A Study to Assess the Safety and Efficacy of SAR425899 in Patients With Type 2 Diabetes Mellitus

A 26-Week Randomized, Double-blind, Placebo-controlled, Dose-ranging Phase 2 Study to Assess the Safety and Efficacy of SAR425899 in Patients With Type 2 Diabetes Mellitus

Primary Objective:

The primary objective of this study was to assess the dose-response relationship of SAR425899 versus placebo in terms of glycemic control as measured by the change in glycosylated hemoglobin (HbA1c).

Secondary Objectives:

• To assess the effect of SAR425899 on body weight.
• To assess the safety and immunogenicity profile of SAR425899, including assessment of the heart rate (HR) change by electrocardiogram (ECG) and Holter monitor.
• To assess the proportion of participants achieving predefined HbA1c targets of <7% and <6.5% as well as the proportion of participants achieving >=5% and >=10% body weight loss.
• To assess the effect of once daily dosing of SAR425899 on additional parameters of glycemic control and lipid metabolism.
• To assess the effect of once daily dosing of SAR425899 on additional pharmacodynamic (PD) biomarkers.
• To assess the pharmacokinetic (PK) profile and parameters of SAR425899, inter-individual and inter-occasion variability in PK parameters using a population PK approach.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Placebo; Drug: Metformin; Drug: SAR425899; Drug: Liraglutide

Detailed Description

The total study duration will be approximately 30 weeks, consisting of 3 weeks screening period at the site, a 26 weeks treatment period, and 3 days post treatment follow up period.

• Study Type: Interventional
• Enrollment (Actual): 296
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G1S 2L6
    • Investigational Site Number 1240008
  • Sainte-Foy, Canada, G1W4R4
    • Investigational Site Number 1240005
  • Sherbrooke, Canada, J1L 0H8
    • Investigational Site Number 1240002
  • Toronto, Canada, M4G 3E8
    • Investigational Site Number 1240001
  • Vancouver, Canada, V5Y 3W2
    • Investigational Site Number 1240003
• Czechia
  • Ceske Budejovice, Czechia, 370 01
    • Investigational Site Number 2030003
  • Krnov, Czechia, 79401
    • Investigational Site Number 2030001
  • Praha 10 - Uhrineves, Czechia, 104 00
    • Investigational Site Number 2030004
  • Praha 9 - Klanovice, Czechia, 19014
    • Investigational Site Number 2030002
• Germany
  • Berlin, Germany, 10115
    • Investigational Site Number 2760003
  • Dresden, Germany, 01307
    • Investigational Site Number 2760001
  • Hohenmölsen, Germany, 06679
    • Investigational Site Number 2760006
• Hungary
  • Balatonfüred, Hungary, 8230
    • Investigational Site Number 3480001
  • Budapest, Hungary, 1027
    • Investigational Site Number 3480002
  • Budapest, Hungary, 1042
    • Investigational Site Number 3480008
  • Budapest, Hungary, 1062
    • Investigational Site Number 3480005
  • Budapest, Hungary, 1062
    • Investigational Site Number 3480006
  • Budapest, Hungary, 1213
    • Investigational Site Number 3480007
• Mexico
  • Actopan, Mexico, 42500
    • Investigational Site Number 4840004
  • Guadalajara, Mexico, 44600
    • Investigational Site Number 4840001
  • Guadalajara, Mexico, 44670
    • Investigational Site Number 4840003
  • Monterrey, Mexico, 64460
    • Investigational Site Number 4840002
  • San Juan Del Rio, Mexico, 76800
    • Investigational Site Number 4840006
• Russian Federation
  • Saratov, Russian Federation, 410030
    • Investigational Site Number 6430003
  • St-Petersburg, Russian Federation, 190068
    • Investigational Site Number 6430002
  • St-Petersburg, Russian Federation, 195257
    • Investigational Site Number 6430001
  • St. Petersburg, Russian Federation, 194358
    • Investigational Site Number 6430004
  • Voronezh, Russian Federation, 394018
    • Investigational Site Number 6430005
• Spain
  • Barcelona, Spain, 08035
    • Investigational Site Number 7240005
  • Ferrol, Spain, 15405
    • Investigational Site Number 7240007
  • La Coruña, Spain, 15006
    • Investigational Site Number 7240001
  • Las Palmas De Gran Canaria, Spain, 35016
    • Investigational Site Number 7240006
  • Madrid, Spain, 28040
    • Investigational Site Number 7240002
  • Málaga, Spain, 29010
    • Investigational Site Number 7240003
  • Málaga, Spain, 29010
    • Investigational Site Number 7240004
  • Sevilla, Spain, 41071
    • Investigational Site Number 7240008
• United States
  • Alabama
    • Sheffield, Alabama, United States, 35660
      • Investigational Site Number 8400028
  • California
    • Huntington Park, California, United States, 90255
      • Investigational Site Number 8400002
    • Los Angeles, California, United States, 90017
      • Investigational Site Number 8400024
    • Los Angeles, California, United States, 90057
      • Investigational Site Number 8400001
    • Port Hueneme, California, United States, 93041
      • Investigational Site Number 8400012
  • Colorado
    • Denver, Colorado, United States, 80209
      • Investigational Site Number 8400027
  • Florida
    • Miami, Florida, United States, 33166
      • Investigational Site Number 8400025
    • Palm Harbor, Florida, United States, 34684
      • Investigational Site Number 8400007
  • Illinois
    • Chicago, Illinois, United States, 60827
      • Investigational Site Number 8400013
  • Kansas
    • Wichita, Kansas, United States, 67205
      • Investigational Site Number 8400016
    • Wichita, Kansas, United States, 67207
      • Investigational Site Number 8400023
  • Louisiana
    • New Orleans, Louisiana, United States, 70119
      • Investigational Site Number 8400018
  • Maryland
    • Rockville, Maryland, United States, 20852
      • Investigational Site Number 8400019
  • Michigan
    • Flint, Michigan, United States, 48532-3447
      • Investigational Site Number 8400014
    • Troy, Michigan, United States, 48085
      • Investigational Site Number 8400003
  • New Jersey
    • Linden, New Jersey, United States, 07036
      • Investigational Site Number 8400020
  • New York
    • New York, New York, United States, 10001
      • Investigational Site Number 8400022
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Investigational Site Number 8400005
  • Texas
    • Austin, Texas, United States, 78731
      • Investigational Site Number 8400004
    • Dallas, Texas, United States, 75230
      • Investigational Site Number 8400006
    • Houston, Texas, United States, 77079
      • Investigational Site Number 8400021
    • San Antonio, Texas, United States, 78229
      • Investigational Site Number 8400026
    • Sugar Land, Texas, United States, 77478
      • Investigational Site Number 8400017

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria :

• Participants with type-2 diabetes mellitus (T2DM) for at least 3 months before the screening visit.
• On diet/exercise and/or treatment with metformin (stable dose of ≥1500 mg/day or maximal tolerated dose) for at least 3 months prior to screening.
• Signed informed consent.

Exclusion criteria:

• At screening, participant's age < legal age of adulthood and >80 years.
• Glycated hemoglobin at screening visit <7.0% or >10.0%.
• Body mass index (BMI) <25 kg/m^2 or >45.0 kg/m^2.
• Pregnant or lactating 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.
• Diagnosis of type 1 diabetes mellitus.
• Fasting plasma glucose of >15 mmol/L (270 mg/dL) measured by the central laboratory at screening (Visit 1), and confirmed (>15 mmol/L [270 mg/dL]) by a repeat test before randomization.
• Treatment with glucose-lowering agents(s) other than metformin, currently or within the 3 months prior to screening.
• Previous insulin use, except for episode(s) of short-term treatment (≤15 consecutive days) for intercurrent illness or pregnancy, or use of insulin within the last 6 months.
• Contraindication(s) to metformin use.
• Contraindication(s) to liraglutide use.
• Significant change in body weight in the 3 months before screening.
• Poorly controlled hypertension (a resting systolic blood pressure (SBP) >160 mm Hg and/or diastolic blood pressure (DBP) >95 mm Hg at screening).
• History of long QT syndrome and/or QTc more than 450 ms at screening visit.
• History of pancreatitis or pancreatectomy.
• History of weight loss surgery.
• Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC.
• Any prior exposure to drugs belonging to the class of glucagon-like peptide-1 (GLP-1) receptor agonists/GLP-1 analogs.
• Contraindications or known hypersensitivity reaction to glucagon.

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo (for SAR425899) subcutaneous (SC) injection once daily (QD) from Week 1 to Week 26, matching 3 SAR425899 dose levels of 0.12 mg, 0.16 mg and 0.20 mg.	Drug: Placebo; Self-administered by SC injection using a solution for injection in cartridge.; Drug: Metformin; Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.
Experimental: SAR425899 0.12 mg; SAR425899 SC injection QD at maintenance dose of 0.12 mg for 25 weeks (Week 2 to Week 26) following 1 week dose increase step (0.06 mg at Week 1).	Drug: Metformin; Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.; Drug: SAR425899; Self-administered by SC injection using a solution for injection in cartridge.
Experimental: SAR425899 0.16 mg; SAR425899 SC injection QD at maintenance dose of 0.16 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase step (0.06 mg at Week 1 and 0.12 mg at Week 2).	Drug: Metformin; Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.; Drug: SAR425899; Self-administered by SC injection using a solution for injection in cartridge.
Experimental: SAR425899 0.20 mg; SAR425899 SC injection QD at maintenance dose of 0.20 mg for 23 weeks (Week 4 to Week 26) following 3 weeks dose increase step (0.06 mg at Week 1, 0.12 mg at Week 2 and 0.16 mg at Week 3).	Drug: Metformin; Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.; Drug: SAR425899; Self-administered by SC injection using a solution for injection in cartridge.
Active Comparator: Liraglutide; Liraglutide SC injection QD at maintenance dose of 1.8 mg for 24 weeks (Week 3 to Week 26) following 2 weeks dose increase steps (0.6 mg daily at Week 1 and by 1.2 mg daily at Week 2).	Drug: Metformin; Orally administered at a stable dose , >=1500 mg daily stable dose or maximal tolerated dose.; Drug: Liraglutide; Self-administered by SC injection using a pre-filled pen.; Other Names: Victoza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HbA1c to Week 26	Change in HbA1c was calculated by subtracting baseline value from Week 26 value. Missing post-baseline values were imputed by placebo control-based multiple imputation (MI) method under the missing not at random framework.	Baseline, Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Body Weight to Week 26	Change in body weight was calculated by subtracting baseline value from Week 26 value. Missing post- baseline values were imputed by placebo control-based MI method under the missing not at random framework.	Baseline, Week 26
Percentage of Participants Reached HbA1c Target of <6.5% or <7% at Week 26	The analysis included assessment collected during the study, including those obtained after IMP discontinuation or introduction of rescue therapy. Participants with no measurement at Week 26 were treated as non-responders.	Week 26
Percentage of Participants Achieving >=5% or >=10% Body Weight Loss at Week 26	The analysis included assessment collected during the study, including those obtained after IMP discontinuation or introduction of rescue therapy. Participants with no measurement at Week 26 were treated as non-responders.	Week 26
Change From Baseline in Fasting Plasma Glucose (FPG) to Week 26	Change in FPG was calculated by subtracting baseline value from Week 26 value. Missing post-baseline values were imputed by placebo control-based MI method under the missing not at random framework.	Baseline, Week 26
Change From Baseline in Average 7 Point Self-Monitoring Plasma Glucose (SMPG) to Week 26	Change in 7-point SMPG profile from baseline to Week 26 was assessed by summary statistics. 7-point SMPG profiles were measured at the following 7 points at each visit (Baseline, and Week 26): pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours postprandial (breakfast, lunch and dinner) is defined as 2 hours after the start of the meal.	Baseline, Week 26
Percentage of Participants Requiring Rescue Therapy	Rescue medication was introduced in case FPG or HbA1c values were above pre-defined thresholds, and if no reasons were found for insufficient glucose control, and appropriate action failed to decrease FPG / HbA1c under the threshold values (from baseline to Week 8: FPG >270 mg/dL 15.0 mmol/L, from Week 8 to Week 14: FPG >13.3 mmol/L, and from Week 14 to Week 26: FPG >11.1 mmol/L or HbA1c>8%). The choice of rescue therapy was at the Investigator's discretion with the exception of using glucagon-like peptide-1 receptor (GLP-1R) agonists or dipeptidyl peptidase 4 (DPP4) inhibitors.	Baseline up to 26 weeks
Change From Baseline in Beta-Cell Function to Week 26	Beta-cell function was assessed by homeostatic model assessment (HOMA)-beta, derived from FPG and fasting plasma insulin (FPI). HOMA-beta was derived from FPG and FPI as (20*FPI [micro units/milliliter]) divided by (FPG [mmol/L] minus 3.5). Change was calculated for HOMA-beta by subtracting the Baseline value from Week 26 value*100.	Baseline, Week 26
Change From Baseline in Insulin Resistance to Week 26	Insulin Resistance was assessed by homeostasis model assessment for insulin resistance (HOMA-IR), derived from FPG and FPI. HOMA-IR was derived from FPG and FPI as (FPI [micro units per milliliter] * FPG [mmol/L]) divided by 22.5. Change was calculated for HOMA-beta by subtracting the Baseline value from Week 26 value.	Baseline, Week 26
Change From Baseline in Pharmacodynamic Biomarkers to Week 26 - Waist and Hip Circumferences	Waist circumference was measured at the midpoint between the lower margin of the least palpable rib and the top of the iliac crest, using a stretch-resistant tape providing a constant 100 gm tension. Hip circumference was measured around the widest portion of the buttocks, with the tape parallel to the floor. Each measurement was repeated twice; if the measurements were within 1 cm of one another, the average was calculated, and if the difference exceeded 1 cm, the measurements were repeated.	Baseline,Week 26

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• Schiavon M, Visentin R, Gobel B, Riz M, Cobelli C, Klabunde T, Dalla Man C. Improved postprandial glucose metabolism in type 2 diabetes by the dual glucagon-like peptide-1/glucagon receptor agonist SAR425899 in comparison with liraglutide. Diabetes Obes Metab. 2021 Aug;23(8):1795-1805. doi: 10.1111/dom.14394. Epub 2021 May 5.
• Gater A, Reaney M, Findley A, Brun-Strang C, Burrows K, Nguyen-Pascal ML, Roborel de Climens A. Development and First Use of the Patient's Qualitative Assessment of Treatment (PQAT) Questionnaire in Type 2 Diabetes Mellitus to Explore Individualised Benefit-Harm of Drugs Received During Clinical Studies. Drug Saf. 2020 Feb;43(2):119-134. doi: 10.1007/s40264-019-00877-4.

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2016
• Primary Completion (Actual): December 27, 2017
• Study Completion (Actual): December 27, 2017

Study Registration Dates

• First Submitted: November 22, 2016
• First Submitted That Met QC Criteria: November 22, 2016
• First Posted (Estimate): November 25, 2016

Study Record Updates

• Last Update Posted (Actual): March 24, 2022
• Last Update Submitted That Met QC Criteria: March 15, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Incretins; Liraglutide; Metformin
• Other Study ID Numbers: DRI13940; 2016-001328-77 (EudraCT Number); U1111-1179-4786 (Other Identifier: UTN)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD 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://vivli.org