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出境医 / 临床实验 / Evaluate the Effect of Lifenol in Improving Bone Status in Postmenopausal Osteopenic Women

Evaluate the Effect of Lifenol in Improving Bone Status in Postmenopausal Osteopenic Women

Study Description
Brief Summary:
A Randomised, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Effect of Lifenol® in Improving Bone Status in Postmenopausal Osteopenic Women. 100 postmenopausal women will be enrolled to investigate the effect of a 12 month supplementation with Lifenol® on bone density DXA parameters and plasma bone biomarkers.

Condition or disease Intervention/treatment Phase
Osteopenia, Generalized Dietary Supplement: Lifenol® Dietary Supplement: Placebo Not Applicable

Detailed Description:

Osteoporosis is a skeletal disorder characterized by reduced bone mass and deterioration in bone architecture leading to an increased bone fragility and fracture risk. Postmenopausal women are a particularly at-risk population as the maintenance of bone homeostasis is influenced by estrogens. Recently, phytoestrogens have drawn attention as an interesting natural way to prevent oestrogen-deficient osteoporosis. Hops contain one of the most potent phytoestrogen known to date: 8-prenylnaringenin (8-PN). Lifenol® is a polyphenolic powdered extract obtained by a patented process from the female hop flowers (Humulus lupulus L.), standardized in 8-PN content.

Therefore, the present clinical trial aims to determine whether long-term consumption of Lifenol® can reduce bone mineral density loss in postmenopausal women with osteopenia taking traditional recommended calcium and vitamin D supplementation (1000 mg of calcium and 800 IU of vitamin D per day).

100 postmenopausal women (>1 year post-menopause) will be enrolled to consume during 12 months either Lifenol® (dose of 100µg of 8-PN per day) or a placebo. Effect of investigational product will be measured notably on bone density DXA parameters and plasma bone biomarkers.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Randomised, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Effect of Lifenol in Improving Bone Status in Postmenopausal Osteopenic Women
Actual Study Start Date : August 1, 2019
Actual Primary Completion Date : December 11, 2020
Actual Study Completion Date : December 11, 2020
Arms and Interventions
Arm Intervention/treatment
Active Comparator: Lifenol
50 participants who meet the eligibility criteria will be randomised under active arm and will receive Lifenol product during 12 months
Dietary Supplement: Lifenol®

Lifenol®, powdered extract obtained from female hops flowers (Humulus lupulus L.) standardized in 8-PN content (100 µg /day) + maltodextrin = 500 mg/capsule

+ 1000 mg of calcium and 800 IU of vitamin D per day


Placebo Comparator: Placebo
50 participants who meet the eligibility criteria will be randomised under Placebo arm and will receive placebo product during 12 months
Dietary Supplement: Placebo

Maltodextrin = 500 mg/capsule

+ 1000 mg of calcium and 800 IU of vitamin D per day


Outcome Measures
Primary Outcome Measures :
  1. Bone mineral density at the L2-L4 lumbar spine region [ Time Frame: baseline and 12 months ]
    Change of bone mineral density at L2-L4 lumbar spine region over 12 months.


Secondary Outcome Measures :
  1. Bone mineral density at the femoral neck region [ Time Frame: baseline, 6 and 12 months ]
    DXA scan will provide this parameter

  2. Bone mineral content at the L2-4 lumbar spine and femoral neck region [ Time Frame: baseline, 6 and 12 months ]
    DXA scan will provide this parameter

  3. T-score [ Time Frame: baseline, 6 and 12 months ]
    DXA scan will provide this parameter

  4. Fracture risk assessment tool (FRAX) score [ Time Frame: baseline, 6 and 12 months ]
    FRAX score will be calculated an online tool (university of sheffield frax tool).

  5. Plasma bone biomarkers [ Time Frame: baseline, 6 and 12 months ]
    Change in plasma bone biomarkers will be measured.

  6. Plasma prenylflavonoids [ Time Frame: baseline, 6 and 12 months ]
    Change in plasma prenylflavonoids will be measured.

  7. Glucose homeostasis and lipid profile [ Time Frame: baseline, 6 and 12 months ]
    Change in plasma glucose, insulin and lipids will be measured.

  8. Quality of life evaluation [ Time Frame: baseline, 3, 6, 9 and 12 months ]
    36-item short form (SF-36) will be performed to assess by quality of life.

  9. Gastrointestinal tolerance evaluation [ Time Frame: baseline, 3, 6, 9 and 12 months ]
    Gastrointestinal tolerance of the product will be assessed by the Gastrointestinal Symptom Rating Scale (GSRS).


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   50 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Be able to give written informed consent;
  2. Be 50 - 85 years of age;
  3. Be a free-living postmenopausal (> 1 year post menopause) woman;
  4. Have a Body Mass Index (BMI) 18 - 32.0 kg/m²;
  5. Present with a stable weight (+/- 3 kg) for at least the last three (3) months;
  6. Be a non-smoker
  7. Maintain existing food and physical activity patterns throughout the study period;
  8. Present with osteopenia defined as a dual energy X-ray absorptiometry (DXA) T score comprised between -1 and -2.5;
  9. Be willing to consume the investigational product daily for the duration of the study.

Be able to give written

Exclusion Criteria:

  1. Are hypersensitive to any of the components of the investigational product;
  2. Is currently involved in any other clinical trial or having participated in a trial within the preceding 60 days;
  3. Has a diagnosis of osteoporosis (defined as a T score strictly inferior to -2.5);
  4. Is currently a smoker;
  5. Trying to lose weight for the last three (3) months (following a diet or exercise regimen designed for weight loss);
  6. Recent (within 4 weeks) gastroenteritis or food borne illness;
  7. Having taken antibiotics or laxatives during the preceding 2 months or anticipated consumption;
  8. Currently taking (and during the past 3 months) any drug for osteoporosis (bisphosphonates, parathyroid hormone, strontium ranelate or denosumab);
  9. Currently taking (and during the past 3 months) treatment with oestrogen or hormone therapy;
  10. Currently taking (and during the past 3 months) treatment with oestrogen agonist or antagonist products (raloxifene or tamoxifene);
  11. Currently taking any supplementation with isoflavones or foods fortified with isoflavones;
  12. Currently taking (and during the past 4 weeks) any vitamin K supplementation.
  13. Exhibiting excess alcohol consumption, defined as greater than 11 standard drinks per week for women or drug dependence,
  14. Has a significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would preclude supplement ingestion and/or assessment of safety and the study objectives;
  15. Has a known organic disease, including an inflammatory bowel disease, a benign or malign tumour of intestine or colon and significant systemic disease;
  16. Has a history of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, or carcinoma in situ with no significant progression over the past 2 years;
  17. Has uncontrolled hypertension (systolic or diastolic blood pressure superior to 160 and 110 respectively). Subject on hypertension medication, must be on stable medication for 3 months;
  18. Has uncontrolled hypothyroidism or hyperthyroidism; subject must be stable on medication for 3 months
  19. Current illnesses which could interfere with the study (e.g. prolonged severe diarrhoea, regurgitation/severe, difficulty swallowing).
  20. Individuals who, in the opinion of the investigator, are considered to be poor attendees or unlikely for any reason to be able to comply with the trial.
Contacts and Locations

Locations
Layout table for location information
Ireland
Atlantia Food Clinical Trials
Cork, Ireland, T23 R50R
Sponsors and Collaborators
Naturex SA
Atlantia Food Clinical Trials
Tracking Information
First Submitted Date  ICMJE June 10, 2019
First Posted Date  ICMJE July 1, 2019
Last Update Posted Date January 6, 2021
Actual Study Start Date  ICMJE August 1, 2019
Actual Primary Completion Date December 11, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 8, 2019)
Bone mineral density at the L2-L4 lumbar spine region [ Time Frame: baseline and 12 months ]
Change of bone mineral density at L2-L4 lumbar spine region over 12 months.
Original Primary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
To evaluate in postmenopausal women with osteopenia, the effect of 12 month Lifenol® treatment on bone mineral density (BMD) at the L2-L4 lumbar spine region. [ Time Frame: 12 months ]
Participants will have a bone density DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide BMD at L2-L4 lumbar spine region.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 8, 2019)
  • Bone mineral density at the femoral neck region [ Time Frame: baseline, 6 and 12 months ]
    DXA scan will provide this parameter
  • Bone mineral content at the L2-4 lumbar spine and femoral neck region [ Time Frame: baseline, 6 and 12 months ]
    DXA scan will provide this parameter
  • T-score [ Time Frame: baseline, 6 and 12 months ]
    DXA scan will provide this parameter
  • Fracture risk assessment tool (FRAX) score [ Time Frame: baseline, 6 and 12 months ]
    FRAX score will be calculated an online tool (university of sheffield frax tool).
  • Plasma bone biomarkers [ Time Frame: baseline, 6 and 12 months ]
    Change in plasma bone biomarkers will be measured.
  • Plasma prenylflavonoids [ Time Frame: baseline, 6 and 12 months ]
    Change in plasma prenylflavonoids will be measured.
  • Glucose homeostasis and lipid profile [ Time Frame: baseline, 6 and 12 months ]
    Change in plasma glucose, insulin and lipids will be measured.
  • Quality of life evaluation [ Time Frame: baseline, 3, 6, 9 and 12 months ]
    36-item short form (SF-36) will be performed to assess by quality of life.
  • Gastrointestinal tolerance evaluation [ Time Frame: baseline, 3, 6, 9 and 12 months ]
    Gastrointestinal tolerance of the product will be assessed by the Gastrointestinal Symptom Rating Scale (GSRS).
Original Secondary Outcome Measures  ICMJE
 (submitted: June 28, 2019)
  • Bone mineral content (BMC) at the l2-4 lumbar spine region [ Time Frame: 12 months ]
    Participants will have a bone density DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide this parameter.
  • T-score at the L2-L4 lumbar spine region [ Time Frame: 12 months ]
    Participants will have a bone density DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide this parameter.
  • Bone mineral density at the femoral neck [ Time Frame: 12 months ]
    Participants will have a bone density DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide this parameter.
  • Bone mineral content at the femoral neck [ Time Frame: 12 months ]
    Participants will have a bone density DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide this parameter.
  • Fracture risk assessment tool (FRAX) score [ Time Frame: 12 months ]
    FRAX score will be calculated an online tool (university of sheffield frax tool). The current National Osteoporosis Foundation Guide recommends treating patients with FRAX 10-year risk scores of > or = 3% for hip fracture or > or = 20% for major osteoporotic fracture, to reduce their fracture risk.
  • Lean Mass [ Time Frame: 12 months ]
    Participants will have a body composition DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide lean mass value.
  • Fat Mass [ Time Frame: 12 months ]
    Participants will have a body composition DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide fat mass value.
  • Percentage (%) Fat [ Time Frame: 12 months ]
    Participants will have a body composition DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide % body fat.
  • Visceral Fat [ Time Frame: 12 months ]
    Participants will have a body composition DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide visceral fat.
  • Total Bone Mineral Density (BMD) [ Time Frame: 12 months ]
    Participants will have a body composition DXA scan 7 days before randomisation and 7 days before their last visit 12 months later. These DXA results will provide bone mineral density.
  • Body Mass Index (BMI) [ Time Frame: 12 months. ]
    Participants weight in kilograms and height in meters is collected every 3 months to report BMI in kg/m^2. Eligible BMI scores are > or = 18 and < or = 32.0 kg/m^2.
  • Waist to hip ratio (WHR) [ Time Frame: 12 months ]
    Participants waist circumference in centimetres and hip circumference in centimetres is collected every 3 months to report WHR. WHR is recommended to be 0.8 or less for females and 1.0 or less for males.
  • Collagen type 1 cross-linked C-telopeptide (CTx) [ Time Frame: 12 months ]
    Plasma samples will be completed every 6 months, the bone marker collagen type 1 cross-linked C-telopeptide (CTx) pg/mL will be completed on these samples.
  • Osteocalcin [ Time Frame: 12 months ]
    Plasma samples will be completed every 6 months, the bone marker osteocalcin ng/mL will be completed on these samples.
  • Procollagen type I N-terminal propeptide (PINP) [ Time Frame: 12 months ]
    Plasma samples will be completed every 6 months, the bone marker procollagen type I N-terminal propeptide (PINP) ng/mL will be completed on these samples.
  • Undercarboxylated osteocalcin [ Time Frame: 12 months ]
    Plasma samples will be completed every 6 months, the bone marker undercarboxylated osteocalcin ng/mL will be completed on these samples.
  • Bone-specific alkaline phosphatase [ Time Frame: 12 months ]
    Plasma samples will be completed every 6 months, the bone marker bone-specific alkaline phosphatase ug/L will be completed on these samples.
  • Sclerostin [ Time Frame: 12 months ]
    Plasma samples will be completed every 6 months, the bone marker sclerostin pmol/L will be completed on these samples.
  • Tartrate-resistant acid phosphatase isoform 5b (TRAP5b) [ Time Frame: 12 months ]
    Plasma samples will be completed every 6 months, the bone marker tartrate-resistant acid phosphatase isoform 5b (TRAP5b) units/L will be completed on these samples.
  • Bone-specific alkaline phosphatase/TRAP5b ratio [ Time Frame: 12 months ]
    Plasma samples will be completed every 6 months, the bone marker bone-specific alkaline phosphatase/TRAP5b ratio ug/L will be completed on these samples.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: June 28, 2019)
  • Vitamin D status [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. Vitamin (D 25 (OH)D nmol/L) analysis will be completed on these samples.
  • Oestrogen level [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. Oestrogen (pg/mL) analysis will be completed on these samples.
  • Plasma prenylflavonoids [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. Plasma prenylflavonoid (g/dL) analysis will be completed on these samples.
  • 8-PN producer status [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. 8-PN producer (umol/L) analysis will be completed on these samples.
  • Fasting blood glucose [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. Fasting blood glucose (mmol/L) analysis will be completed on these samples.
  • Fasting insulinaemia [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. Fasting insulinaemia (U-100)analysis will be completed on these samples.
  • Hba1c [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. Hba1c (mmol/mol) analysis will be completed on these samples.
  • HOMA IR [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. HOMA IR (nmol/L) analysis will be completed on these samples.
  • Insulin sensitivity index [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. Insulin sensitivity (mmol/L) analysis will be completed on these samples.
  • Quantitative insulin sensitivity check index [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months. Quantitative insulin sensitivity check index (mmol/L) analysis will be completed on these samples.
  • Total cholesterol [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months, total cholesterol mg/dL will be completed on these samples.
  • HDL cholesterol [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months, HDL cholesterol mmol/L will be completed on these samples
  • LDL cholesterol [ Time Frame: 12 months ]
    Blood samples will be collected every 6 months, LDL cholesterol mmol/L will be completed on these samples.
  • Triglycerides [ Time Frame: 12 months ]
    Blood samples will be completed every 6 months, Triglycerides mmol/L will be completed on these samples.
 
Descriptive Information
Brief Title  ICMJE Evaluate the Effect of Lifenol in Improving Bone Status in Postmenopausal Osteopenic Women
Official Title  ICMJE A Randomised, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Effect of Lifenol in Improving Bone Status in Postmenopausal Osteopenic Women
Brief Summary A Randomised, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Effect of Lifenol® in Improving Bone Status in Postmenopausal Osteopenic Women. 100 postmenopausal women will be enrolled to investigate the effect of a 12 month supplementation with Lifenol® on bone density DXA parameters and plasma bone biomarkers.
Detailed Description

Osteoporosis is a skeletal disorder characterized by reduced bone mass and deterioration in bone architecture leading to an increased bone fragility and fracture risk. Postmenopausal women are a particularly at-risk population as the maintenance of bone homeostasis is influenced by estrogens. Recently, phytoestrogens have drawn attention as an interesting natural way to prevent oestrogen-deficient osteoporosis. Hops contain one of the most potent phytoestrogen known to date: 8-prenylnaringenin (8-PN). Lifenol® is a polyphenolic powdered extract obtained by a patented process from the female hop flowers (Humulus lupulus L.), standardized in 8-PN content.

Therefore, the present clinical trial aims to determine whether long-term consumption of Lifenol® can reduce bone mineral density loss in postmenopausal women with osteopenia taking traditional recommended calcium and vitamin D supplementation (1000 mg of calcium and 800 IU of vitamin D per day).

100 postmenopausal women (>1 year post-menopause) will be enrolled to consume during 12 months either Lifenol® (dose of 100µg of 8-PN per day) or a placebo. Effect of investigational product will be measured notably on bone density DXA parameters and plasma bone biomarkers.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Osteopenia, Generalized
Intervention  ICMJE
  • Dietary Supplement: Lifenol®

    Lifenol®, powdered extract obtained from female hops flowers (Humulus lupulus L.) standardized in 8-PN content (100 µg /day) + maltodextrin = 500 mg/capsule

    + 1000 mg of calcium and 800 IU of vitamin D per day

  • Dietary Supplement: Placebo

    Maltodextrin = 500 mg/capsule

    + 1000 mg of calcium and 800 IU of vitamin D per day

Study Arms  ICMJE
  • Active Comparator: Lifenol
    50 participants who meet the eligibility criteria will be randomised under active arm and will receive Lifenol product during 12 months
    Intervention: Dietary Supplement: Lifenol®
  • Placebo Comparator: Placebo
    50 participants who meet the eligibility criteria will be randomised under Placebo arm and will receive placebo product during 12 months
    Intervention: Dietary Supplement: Placebo
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: June 28, 2019)
100
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 11, 2020
Actual Primary Completion Date December 11, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Be able to give written informed consent;
  2. Be 50 - 85 years of age;
  3. Be a free-living postmenopausal (> 1 year post menopause) woman;
  4. Have a Body Mass Index (BMI) 18 - 32.0 kg/m²;
  5. Present with a stable weight (+/- 3 kg) for at least the last three (3) months;
  6. Be a non-smoker
  7. Maintain existing food and physical activity patterns throughout the study period;
  8. Present with osteopenia defined as a dual energy X-ray absorptiometry (DXA) T score comprised between -1 and -2.5;
  9. Be willing to consume the investigational product daily for the duration of the study.

Be able to give written

Exclusion Criteria:

  1. Are hypersensitive to any of the components of the investigational product;
  2. Is currently involved in any other clinical trial or having participated in a trial within the preceding 60 days;
  3. Has a diagnosis of osteoporosis (defined as a T score strictly inferior to -2.5);
  4. Is currently a smoker;
  5. Trying to lose weight for the last three (3) months (following a diet or exercise regimen designed for weight loss);
  6. Recent (within 4 weeks) gastroenteritis or food borne illness;
  7. Having taken antibiotics or laxatives during the preceding 2 months or anticipated consumption;
  8. Currently taking (and during the past 3 months) any drug for osteoporosis (bisphosphonates, parathyroid hormone, strontium ranelate or denosumab);
  9. Currently taking (and during the past 3 months) treatment with oestrogen or hormone therapy;
  10. Currently taking (and during the past 3 months) treatment with oestrogen agonist or antagonist products (raloxifene or tamoxifene);
  11. Currently taking any supplementation with isoflavones or foods fortified with isoflavones;
  12. Currently taking (and during the past 4 weeks) any vitamin K supplementation.
  13. Exhibiting excess alcohol consumption, defined as greater than 11 standard drinks per week for women or drug dependence,
  14. Has a significant cardiovascular, pulmonary, renal, liver, infectious disease, immune disorder, or metabolic/endocrine disorders or other disease that would preclude supplement ingestion and/or assessment of safety and the study objectives;
  15. Has a known organic disease, including an inflammatory bowel disease, a benign or malign tumour of intestine or colon and significant systemic disease;
  16. Has a history of cancer within the last 5 years, except basal cell carcinoma, non-squamous skin carcinoma, or carcinoma in situ with no significant progression over the past 2 years;
  17. Has uncontrolled hypertension (systolic or diastolic blood pressure superior to 160 and 110 respectively). Subject on hypertension medication, must be on stable medication for 3 months;
  18. Has uncontrolled hypothyroidism or hyperthyroidism; subject must be stable on medication for 3 months
  19. Current illnesses which could interfere with the study (e.g. prolonged severe diarrhoea, regurgitation/severe, difficulty swallowing).
  20. Individuals who, in the opinion of the investigator, are considered to be poor attendees or unlikely for any reason to be able to comply with the trial.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 50 Years to 85 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 Ireland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04004013
Other Study ID Numbers  ICMJE AFCRO-100
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Plan Description: To revisit this after investigation period
Responsible Party Naturex SA
Study Sponsor  ICMJE Naturex SA
Collaborators  ICMJE Atlantia Food Clinical Trials
Investigators  ICMJE Not Provided
PRS Account Naturex SA
Verification Date January 2021

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