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出境医 / 临床实验 / A Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics and Safety and Tolerability of a Single Oral Dose of Risdiplam Compared to Matched Healthy Participants With Normal Hepatic Function

A Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics and Safety and Tolerability of a Single Oral Dose of Risdiplam Compared to Matched Healthy Participants With Normal Hepatic Function

Study Description
Brief Summary:
This is a multi-center, open-label, non-randomized, parallel-group, 2-part study to evaluate the effect of hepatic impairment on the PK and safety and tolerability of a single oral dose of risdiplam compared to matched healthy participants with normal hepatic function.

Condition or disease Intervention/treatment Phase
Muscular Atrophy, Spinal Drug: Risdiplam Phase 1

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label, Single-Dose, Parallel-Group, Two-Part Study to Evaluate the Pharmacokinetics and Safety of Risdiplam in Subjects With Mild or Moderate Hepatic Impairment Compared to Subjects With Normal Hepatic Function
Actual Study Start Date : May 16, 2019
Actual Primary Completion Date : January 2, 2020
Actual Study Completion Date : January 2, 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: Part 1
Participants with mild hepatic impairment and demographically matched healthy participants with normal hepatic function will be enrolled. Participants will receive a single oral dose of 5 mg risdiplam.
 Drug: Risdiplam
5 milligram (mg) oral dose administered in fasted state
Experimental: Part 2
Participants with moderate hepatic impairment and demographically matched healthy participants with normal hepatic function will be enrolled. Participants will receive a single oral dose of 5 mg risdiplam.
 Drug: Risdiplam
5 milligram (mg) oral dose administered in fasted state
Outcome Measures
Primary Outcome Measures :
  1. Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  2. Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  3. Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  4. Part 2: AUCinf of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  5. Part 2: AUClast of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  6. Part 2: Cmax of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]

Secondary Outcome Measures :
  1. Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  2. Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  3. Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  4. Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  5. Part 1: Apparent Total Clearance (CL/F) of Risdiplam [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  6. Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  7. Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  8. Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  9. Part 2: Tmax of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  10. Part 2: t1/2 of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  11. Part 2: %AUCextrap of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  12. Part 2: λz of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  13. Part 2: CL/F of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  14. Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  15. Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  16. Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  17. Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 31 Days ]
    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

All Participants:

  • BMI between 18.0 and 36.0 kilograms per square metre (kg/m2), inclusive, and body weight > / = 50 kg
  • Females must not be pregnant or lactating and must be of non-childbearing potential
  • Male participants (whether surgically sterilized or not) with female partners of childbearing potential must use methods of contraception from Screening until 4 months after their dose of the study drug as detailed in the protocol
  • Male participants must not donate sperm from Check-in (Day -1) until 4 months after their dose of the study drug

Participants with Normal Hepatic Function Only:

  • Matched to participants with mild or moderate hepatic function in sex, age, BMI, and smoking status
  • In good health, as determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations

Participants with Hepatic Impairment Only:

  • Documented chronic stable liver disease
  • Currently on a stable medication regimen, defined as not starting new drug(s) or changing drug dose(s) within 3 months of administration of study drug
  • Anemia secondary to hepatic disease will be acceptable, if hemoglobin >/= 9 gram per decilitre (g/dL). Participants must have a platelet count </= 35 000 platelets

Exclusion Criteria:

All Participants

  • Significant history or clinical manifestation of any metabolic, allergic, dermatological, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder
  • History of significant hypersensitivity, intolerance, or allergy to any drug compound, constituents or excipients of the study drug, food, or other substance
  • History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered
  • Ventricular dysfunction or history of risk factors for Torsades de Pointes
  • Evidence of hepatorenal syndrome and estimated creatinine clearance range < 60 millilitre per minute (mL/min) or abnormal sodium and potassium levels
  • Clinically significant physical examination abnormality
  • History of diabetes mellitus
  • Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's Wort
  • Positive human immunodeficiency virus (HIV) test
  • Participation in a clinical study involving administration of an investigational drug prior to dosing
  • Smoke more than 10 cigarettes or use the equivalent tobacco- or nicotine-containing products per day
  • Receipt of blood products within 2 months prior to study
  • Donation of blood, plasma, or platelets prior to Screening
  • Poor peripheral venous access
  • Have previously completed or withdrawn from this study or any other study investigating risdiplam, and have previously received the investigational product

Participants with Normal Hepatic Function Only:

  • Confirmed supine blood pressure > 150 millimetre of mercury (mmHg) or < 90 mmHg
  • Positive test for hepatitis B or C virus
  • Clinically significant abnormal laboratory values
  • Significant history or clinical manifestation of hepatic disorder
  • History or presence of liver disease or liver injury

  • Use or intend to use any prescription medications/products within 14 days prior to dosing

    -. Use or intend to use slow-release medications/products considered to still be active within 14 days prior to dosing

  • Use or intend to use any non-prescription medications/products within 7 days prior to dosing

Participants with Hepatic Impairment Only:

  • Confirmed supine blood pressure > 159 mmHg or < 90 mmHg
  • Values outside the normal range for liver function tests that are not consistent with their hepatic condition
  • Use of a new medication, or a change in dose, for the treatment, or worsening of, hepatic encephalopathy
  • Use of prescription drugs within 14 days of study drug administration
  • Recent history of, or the treatment of, esophageal bleeding
  • Presence of a portosystemic shunt
  • Recent history of paracentesis
  • Current functioning organ transplant or are waiting for an organ transplant
  • Evidence of severe ascites
  • History or current symptoms of hepatic encephalopathy Grade 2 or above
Contacts and Locations

Locations
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United States, Florida
Clinical Pharmacology of Miami, Inc.
Miami, Florida, United States, 33014
Orlando Clinical Research Center
Orlando, Florida, United States, 32809
United States, Texas
American Research Corporation Inc.
San Antonio, Texas, United States, 78215
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical Trials Hoffmann-La Roche
Tracking Information
First Submitted Date  ICMJE April 17, 2019
First Posted Date  ICMJE April 19, 2019
Results First Submitted Date  ICMJE December 16, 2020
Results First Posted Date  ICMJE February 21, 2021
Last Update Posted Date February 21, 2021
Actual Study Start Date  ICMJE May 16, 2019
Actual Primary Completion Date January 2, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 2, 2021)
  • Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) of Risdiplam and Its Metabolite (M1) [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 1: Maximum Observed Plasma Concentration (Cmax) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: AUCinf of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: AUClast of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: Cmax of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
Original Primary Outcome Measures  ICMJE
 (submitted: April 17, 2019)
  • Area Under the Plasma Concentration-Time Curve from Time 0 to Infinity (AUCinf) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
  • Area Under the Plasma Concentration-Time Curve from time 0 to the Last Measurable Concentration (AUClast) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
    This measure will be used for pharmacokinetics (PK) comparison if AUCinf cannot be estimated with sufficient accuracy
  • Maximum Observed Plasma Concentration (Cmax) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 2, 2021)
  • Part 1: Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 1: Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 1: Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 1: Terminal Elimination Rate Constant (λz=Lambda-Z) of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 1: Apparent Total Clearance (CL/F) of Risdiplam [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 1: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: Tmax of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: t1/2 of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: %AUCextrap of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: λz of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: CL/F of Risdiplam and M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUCinf of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for Cmax of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 2: Molecular Weight-Adjusted Metabolite-to-Parent Ratio for AUClast of Risdiplam M1 [ Time Frame: Predose, 1, 2, 4, 6, 8, 10, 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, 216, 240, 264, 312, 336, 360, 408, 456, 504, and 552 hours Postdose ]
  • Part 1 and Part 2: Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 31 Days ]
    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 17, 2019)
  • Time of the Maximum Observed Plasma Concentration (Tmax) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
  • Apparent Plasma Terminal Elimination Half-Life (t1/2) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
  • Percentage of Area Under the Plasma Concentration-Time Curve Due to Extrapolation (%AUCextrap) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
  • Terminal Elimination Rate Constant (λz) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
  • Adjusted Coefficient for Determination of Exponential Fit (R2-adjusted) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
  • Apparent Total Clearance (CL/F) of Risdiplam [ Time Frame: Day 1 to Day 24 ]
  • Fraction of Drug Unbound [ Time Frame: Day 1 to Day 24 ]
    Risdiplam and Metabolite (M1), as appropriate
  • Molecular Weight-Adjusted Metabolite-To-Parent Ratio for AUCinf, Cmax, and AUClast [ Time Frame: Day 1 to Day 24 ]
  • Percentage of Participants with Adverse Event (AE) or Serious Adverse Event (SAE) [ Time Frame: From Screening to Day 28 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study to Investigate the Effect of Hepatic Impairment on the Pharmacokinetics and Safety and Tolerability of a Single Oral Dose of Risdiplam Compared to Matched Healthy Participants With Normal Hepatic Function
Official Title  ICMJE An Open-Label, Single-Dose, Parallel-Group, Two-Part Study to Evaluate the Pharmacokinetics and Safety of Risdiplam in Subjects With Mild or Moderate Hepatic Impairment Compared to Subjects With Normal Hepatic Function
Brief Summary This is a multi-center, open-label, non-randomized, parallel-group, 2-part study to evaluate the effect of hepatic impairment on the PK and safety and tolerability of a single oral dose of risdiplam compared to matched healthy participants with normal hepatic function.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Muscular Atrophy, Spinal
Intervention  ICMJE Drug: Risdiplam
5 milligram (mg) oral dose administered in fasted state
Study Arms  ICMJE
  • Experimental: Part 1
    Participants with mild hepatic impairment and demographically matched healthy participants with normal hepatic function will be enrolled. Participants will receive a single oral dose of 5 mg risdiplam.
    Intervention: Drug: Risdiplam
  • Experimental: Part 2
    Participants with moderate hepatic impairment and demographically matched healthy participants with normal hepatic function will be enrolled. Participants will receive a single oral dose of 5 mg risdiplam.
    Intervention: Drug: Risdiplam
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: January 8, 2020) 		26
Original Estimated Enrollment  ICMJE
 (submitted: April 17, 2019) 		32
Actual Study Completion Date  ICMJE January 2, 2020
Actual Primary Completion Date January 2, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

All Participants:

  • BMI between 18.0 and 36.0 kilograms per square metre (kg/m2), inclusive, and body weight > / = 50 kg
  • Females must not be pregnant or lactating and must be of non-childbearing potential
  • Male participants (whether surgically sterilized or not) with female partners of childbearing potential must use methods of contraception from Screening until 4 months after their dose of the study drug as detailed in the protocol
  • Male participants must not donate sperm from Check-in (Day -1) until 4 months after their dose of the study drug

Participants with Normal Hepatic Function Only:

  • Matched to participants with mild or moderate hepatic function in sex, age, BMI, and smoking status
  • In good health, as determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory evaluations

Participants with Hepatic Impairment Only:

  • Documented chronic stable liver disease
  • Currently on a stable medication regimen, defined as not starting new drug(s) or changing drug dose(s) within 3 months of administration of study drug
  • Anemia secondary to hepatic disease will be acceptable, if hemoglobin >/= 9 gram per decilitre (g/dL). Participants must have a platelet count </= 35 000 platelets

Exclusion Criteria:

All Participants

  • Significant history or clinical manifestation of any metabolic, allergic, dermatological, renal, hematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder
  • History of significant hypersensitivity, intolerance, or allergy to any drug compound, constituents or excipients of the study drug, food, or other substance
  • History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered
  • Ventricular dysfunction or history of risk factors for Torsades de Pointes
  • Evidence of hepatorenal syndrome and estimated creatinine clearance range < 60 millilitre per minute (mL/min) or abnormal sodium and potassium levels
  • Clinically significant physical examination abnormality
  • History of diabetes mellitus
  • Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's Wort
  • Positive human immunodeficiency virus (HIV) test
  • Participation in a clinical study involving administration of an investigational drug prior to dosing
  • Smoke more than 10 cigarettes or use the equivalent tobacco- or nicotine-containing products per day
  • Receipt of blood products within 2 months prior to study
  • Donation of blood, plasma, or platelets prior to Screening
  • Poor peripheral venous access
  • Have previously completed or withdrawn from this study or any other study investigating risdiplam, and have previously received the investigational product

Participants with Normal Hepatic Function Only:

  • Confirmed supine blood pressure > 150 millimetre of mercury (mmHg) or < 90 mmHg
  • Positive test for hepatitis B or C virus
  • Clinically significant abnormal laboratory values
  • Significant history or clinical manifestation of hepatic disorder
  • History or presence of liver disease or liver injury

  • Use or intend to use any prescription medications/products within 14 days prior to dosing

    -. Use or intend to use slow-release medications/products considered to still be active within 14 days prior to dosing

  • Use or intend to use any non-prescription medications/products within 7 days prior to dosing

Participants with Hepatic Impairment Only:

  • Confirmed supine blood pressure > 159 mmHg or < 90 mmHg
  • Values outside the normal range for liver function tests that are not consistent with their hepatic condition
  • Use of a new medication, or a change in dose, for the treatment, or worsening of, hepatic encephalopathy
  • Use of prescription drugs within 14 days of study drug administration
  • Recent history of, or the treatment of, esophageal bleeding
  • Presence of a portosystemic shunt
  • Recent history of paracentesis
  • Current functioning organ transplant or are waiting for an organ transplant
  • Evidence of severe ascites
  • History or current symptoms of hepatic encephalopathy Grade 2 or above
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03920865
Other Study ID Numbers  ICMJE BP40995
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Qualified researchers may request access to individual patient level data through the clinical study data request platform (www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available here (https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).
Responsible Party Hoffmann-La Roche
Study Sponsor  ICMJE Hoffmann-La Roche
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Trials Hoffmann-La Roche
PRS Account Hoffmann-La Roche
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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