Clinical trial NCT03462017: Pharmacodynamic Study to Assess the Effects of Repeated Dosing of SAR247799 on Endothelial Function in Patients With Type 2 Diabetes Mellitus
Official title: Study to Assess the Pharmacodynamic Effects of Repeated Oral Doses of SAR247799 on Endothelial Function in Male and Female Patients With Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Microvascular Coronary Artery Disease
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2018-03-12
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 64
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: BASIC_SCIENCE

Brief summary: Primary Objective:

To assess the pharmacodynamic effects of SAR247799 on macrovascular endothelial function of the brachial artery using flow-mediated dilation (FMD) in patients with type 2 diabetes mellitus (T2DM).

Secondary Objective:

* To assess the pharmacodynamic effects of SAR247799 on microvascular endothelial function using laser Doppler perfusion monitoring in patients with T2DM.
* To assess the safety profile of SAR247799 in patients with T2DM.
* To assess the plasma pharmacokinetic profile of SAR247799 in patients with T2DM.

Detailed description: Study duration per patient is approximately 10 weeks including a 4-week treatment period.

Eligibility criteria: Inclusion criteria :

* Male and female stable Type 2 diabetes mellitus (T2DM) patients.
* Body Mass Index between 18 and 35 kg/m\^2.
* Stable T2DM patients, but otherwise healthy as assessed by a clinical and laboratory assessments and detailed medical history.
* Diagnosis of T2DM for at least 6 months at the time of the screening visit.
* Glycosylated hemoglobin (HbA1c) \< 8.5%.
* estimated glomerular filtration rate ˃60 mL/min/1.73 m\^2.
* Flow-mediated dilatation (FMD) ≤7% at screening.
* Treatment of T2DM with lifestyle interventions or stable oral antidiabetic treatment for at least 3 months prior to inclusion.
* No clinically significant abnormality detected in cardiac echography, as assessed by certified Cardiologist, performed at screening.

Exclusion criteria:

* Any history or presence of clinically relevant or symptomatic gastrointestinal, hepatic, metabolic (except stable T2DM and controlled dyslipidemia), hematological, osteomuscular, articular, psychiatric, systemic, gynecologic (if female), or infectious disease, or ongoing cancer (including basal cell skin carcinoma), or signs of acute illness which as judged by the Investigator, may affect the patient's participation in or the outcome of this study.
* Symptomatic postural hypotension, irrespective of the decrease in blood pressure, or asymptomatic postural hypotension defined as a decrease in systolic blood pressure ≥30 mmHg within 3 minutes when changing from 10 min supine to standing position, at screening.
* History of symptomatic bradycardia, fainting, collapse, syncope, or vasovagal reactions in the last 6 months.
* Presence or history of drug hypersensitivity and/or allergy to any ingredients of the investigational product and/or non-investigational product diagnosed and treated by a physician.
* Any subject who cannot be treated with sildenafil because of conditions mentioned in the contra-indication, warning and precautions sections of sildenafil product information notably subjects with anatomical deformity of the penis.
* Loss of vision due to non-arteritic, neuro-optic, anterior ischemia assessed in ophtalmologic examination at screening.
* If female, pregnancy (defined as positive β-human chorionic gonadotropin blood and urine test), breast-feeding.
* Generally any medication which has a potential to interfere with the safety, pharmacokinetics of SAR247799 and sildenafil, or with study measurements is not allowed, and in particular:
* Nitrates, all calcium channel blockers, phosphodiesterase type 5 inhibitors (except investigational medicinal product \[IMP\]), guanylate cyclase stimulators use or anticipated during the study;
* Beta-blockers;
* Glucagon-like peptide-1 agonists;
* Insulins (all types);
* Anticoagulants, antithrombotics except aspirin;
* Any drugs which decrease heart rate;
* Antiarrhythmics;
* Digoxin;
* Cholinergic agents eg pilocarpine or cholinesterase inhibitors eg neostigmine, guanidine;
* Recent (≤3 months) use of systemic immunosuppressive or corticosteroid therapy;
* Any inactivated vaccination (eg, seasonal influenza) during study treatment, any attenuated vaccination within 2 months before inclusion, and any biologics (antibody or its derivatives) given within 4 months before inclusion;
* Any consumption of citrus fruits (grapefruit, orange, etc) or their juices within 3 days before inclusion as weak inhibitor of CYP3A4 gut wall metabolism.
* Any severe dyslipidemia with fasting triglycerides \> 450 mg/dL.
* Any hyperosmolar hyperglycemic episode with severe neurological symptoms (eg, coma, aphasia) in the last 3 months before screening.
* Weight change of ≥5 kg during the last 2 months prior to screening.
* History or presence of clinically relevant or symptomatic pulmonary disease, such as asthma, chronic obstructive pulmonary disease, pulmonary embolism, pulmonary fibrosis, pulmonary hypertension which as judged by the Investigator, may affect the patient's participation in or the outcome of this study.
* Cardiovascular history such as:
* History or presence of a clinically relevant or symptomatic cardiovascular disease such as acute coronary syndrome (ACS), stroke, transient ischemic accident (TIA), obstructive or congestive heart failure, or structural heart disease (e.g., valvular disease) which as judged by the Investigator, may affect the patient's participation in or the outcome of this study.
* History of elective percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within the past 6 months.
* History of clinically relevant or symptomatic cardiac arrhythmia such as sustained ventricular arrhythmia, non-fixed supra-ventricular arrhythmia which as judged by the Investigator, may affect the patient's participation in or the outcome of this study or which occurred within the past 6 months
* History of clinically relevant or symptomatic cardiac conduction abnormalities (any type of atrioventricular (AV) block, sick sinus syndrome, sinus node disease).
* Patients with a pacemaker or implantable cardioverter defibrillator.
* Known history of autoimmune disorders.
* Any severe viral, systemic, fungal, bacterial or protozoal infection within the past 6 months or chronic severe infection (hepatitis, HIV infection, tuberculosis).
* Presence of macular edema at fundus examination performed within 6 months before the first study drug administration.

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

Primary outcomes:
measure: Change in Flow Mediated Dilation (FMD)
timeFrame: Baseline to Days 14, 21, 28, 35, and 42
Secondary outcomes:
measure: Microvascular reactivity
timeFrame: Baseline to Days 14, 21, 28, 35, and 42
measure: Number of adverse events
timeFrame: Up to Day 42
measure: Assessment of pharmacokinetic (PK) parameter: Cmax
timeFrame: Days 1, 2, 3, 7, and 14
measure: Assessment of PK parameter: Ctrough
timeFrame: Days 1, 2, 3, 7, and 14
measure: Assessment of PK parameter: tmax
timeFrame: Days 1, 2, 3, 7, and 14
measure: Assessment of PK parameter: AUC0-24
timeFrame: Days 1, 2, 3, 7, and 14
Other outcomes:
Locations:
city: Mainz
country: Germany
facility: Investigational Site Number 2760002
city: Neuss
country: Germany
facility: Investigational Site Number 2760001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Bergougnan L, Andersen G, Plum-Morschel L, Evaristi MF, Poirier B, Tardat A, Ermer M, Herbrand T, Arrubla J, Coester HV, Sansone R, Heiss C, Vitse O, Hurbin F, Boiron R, Benain X, Radzik D, Janiak P, Muslin AJ, Hovsepian L, Kirkesseli S, Deutsch P, Parkar AA. Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial. Br J Clin Pharmacol. 2021 May;87(5):2303-2320. doi: 10.1111/bcp.14632. Epub 2020 Nov 26.