Clinical trial NCT03350191: A Clinical Study to Investigate if SAR425899 Binds to the Liver and Pancreas in Overweight to Obese Type 2 Diabetes Mellitus Patients
Official title: A PET/CT Study to Assess the Receptor Occupancy by SAR425899 After Repeat Dosing Using Radiolabelled Tracers for the Glucagon and GLP-1 Receptor in Overweight to Obese T2DM Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 2 Diabetes Mellitus
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Antaros Medical
First posted: 2017-11-22
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Primary Objectives:

To assess in overweight to obese T2DM patients:

* The glucagon receptor occupancy of SAR425899 at two dose levels in the human liver with positron-emission tomography (PET) imaging using \[68Ga\]Ga-DO3A-VS-Cys40-Tuna-2 as a tracer compound.
* The GLP-1 receptor occupancy of SAR425899 at two dose levels in the human pancreas with PET imaging using \[68Ga\]Ga-DO3A-VS-Cys40-Exendin-4 as a tracer compound.
* Pharmacodynamic effects on fasting plasma glucose and biomarkers of lipid metabolism.
* Pharmacokinetic parameters for SAR425899 after repeated subcutaneous (SC) doses in plasma.
* Safety and tolerability of SAR425899.

Detailed description: Study duration is approximately 7 weeks with a 20 days treatment period.

Eligibility criteria: Inclusion criteria :

* Male and female patients, between 18 and 75 years of age, inclusive.
* Body weight between 60.0 and 120.0 kg, inclusive, body mass index between 28.0 and 38.0 kg/m2, inclusive.
* Diagnosis of type 2 diabetes mellitus for at least 1 year at the time of inclusion with stable metformin treatment prior to inclusion, with or without comorbidities related to type 2 diabetes mellitus.
* Fasting plasma glucose ≥ 90 mg/dL at screening.
* Glycosylated hemoglobin (HbA1c) ≥6.5% and ≤9 % at screening.

Exclusion criteria:

* Any history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurological, osteomuscular, articular, psychiatric, systemic, ocular, gynecologic (if female), urologic or infectious disease, hormonal active tumors (e.g. pheochromocytoma or insulinoma), or signs of acute illness that is not related to the metabolic status of the patient.
* Presence or history of drug hypersensitivity (including known allergic reactions associated with glucagon like peptide-1 (GLP-1) agonist treatment \[exenatide, liraglutide, lixisenatide\]), or allergic disease diagnosed and treated by a physician.
* Any intake of menopausal hormone replacement therapy, systemic corticosteroids, growth hormones, weight-loss drugs, antihyperlipidemic treatment, antihyperglycemic treatment \[e.g., GLP-1 agonists, insulin, thiazolidinediones, dipeptidylpeptidase (DPP-IV) inhibitors, sodium/glucose cotransporter-2 (SGLT-2) inhibitors etc.\]) during the treatment period and within 21 days before first dosing or within 5 times the elimination half-life or pharmacodynamic half-life of the medication (if known), with the exception of metformin, sulphonylureas (SU), standard antihypertensive treatment, statins and acetyl salicylic acid.
* Any condition possibly affecting gastric emptying or absorption from gastro-intestinal tract (e.g., gastric surgery, gastrectomy, bariatric surgery, malabsorption syndromes, gastroparesis, abdominal surgery other than appendectomy, hysterectomy, cholecystectomy and herniaplasty).
* Surgically treated obesity, bariatric surgery.
* Severe dyslipidemia with fasting triglycerides \>450 mg/dL at screening.
* Severe hypoglycemia resulting in seizure/unconsciousness/coma or hospitalization for diabetic ketoacidosis in the last 3 months before screening.
* Persistent hyperglycemia not adequately controlled by metformin, SUs and/or diet/exercise.
* Diagnosed diabetic neuropathy, retinopathy, nephropathy or renal impairment (GFR \<60 mL/min; estimate after Cockcroft-Gault) at screening.
* Unstable hypo- or hyperthyroidism (as assessed by TSH) at screening.
* History of pancreatitis or pancreatectomy.
* Amylase and/or lipase \> 2 upper limit of normal (ULN) at screening.
* Personal history or family history of medullary thyroid cancer or a genetic condition that predisposes to medullary thyroid cancer.
* Elevated basal calcitonin (≥20 pg/mL / 5.9 pmol/L) at screening.
* Known past or present diseases or disorders of any target organ (liver, pancreas, spleen).
* Medical positron emitting tomography (PET), single photon emission computer tomography (SPECT), abdominal or thoracic computer tomography (CT) examination during the previous 12 months' time period.
* Claustrophobia.

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

Primary outcomes:
measure: Glucagon receptor occupancy
timeFrame: Day 1 and Day 20
Secondary outcomes:
measure: GLP-1 receptor occupancy
timeFrame: Day 1 and Day 17
measure: Adverse events
timeFrame: Up to 27 days
measure: Pharmacokinetics
timeFrame: Day 20
measure: Change in fasting plasma glucose (FPG)
timeFrame: Day 1 to Day 20
measure: Change in ketone bodies
timeFrame: Day 1 to Day 20
measure: Change lipid biomarkers
timeFrame: Day 1 to Day 20
measure: Change in volume of distribution (Vt) in the liver
timeFrame: Day 1 and Day 20
measure: Change in Vt in the pancreas
timeFrame: Day 1 and Day 17
measure: Average standard uptake values (SUVs) of PET tracers in the liver and pancreas
timeFrame: Day 1, Day 17 and Day 20
measure: Pharmacokinetics
timeFrame: Day 20
measure: Pharmacokinetics
timeFrame: Day 20
measure: Pharmacokinetics
timeFrame: Day 20
measure: Pharmacokinetics
timeFrame: Day 20
measure: Change lipid biomarkers
timeFrame: Day 1 to Day 20
measure: Change lipid biomarkers
timeFrame: Day 1 to Day 20
Other outcomes:
Locations:
city: Uppsala
country: Sweden
facility: Investigational Site Number 7520001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Eriksson O, Velikyan I, Haack T, Bossart M, Laitinen I, Larsen PJ, Berglund JE, Antoni G, Johansson L, Pierrou S, Tillner J, Wagner M. Glucagonlike Peptide-1 Receptor Imaging in Individuals with Type 2 Diabetes. J Nucl Med. 2022 May;63(5):794-800. doi: 10.2967/jnumed.121.262506. Epub 2021 Sep 9.