Clinical trial NCT02322450: Phase IIa Study of the Product QGC001 Compared With Placebo in Patients With Essential Hypertension
Official title: Multicenter, Randomized, Double-blind, Two-period, Placebo Controlled, Forced-titration Proof of Concept Crossover Study to Compare QGC001 With Placebo in Patients With Grade I or II Essential Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Essential Hypertension
Lead sponsor: Quantum Genomics SA
Sponsor class: INDUSTRY
First posted: 2014-12-23
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 2QG1 is a Phase IIa study aiming to assess the blood pressure lowering effect of 4-week administration of QGC001 oral doses in patients with grade I or II essential hypertension compared to placebo, to assess the safety and tolerability, to obtain preliminary PK information for QGC001 given as multiple oral doses and to determine preliminary PD profile of QGC001 multiple oral doses on plasma and urine hormones, which will be compared to that of placebo.


Eligibility criteria: Inclusion Criteria:

* Male and female of non-childbearing potential patients (post-menopausal since at least 12 months or surgically sterilized) aged 18 to 75 years;
* Body weight ≥50 kg with a body mass index (BMI) calculated as weight in kg/(height in m2) from 18 to 40 kg/m2 at screening;
* A signed and dated informed consent form before any study-specific screening procedure is performed;
* With a diagnosis of essential grade I or II hypertension defined as:

  * a supine office systolic BP (SBP) of 140-159 mmHg or diastolic BP (DBP) of 90-99 mmHg who should have an additional clinical indication according to ESH guidelines for antihypertensive treatment after a 2-week placebo run-in period,
  * or a supine office SBP of 160-179 mmHg or DBP of 100-109 mmHg after a 2-week placebo run-in period with a diagnosis of essential grade II hypertension;
* Diagnosis of permanent hypertension confirmed by a mean SBP or DBP higher than135 or 85 mmHg on daytime ambulatory blood pressure monitoring (ABPM) after a 2-week placebo run-in period;
* Estimated glomerular filtration rate (Modification of Diet in Renal Disease (MDRD) formula) ≥ 60 ml/min/1.73 m2.

Exclusion Criteria:

* Any significant hepatic, renal, respiratory (e.g., asthma), gastrointestinal, endocrine (e.g., diabetes, dyslipidemia necessitating drug therapy), immunologic, dermatological, hematological, neurologic, psychiatric disease or history of any clinically important drug allergy;
* Acute disease state (e.g., vomiting, fever, diarrhea) within 7 days before study day 1;
* Any history of transient ischemic accident (TIA) or cerebrovascular accident (CVA);
* Any history of acute heart failure or heart failure;
* Any history of myocardial infarction, unstable angina, coronary bypass or percutaneous coronary angioplasty;
* History of malignant tumor during the past 5 years;
* Any medical or surgical disorder considered by the investigator as increasing the risks of participation in the study, or liable to prevent the patient from complying with the requirements of the study or from continuing the study to completion;
* Any situation which, in the investigator's opinion, might compromise assessment of efficacy or of safety;
* History of non-adherence to treatment;
* History of drug abuse within 1 year before study day 1;
* History of alcoholism within 1 year before day 1;
* Positive serologic findings for human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg), and/or hepatitis C virus (HCV) antibodies;
* Use of any investigational drug within 30 days before IMP administration;
* Donation of blood (i.e., 500 ml) within 90 days before study day 1;
* Known secondary hypertension;
* Grade III hypertension;
* Estimated glomerular filtration rate (MDRD formula) below 60 ml/min/1.73 m2 ;
* Type I diabetes mellitus or uncontrolled type II diabetes mellitus (HbA1C ≥ 8%);
* Severe obesity (BMI ≥ 40 kg/m2);
* Arm circumference ≥ 42 cm;
* Atrial fibrillation;
* Known hypersensitivity to drugs;
* History of spontaneous or drug induced angioneurotic edema;
* Use of any of the following medications within the four (4) weeks prior to dosing:

  * Thyroid medication, statin therapy, oral antidiabetic drugs, estrogen replacement therapy and/or chronic low dose aspirin (75 mg/day) unless the patient has been on a stable maintenance dose for at least 3 months prior to screening.
  * Anticoagulant treatments
  * Cholestyramine resins.
  * Treatment with oral, topical, inhaled, eye drop corticosteroids
  * Treatment with class Ia, Ib and Ic or III anti-arrhythmics
  * CNS drugs
  * P-glycoprotein (P-gp) inhibitors (e.g., verapamil, quinidine, ritonavir),
  * known cytochrome P450 inducers or inhibitors (eg, ketoconazole/CYP3A4, quinidine/CYP2D6, gemfibrozil/CYP2C8)
  * Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDS) or cyclooxygenase (COX)-2 inhibitors.
  * Vasodilators or vascular muscle relaxants prescribed for other conditions
* Unlikely to cooperate in the study and/or poor compliance anticipated by the investigator, e.g., uncooperative attitude, inability to return for follow-up visit, and unlikelihood of completing the study;
* Participation in another interventional study at the same time or within 3 months prior to the beginning of the present study;
* Participant not affiliated with the French social security;
* No written informed consent;
* A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval \>450 ms);
* A history of additional risk factors for Torsade de Pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome);
* The use of concomitant medications that prolong the QT/QTc interval.

Primary outcomes:
measure: Efficacy - 24h ABPM
timeFrame: Change from Period 1 to Period 2 up to 16 weeks (end-of-study visit).
Secondary outcomes:
measure: Efficacy - Self BP measurements at home
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Efficacy - Office BP measurements
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Efficacy - Hormonal measurements
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Pharmacokinetics - Plasma levels of QGC001
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Pharmacokinetics - Plasma levels of EC33
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Safety - Reported signs and symptoms
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Safety - Physical examination
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Safety - Vital sign measurements
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Safety - Adverse events
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Safety - Morisky Medication Adherence Questionnaire
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Safety - Electrocardiogram
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
measure: Safety - Clinical laboratory tests
timeFrame: Change from Period 1 to Period 2 up to 16 weeks.
Other outcomes:
Locations:
city: Dinard
country: France
facility: Hôpital Arthur Gardiner
city: Lille
country: France
facility: Hôpital Cardiologique, CHRU de Lille
city: Lyon
country: France
facility: Hospices Civils de Lyon - Hôpital de la Croix Rousse
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
Study officials:
References:
citation: Khosla J, Aronow WS, Frishman WH. Firibastat: An Oral First-in-Class Brain Aminopeptidase A Inhibitor for Systemic Hypertension. Cardiol Rev. 2022 Jan-Feb 01;30(1):50-55. doi: 10.1097/CRD.0000000000000360.
citation: Azizi M, Courand PY, Denolle T, Delsart P, Zhygalina V, Amar L, Lantelme P, Mounier-Vehier C, De Mota N, Balavoine F, Llorens-Cortes C. A pilot double-blind randomized placebo-controlled crossover pharmacodynamic study of the centrally active aminopeptidase A inhibitor, firibastat, in hypertension. J Hypertens. 2019 Aug;37(8):1722-1728. doi: 10.1097/HJH.0000000000002092.