A Study to Evaluate Safety, Pharmacokinetics, and Pharmacodynamics of a Single Dose of SAR438544 in Comparison to Glucagon in Type 1 Diabetes Mellitus Patients Under Induced Hypoglycemia

SAR438544 - Clinical & Exploratory Pharmacology

Primary Objective:

To assess the pharmacodynamic response (PD) of a single subcutaneous (SC) dose of SAR438544 versus recombinant glucagon in type 1 diabetes mellitus (T1DM) patients under induced hypoglycemia.

Secondary Objective:

To assess the safety and tolerability and pharmacokinetics (PK) of a single SC dose of SAR438544 versus recombinant glucagon in T1DM patients under induced hypoglycemia.

Study Overview

• Status: Withdrawn
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: SAR438544; Drug: insulin; Drug: r-glucagon

Detailed Description

The total duration of study per patient is up to 8 weeks with 3 to 28 days screening period, 1 day for treatment for both periods and 7 to 14 days wash out between 2 administrations, and 7 days (+/- 1 day) follow-up after last IMP administration.

• Study Type: Interventional
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria :

• Male or female patients, between 18 and 60 years of age, inclusive, with T1DM for at least one year, as defined by the American Diabetes Association (ADA).
• Total (basal+short acting) daily insulin dose of <1.2 U/kg/day.
• Body weight between 50.0 and 110 kg, inclusive, the body mass index (BMI) between 18.5 and 30.0 kg/m^2, inclusive.
• Fasting serum C-peptide <0.3 nmol/L.
• Glycohemoglobin (HbA1c) ≤75 mmol/mol (≤9%).
• Stable insulin regimen for at least 2 months prior to study and self-monitoring of blood glucose before screening visit.
• Certified as otherwise healthy for T1DM by assessment of medical history and physical examination (cardiovascular system, chest and lungs, thyroid, abdomen, nervous system, skin and mucosae, and musculoskeletal system), unless the Investigator considers any abnormality to be clinically irrelevant and not interfering with the conduct of the study.
• Female subject must use a double contraception method, including a highly effective method of birth control, except if she has undergone sterilization defined as tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy, and bilateral tubal ligation at least 3 months earlier or is postmenopausal.

The accepted double contraception methods include the use of intrauterine device or hormonal contraception started at least 30 days prior to the screening start and continued for at least 3 months after IMP dosing in addition to one of the following contraceptive options: (1) condom plus spermicide; (2) diaphragm plus spermicide or cervical/vault cap plus spermicide. Menopause is defined as being amenorrheic for at least 2 years with plasma follicle-stimulating hormone (FSH) level >30 UI/L in women older than 40 years of age.

• Having given written informed consent prior to undertaking any study-related procedure.
• Not under any administrative or legal supervision.
• Male subject, whose partners are of childbearing potential (including lactating women), must accept to use, during sexual intercourse, a double contraception method according to the following algorithm: (condom, diaphragm or cervical cap, plus spermicide) plus (intra-uterine device or hormonal contraceptive) from the inclusion up to 3 months after the last dosing (except if sterilized).
• Male subject whose partners are pregnant must use during sexual intercourse a condom from the inclusion up to 3 months after the last dosing.
• Male subject has agreed not to donate sperm from the inclusion up to 3 months after the last dosing.

Exclusion criteria:

• Any history or presence of clinically relevant cardiovascular (includes ischemia, atrioventricular (AV) block; arrhythmias), pulmonary, gastrointestinal, hepatic, renal, metabolic (apart from T1DM), hematological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, gynecologic (if female), or infectious disease, or signs of acute illness.
• Severe hypoglycemia resulting in coma/seizures or requiring assistance of another person, and/or hospitalization for diabetic ketoacidosis in the last 6 months before screening visit.
• Frequent severe headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month).
• Blood loss (>300 mL) within 3 months before inclusion.
• Symptomatic postural hypotension, irrespective of the decrease in blood pressure (BP), or asymptomatic postural hypotension defined as a decrease in systolic BP ≥20 mmHg within 3 minutes when changing from supine to standing position.
• Presence or history of drug hypersensitivity, or allergic disease diagnosed and treated by a physician.
• Likelihood of requiring treatment during the study period with drugs not permitted by the clinical study protocol.
• If female, pregnancy (defined as positive beta-human chorionic gonadotropin [β-HCG] blood test), breast-feeding at screening and before any treatment periods (defined as positive β-HCG urine test).
• Any patient who, in the judgment of the Investigator, is likely to be noncompliant during the study, or unable to cooperate because of a language problem or poor mental development.
• Positive result on any of the following tests: hepatitis B surface antigen (HBs Ag), anti-hepatitis C virus (HCV) Abs, anti-human immunodeficiency virus 1 (HIV1) and anti-HIV2 Abs, and HIV1 Ag.
• Positive result on urine drug screen (amphetamines/methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates).
• Positive alcohol breath test.
• Known hypersensitivity to glucagon, lactose or any other constituent in GlucaGen^® HypoKit and SAR438544 or Novolin^®R and their excipients.
• Any contraindication from the use of glucagon:
• Pheochromocytoma
• Insulinoma and glucagonoma

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: SAR438544 dose 1; Single dose of SAR438544 given SC under fasting conditions and under induced hypoglycemia. Novolin^®R will be used to induce hypoglycemia.	Drug: SAR438544; Pharmaceutical form:solution Route of administration: subcutaneous; Drug: insulin; Pharmaceutical form:solution Route of administration: intravenous; Other Names: Novolin® R
Active Comparator: Glucagon; Single dose of glucagon given SC under fasting conditions and under induced hypoglycemia. Novolin^®R will be used to induce hypoglycemia.	Drug: insulin; Pharmaceutical form:solution Route of administration: intravenous; Other Names: Novolin® R; Drug: r-glucagon; Pharmaceutical form:solution Route of administration: subcutaneous; Other Names: GlucaGen® HypoKit
Experimental: SAR438544 Optional Dose; Optional lower, intermediate, or higher dose of SAR438544 given SC under fasting conditions and under induced hypoglycemia. Novolin^®R will be used to induce hypoglycemia.	Drug: SAR438544; Pharmaceutical form:solution Route of administration: subcutaneous; Drug: insulin; Pharmaceutical form:solution Route of administration: intravenous; Other Names: Novolin® R

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to reach a smoothed blood glucose of 70 mg/dL after initial administration of investigational medicinal product	Day 1

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of patients with adverse events	Day 1 to Day 7 (+/- 1 day)
Assessment of PD parameter: continuous monitoring of blood glucose levels over a period of 6 hours post-dose	Day 1
Assessment of PD parameter: BG-maximum concentration (BG-Cmax)	Day 1
Assessment of PD parameter: BG-time to Cmax (BG-tmax)	Day 1
Assessment of PK parameter (recombinant glucagon and SAR438544): Cmax	Day 1
Assessment of PK parameter (recombinant glucagon and SAR438544): tmax	Day 1
Assessment of PK parameter (recombinant glucagon and SAR438544): tlast	Day 1
Assessment of PK parameter (recombinant glucagon and SAR438544): area under curve from zero time until the last measurable concentration (AUClast)	Day 1
Assessment of PK parameter (recombinant glucagon and SAR438544): AUC	Day 1
Assessment of PK parameter (recombinant glucagon and SAR438544): partial AUCs (AUC0-t)	Day 1
Assessment of PD parameter: area under plasma concentration of the BG-time curve between IMP dosing and time t (BG-AUC0-t)	Day 1
Assessment of PK parameter (recombinant glucagon and SAR438544): terminal half-life	Day 1
Time to reach a smoothed blood glucose of 90 mg/dL after initial administration of investigational medicinal product	Day 1

Collaborators and Investigators

• Sponsor: Sanofi

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Anticipated): November 1, 2016
• Study Completion (Anticipated): November 1, 2016

Study Registration Dates

• First Submitted: December 16, 2015
• First Submitted That Met QC Criteria: December 16, 2015
• First Posted (Estimate): December 18, 2015

Study Record Updates

• Last Update Posted (Estimate): September 2, 2016
• Last Update Submitted That Met QC Criteria: September 1, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Physiological Effects of Drugs; Gastrointestinal Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Glucagon
• Other Study ID Numbers: PDY14452; U1111-1172-1152 (Other Identifier: UTN)