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Assessment of the Safety and Effect of SAR425899 Versus Placebo for the Treatment of Non-alcoholic Fatty Liver Disease (Restore)

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ClinicalTrials.gov Identifier: NCT03437720
Recruitment Status : Withdrawn (Sponsor decision to cancel TRIAL, not related to safety concern.)
First Posted : February 19, 2018
Last Update Posted : April 8, 2019
Sponsor:
Information provided by (Responsible Party):
Sanofi

Brief Summary:

Primary Objective:

- To evaluate the dose response relationship of SAR425899 compared to placebo on resolution of non-alcoholic steatohepatitis (NASH) with no worsening of fibrosis in diabetic and non-diabetic patients with histopathologically-confirmed NASH.

Secondary Objectives:

  • To assess the effect of SAR425899 on overall non-alcoholic fatty liver disease (NAFLD) activity score (NAS), individual components of NAS (steatosis, hepatocyte ballooning, and lobular inflammation), and fibrosis score.
  • To assess to the effect of SAR425899 on MRI-PDFF (Magnetic Resonance Imaging-determined Proton Density Fat Fraction) derived parameters (total liver fat, liver volume, and fractional liver fat content).
  • To assess the effect of SAR425889 on body weight and waist/hip circumference ratio.
  • To assess SAR425899 pharmacokinetics.
  • To assess safety and tolerability of SAR425899.

Condition or disease Intervention/treatment Phase
Non-alcoholic Steatohepatitis Type 2 Diabetes Mellitus Drug: SAR425899 Drug: Placebo Phase 2

Detailed Description:
Study duration per participant will be approximately 64 weeks, consisting of up to 8 weeks screening plus 52 weeks treatment and 4 weeks post treatment follow-up.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A 52-week Double-blind, Randomized, Placebo-controlled, Phase 2 Study to Assess the Efficacy and Safety of SAR425899 for the Treatment of Non-alcoholic Steatohepatitis (NASH)
Estimated Study Start Date : May 23, 2019
Estimated Primary Completion Date : August 25, 2021
Estimated Study Completion Date : August 25, 2021


Arm Intervention/treatment
Experimental: SAR425899 (Low Dose)
Once daily dose with weekly dose escalations, if tolerated, until target dose is reached. From week 14 (Day 99) until week 52, no further dose adjustments are planned.
Drug: SAR425899

Pharmaceutical form: Solution for injection

Route of administration: Subcutaneous injection


Experimental: SAR425899 (High Dose)
Once daily dose with weekly dose escalations, if tolerated, until target dose is reached. From week 14 (Day 99) until week 52, no further dose adjustments are planned.
Drug: SAR425899

Pharmaceutical form: Solution for injection

Route of administration: Subcutaneous injection


Placebo Comparator: Placebo (Low Dose)
Once daily dose with weekly dose escalations, if tolerated, until target dose is reached. From week 14 (Day 99) until week 52, no further dose adjustments are planned.
Drug: Placebo

Pharmaceutical form: Solution for injection

Route of administration: Subcutaneous injection


Placebo Comparator: Placebo (High Dose)
Once daily dose with weekly dose escalations, if tolerated, until target dose is reached. From week 14 (Day 99) until week 52, no further dose adjustments are planned.
Drug: Placebo

Pharmaceutical form: Solution for injection

Route of administration: Subcutaneous injection





Primary Outcome Measures :
  1. Resolution of Non-alcoholic steatohepatitis (NASH) [ Time Frame: Week 52 ]
    Percentage of participants with absence of hepatocyte ballooning (NAFLD - non-alcoholic fatty liver disease - activity score, NAS = 0) without worsening of fibrosis score at week 52. -


Secondary Outcome Measures :
  1. No hepatocyte ballooning, lobular inflammation score 0 or 1, without worsening of fibrosis [ Time Frame: Week 52 ]
    Percentage of participants with absence of hepatocyte ballooning (NAS = 0), lobular inflammation NAS = 0 or 1, without worsening of fibrosis score at week 52.

  2. Change in overall NAFLD activity score (NAS) [ Time Frame: Baseline to week 52 ]
    Change from baseline to week 52 in overall NAFLD activity score (NAS).

  3. Change in NAS individual components [ Time Frame: Baseline to week 52 ]
    Change from baseline to week 52 in individual components of NAS (steatosis).

  4. Change in NAS individual components [ Time Frame: Baseline to week 52 ]
    Change from baseline to week 52 in individual components of NAS (hepatocyte ballooning).

  5. Change in NAS individual components [ Time Frame: Baseline to week 52 ]
    Change from baseline to week 52 in individual components of NAS (lobular inflammation).

  6. Change in fibrosis score [ Time Frame: Baseline to week 52 ]
    Change from baseline to week 52 in fibrosis score.

  7. Major adverse cardiac events [ Time Frame: Baseline to week 52 ]
    Number of patients with major cardiac events

  8. Change in Magnetic Resonance Imaging-determined Proton Density Fat Fraction (MRI-PDFF) [ Time Frame: Baseline to week 26 and week 52 ]
    Change from baseline to week 26 and to week 52 in MRI-PDFF-derived total liver fat, liver volume and fractional liver fat content.

  9. Improvement of fibrosis without worsening of hepatocyte ballooning component of NAS [ Time Frame: Week 52 ]
    Percentage of participants with improvement of fibrosis by at least 1 stage without worsening of hepatocyte ballooning component of NAS at week 52

  10. Change in body weight [ Time Frame: Baseline to week 52 ]
    Change from baseline to week 52 in body weight

  11. Change in waist circumference [ Time Frame: Baseline to week 52 ]
    Change from baseline to week 52 in waist circumference

  12. Change in hip circumference [ Time Frame: Baseline to week 52 ]
    Change from baseline to week 52 in hip circumference

  13. Change in waist to hip ratio [ Time Frame: Baseline to week 52 ]
    Change from baseline to week 52 in waist to hip ratio

  14. Assessment of pharmacokinetic (PK) parameter: AUC0-24 [ Time Frame: Week 52 ]
    Area under the concentration-time curve from 0 to 24 hours (AUC0-24)

  15. Assessment of PK parameter: Cmax [ Time Frame: Week 52 ]
    Observed maximum plasma concentration after administration (Cmax)

  16. Assessment of PK parameter: Ctrough [ Time Frame: Baseline to week 52 ]
    Plasma concentration immediately prior to treatment administration during repeat dosing levels (Ctrough)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria :

  • Non-diabetic or type 2 diabetes mellitus with confirmed non-alcoholic steatohepatitis.
  • Non-alcoholic fatty liver disease (NAFLD) activity score (NAS) >=4 with each of its components >=1.
  • Patients without Type 2 diabetes determined by HbA1c (glycated hemoglobin) <6.5% and Fasting Plasma Glucose (FPG) <7.0 mmol/L (<126 mg/dL).
  • Stable glycemic control (HbA1c <9.0%) and metabolic disorders managed with diet/exercise and/or stable dose metformin and/or sulphonylureas for at least 3 months prior to screening (type 2 diabetes patients).
  • Signed written informed consent form.

Exclusion criteria:

  • Diagnosis of type 1 diabetes mellitus.
  • Previous insulin use or use of insulin within the last 6 months, except for episode(s) of short-term treatment (<15 consecutive days) due to intercurrent illness.
  • Body Mass Index (BMI) <25 kg/m2 or >45.0 kg/m2.
  • Current participation in organized diet/weight reduction program or clinical trial of weight control (within the last 3 months prior to screening), or weight loss attempt, plans for major changes in physical activities or significant change in body weight in the 2 months prior to screening (significant change in body weight is defined as >=5% self-reported change within 6 months prior to randomization if a pre-existing liver biopsy sample was collected prior to screening period.
  • Current treatment with glucose-lowering agent(s) other than metformin or sulphonylureas, weight loss drugs including orlistat, systemic steroids, methotrexate, amiodarone, or Vitamin E.
  • Alcoholism (past or present) and/or average alcohol consumption per week >21 units (210 g) for males, >14 units (140 g) for females within the last 5 years.
  • Poorly controlled hypertension (resting systolic blood pressure (SBP) >160 mm Hg and/or resting diastolic blood pressure (DBP) >95 mm Hg) at screening.
  • Some liver diseases, pancreatic disease, liver transplantation and types of cancer.
  • Pregnant or breast-feeding women.
  • Women of childbearing potential (WOCBP) not protected by highly-effective method(s) of birth control and/or who are unwilling or unable to be tested for pregnancy.
  • Male subjects, whose partners are able to become pregnant, who do not accept to use a condom during sexual intercourse from study inclusion up to 3 months after last dosing; or who are planning to donate sperm from study inclusion up to 3 months after last dosing.
  • Patients with coronary, carotid, or peripheral artery revascularization procedures planned during the screening or treatment phases of the protocol.
  • Patients with unstable heart conditions.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03437720


Sponsors and Collaborators
Sanofi
Investigators
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Study Director: Clinical Sciences & Operations Sanofi

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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT03437720     History of Changes
Other Study ID Numbers: ACT15067
2017-002371-26 ( EudraCT Number )
U1111-1191-5486 ( Other Identifier: UTN )
First Posted: February 19, 2018    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Fatty Liver
Non-alcoholic Fatty Liver Disease
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Liver Diseases
Digestive System Diseases