4+ indicating proportional concentrations in the urine sample. Only participants with abnormal findings for urinalysis at any visit has been presented.

  89. Period 1: Absolute Values of ECG Mean Heart Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.

  90. Period 2: Absolute Values of ECG Mean Heart Rate [ Time Frame: Baseline (Day 11, Pre
Tracking Information
First Submitted Date  ICMJE June 10, 2019
First Posted Date  ICMJE June 13, 2019
Results First Submitted Date  ICMJE July 20, 2020
Results First Posted Date  ICMJE August 27, 2020
Last Update Posted Date August 27, 2020
Actual Study Start Date  ICMJE June 13, 2019
Actual Primary Completion Date August 16, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 18, 2020)
  • Period 1: Area Under the Plasma Concentration-time Curve From Time 0 to the End of the Dosing Interval at Steady State (AUC [0-tau]) of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of EE. PK parameters were calculated by standard non-compartmental analysis. The PK population included all participants who underwent plasma PK sampling and had evaluable PK parameters estimated.
  • Period 2: AUC (0-tau) of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of EE. PK parameters were calculated by standard non-compartmental analysis.
  • Period 1:AUC (0-tau) of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of LNG. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: AUC (0-tau) of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of LNG. PK parameters were calculated by standard non-compartmental analysis.
  • Period 1: Maximum Observed Concentration (Cmax) and Plasma Concentration at the End of the Dosing Interval (Ctau) of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of EE. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: Cmax and Ctau of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of EE. PK parameters were calculated by standard non-compartmental analysis.
  • Period 1:Cmax and Ctau of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of LNG. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: Cmax and Ctau of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of LNG. PK parameters were calculated by standard non-compartmental analysis.
Original Primary Outcome Measures  ICMJE
 (submitted: June 10, 2019)
  • Area under the plasma concentration-time curve from time 0 to the end of the dosing (AUC[0 to tau]) for EE [ Time Frame: Up to Day 24 ]
    Blood samples will be collected at the indicated time points for pharmacokinetic analysis of EE.
  • AUC(0 to tau) for LNG [ Time Frame: Up to Day 24 ]
    Blood samples will be collected at the indicated time points for pharmacokinetic analysis of LNG.
  • Maximum observed concentration (Cmax) for EE [ Time Frame: Up to Day 24 ]
    Blood samples will be collected at the indicated time points for pharmacokinetic analysis of EE.
  • Cmax for LNG [ Time Frame: Up to Day 24 ]
    Blood samples will be collected at the indicated time points for pharmacokinetic analysis of LNG.
  • Plasma concentration at the end of the dosing (Ctau) for EE [ Time Frame: Up to Day 24 ]
    Blood samples will be collected at the indicated time points for pharmacokinetic analysis of EE.
  • Ctau for LNG [ Time Frame: Up to Day 24 ]
    Blood samples will be collected at the indicated time points for pharmacokinetic analysis of LNG.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 18, 2020)
  • Period 1: Effect of GSK3640254 on PD of EE/LNG- Serum Progesterone Level [ Time Frame: At Day 1 and Day 10 ]
    Serum samples were collected for the analysis of progesterone concentration levels when GSK3640254 is co-administered with EE/LNG. PD concentration Population comprised of all participants who underwent plasma PD sampling and had evaluable PD assay results.
  • Period 2: Effect of GSK3640254 on PD of EE/LNG- Serum Progesterone Level [ Time Frame: At Days 11, 21 and 22 ]
    Serum samples were collected for the analysis progesterone concentration levels when GSK3640254 is co-administered with EE/LNG.
  • Period 1: Absolute Values of Effect of GSK3640254 on Luteinizing Hormone (LH) and Follicle-stimulating Hormone (FSH) [ Time Frame: At Day 1 and Day 10 ]
    Serum samples were collected for the analysis of effect of GSK3640254 on LH and FSH.
  • Period 2: Absolute Values of Effect of GSK3640254 on LH and FSH [ Time Frame: At Days 11, 21 and 22 ]
    Serum samples were collected for the analysis of effect of GSK3640254 on LH and FSH.
  • Period 2: AUC (0-tau) of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of AUC (0-tau) of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: Cmax and Ctau of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of Cmax and Ctau of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: Apparent Terminal Phase Half-life (t1/2) of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 hours; Day 22: 24 hours; Day 23: 48 hours; Day 24: 72 hours and Day 25: 96 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: Time of Maximum Observed Concentration (Tmax) of GSK3640254 [ Time Frame: Day 21: Pre-dose, 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8 and 12 and 24 hours post dose ]
    Blood samples were collected at indicated time points for the analysis of Tmax of GSK3640254. PK parameters were calculated by standard non-compartmental analysis.
  • Period 1: t1/2 of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of EE. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: t1/2 of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of EE. PK parameters were calculated by standard non-compartmental analysis.
  • Period 1: Tmax of EE [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of EE. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: Tmax of EE [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of EE. PK parameters were calculated by standard non-compartmental analysis.
  • Period 1: t1/2 of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of LNG. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: t1/2 of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours; Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of t1/2 of LNG. PK parameters were calculated by standard non-compartmental analysis.
  • Period 1: Tmax of LNG [ Time Frame: Day 10: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours and Day 11: 24 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of LNG. PK parameters were calculated by standard non-compartmental analysis.
  • Period 2: Tmax of LNG [ Time Frame: Day 21: Pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 7, 12 hours; Day 22: 24 hours; Day 23: 48 hours and Day 24: 72 hours ]
    Blood samples were collected at indicated time points for the analysis of Tmax of LNG. PK parameters were calculated by standard non-compartmental analysis.
  • Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAE) (Treatment Period) [ Time Frame: Up to Day 25 ]
    An adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before. Safety Population comprised of all participants who received at least one dose of study medication.
  • Number of Participants With Non-SAEs and SAE (Run-in Period) [ Time Frame: From Day -3 to Day -1 ]
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events that may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed before.
  • Period 1: Change From Baseline in Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and Blood Urea Nitrogen (BUN) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and BUN [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Creatine Kinase, Lactate Dehydrogenase, Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) and Gamma Glutamyl Transferase (GGT) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST and GGT [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Clinical Chemistry Parameters: Plasma Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Clinical Chemistry Parameters: Plasma Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Urine Concentration: Urine Potential of Hydrogen (pH) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Urine Concentration: Urine pH [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Electrocardiogram (ECG) Mean Heart Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in ECG Mean Heart Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11: 2, 4, 6 hours, Day 15: 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the average of the triplicate predose assessments on Day 11. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, Fridericia QT Correction Formula (QTcF) Interval, and Bazett QT Correction Formula (QTcB) Interval [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure PR interval, QRS duration, QT Interval, QTcF Interval and QTcB interval. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF and QTcB Interval [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11: 2, 4, 6 hours, Day 15: 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the average of the triplicate predose assessments on Day 11. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate pre-dose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Vital Signs: SBP and DBP [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as as the average of the triplicate pre-dose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate predose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Pulse Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate predose assessments. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Respiratory rate was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Respiratory Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Respiratory rate was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Change From Baseline in Temperature [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 2: Change From Baseline in Temperature [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment. Change from Baseline was defined as post-dose visit value minus Baseline value.
  • Period 1: Absolute Values of Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and BUN [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Clinical Chemistry Parameters: Glucose, Cholesterol, Triglycerides, Anion Gap, Calcium, Carbon Dioxide, Chloride, Phosphate, Potassium, Sodium and BUN [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Glucose, cholesterol, triglycerides, anion gap, calcium, carbon dioxide, chloride, phosphate, potassium, sodium and BUN. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Albumin, Globulin and Protein [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma albumin, globulin and protein. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Amylase and Lipase [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including plasma amylase and lipase. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Clinical Chemistry Parameters: Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST and GGT [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Creatine Kinase, Lactate Dehydrogenase, ALT, ALP, AST and GGT [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma creatine kinase, lactate dehydrogenase, ALT, ALP, AST and GGT. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Clinical Chemistry Parameters: Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Clinical Chemistry Parameters: Plasma Urate, Creatinine, Total Bilirubin and Direct Bilirubin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of clinical chemistry parameters including Plasma urate, creatinine, total bilirubin and direct bilirubin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Hematology Parameters: Basophils, Eosinophils, Leukocytes, Lymphocytes, Monocytes, Neutrophils and Platelets [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameters including Basophils, eosinophils, leukocytes, lymphocytes, monocytes, neutrophils and platelets. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Hematology Parameter: Erythrocytes Mean Corpuscular Volume [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes mean corpuscular volume. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Hematology Parameter: Erythrocytes [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter erythrocytes. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Hematology Parameter: Hematocrit [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hematocrit. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Hematology Parameter: Hemoglobin [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Blood samples were collected at indicated time points for the analysis of hematology parameter hemoglobin. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Urine Concentration: Urine Specific Gravity [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of specific gravity. Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Urine Concentration: Urine Urobilinogen [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of urine urobilinogen. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Urine Concentration: Urine pH [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Urine Concentration: Urine pH [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    Urine samples were collected at indicated time points for the assessment of Urinary pH. Urine pH is an acid-base measurement. pH is measured on a numeric scale ranging from 0 to 14; values on the scale refer to the degree of alkalinity or acidity. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. Normal urine has a slightly acid pH (5.0 - 6.0). Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Number of Participants With Abnormal Urinalysis Parameters Using Dipstick Method. [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    The dipstick test gives results in a semi-quantitative manner and results for urinalysis parameters (ketones, glucose, bilirubin, occult blood, nitrite and blood protein) can be read as positive, trace, 1+, 2+, 3+ and 4+ indicating proportional concentrations in the urine sample. Only participants with abnormal findings for urinalysis at any visit has been presented.
  • Period 2: Number of Participants With Abnormal Urinalysis Parameters Using Dipstick Method. [ Time Frame: Baseline (Day 10) and at Days 21 and 24 ]
    The dipstick test gives results in a semi-quantitative manner and results for urinalysis parameters (ketones, glucose, bilirubin, occult blood, nitrite and blood protein) can be read as positive, trace, 1+, 2+, 3+ and 4+ indicating proportional concentrations in the urine sample. Only participants with abnormal findings for urinalysis at any visit has been presented.
  • Period 1: Absolute Values of ECG Mean Heart Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of ECG Mean Heart Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11: 2, 4, 6 hours, Day 15: 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure heart rate. Baseline is defined as the average of the triplicate predose assessments on Day 11.
  • Period 1: Absolute Values of ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF Interval, and QTcB Interval [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure PR interval, QRS duration, QT Interval, QTcF Interval and QTcB interval. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of ECG Parameters: PR Interval, QRS Duration, QT Interval, QTcF and QTcB Interval [ Time Frame: Baseline (Day 11, Pre-dose) and at Day 11- 2, 4, 6 hours, Day 15- 2, 4, 6 hours, Day 21 and 24 ]
    Twelve-lead ECGs were performed with the participant in a supine or semi-supine position after a rest of at least 10 minutes using an automated ECG machine to measure PR Interval, QRS Duration, QT Interval, QTcF and QTcB Interval. Baseline is defined as the average of the triplicate predose assessments on Day 11.
  • Period 1: Absolute Values of Vital Signs: SBP and DBP [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the average of the triplicate predose assessments on Day 11.
  • Period 2: Absolute Values of Vital Signs: SBP and DBP [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    SBP and DBP were assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Pulse Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Pulse Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Pulse rate was assessed in the semi-recumbent position with a completely automated device at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Respiratory Rate [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Respiratory rate was assessed indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Respiratory Rate [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Respiratory rate was assessed indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 1: Absolute Values of Temperature [ Time Frame: Baseline (Day 1, Pre-dose) and at Day 10 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
  • Period 2: Absolute Values of Temperature [ Time Frame: Baseline (Day 11, Pre-dose) and at Days 15, 21 and 24 ]
    Temperature was assessed at indicated time-points. Baseline is defined as the latest pre-dose assessment with a non-missing value, including those from unscheduled visits, within each treatment.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 10, 2019)
  • Serum progesterone levels [ Time Frame: Up to Day 22 ]
    Venous blood samples will be collected for measurement of serum progesterone levels.
  • Serum follicle-stimulating hormone (FSH) levels [ Time Frame: Up to Day 22 ]
    Venous blood samples will be collected for measurement of serum FSH levels.
  • Serum luteinizing hormone (LH) levels [ Time Frame: Up to Day 22 ]
    Venous blood samples will be collected for measurement of serum LH lev

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