Study of Cicletanine for Pulmonary Arterial Hypertension (PAH)

Study Overview
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Brief Summary
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This Phase 2, randomized, double-blind, placebo-controlled, multicenter, dose-ranging study will compare the efficacy, safety, and tolerability of cicletanine hydrochloride (HCl) to placebo in subjects with PAH. Study drug will be administered alone, or on the background of stable PAH therapy. The study will consist of 3 periods: a screening period, a 12-week placebo-controlled treatment period, and a long-term, blinded extension period.

Detailed Description
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The primary objective of this study is to compare the change in exercise capacity following treatment with cicletanine HCl or placebo in subjects with PAH. The secondary objectives of this study are: To compare the change in other clinical measures of PAH following treatment with cicletanine HCl or placebo in subjects with PAH To compare the safety and tolerability of cicletanine HCl to placebo in subjects with PAH Additionally, the long-term safety, tolerability, and efficacy of cicletanine HCl treatment will be evaluated.

Official Title
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A Phase 2, Randomized, Double-blind, Placebo-controlled, Multicenter, Dose-ranging Study of Cicletanine in Subjects With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Cicletanine
* Drug: Cicletanine Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Between 16 and 70 years of age Weigh greater than or equal to 40 kg Have a current diagnosis of IPAH, FPAH, or PAH that is primarily due to: connective tissue disease, congenital heart defects, drug and toxin use, and HIV infection Meet all of the following hemodynamic criteria by means of a RHC completed prior to or during Screening: mPAP of greater than or equal to 25 mmHg, PVR greater than 240 dyne.sec/cm5, PCWP or LVEDP of less than or equal to1 5 mmHg Walk a distance of at least 100 m but no more than 450 m during the screening 6MWT Have WHO functional class II, III, or IV symptoms Meet all of the following pulmonary function tests completed no more than 12 weeks before the Screening visit: TLC greater than or equal to 60% of predicted normal & FEV1 greater than or equal to 65% of predicted normal, FEV1:FVC ratio greater than 0.60 Have laboratory results within 90% of the lower limit of normal to 1.5 times the upper limit of normal Receiving treatment with an approved ERA, PDE5i, and/or parenteral prostanoid must be receiving this therapy for greater than or equal to 12 weeks prior to the Screening Visit and must be at a stable dose for greater than or equal to 4 consecutive weeks prior to the Screening Visit. Eligible therapies allowed at Screening include:a. Monotherapy with an ERA, PDE5i, or parenteral prostanoid that is approved for the treatment of PAH b. Combination therapy with two eligible PAH treatments (any combination of ERA, PDE5i, or parenteral prostanoid Subject receiving diuretic treatment must be on stable therapy If receiving digitalis, CCBs, angiotensin receptor blockers (ARBs), angiotensin converting enzyme (ACE) inhibitors, or beta-blocking agents subject must be on stable therapy If receiving HMG-CoA reductase inhibitors, subject must be on stable therapy If diagnosis of HIV subject must have stable disease status Female subjects of childbearing potential must have a negative serum pregnancy test Female subjects of childbearing potential must agree to use 2 reliable methods of contraception Must agree not to participate in a clinical study involving another investigational drug or device Must be competent to understand and sign the IRB approved ICF Has not enrolled in an exercise training program for pulmonary rehabilitation and must agree not to enroll in an exercise training program for pulmonary rehabilitation If subject has been enrolled in an exercise training program for pulmonary rehabilitation for greater than 12 weeks prior to the Screening Visit and must agree to maintain their current level of rehabilitation for the first 12 weeks of the study Must be on background PAH therapy at Screening unless the subject does not have access to or can not tolerate currently approved PAH medical therapies Exclusion Criteria Subject with a current PH diagnosis other than IPAH, FPAH, or PAH that is primarily due to: Connective tissue disease, Congenital heart defects, Drug and toxin use, or HIV infection Subject with LVEF less than or equal to 40% or clinically significant ischemic, valvular, or constrictive heart disease Subject with WHO functional class I symptoms Subject has chronically received an ineligible PAH treatment regimen within the 4 weeks prior to the Screening Visit, specifically: a. inhaled iloprost or inhaled treprostinil, b. combination treatment with three PAH therapies, c.any investigational therapy for the treatment of PAH d.Chronic use is considered greater than 7 consecutive days of treatment Subject receiving iv inotropes within 2 weeks prior to the Screening Visit Subject with SBP greater than or equal to 150 mmHg or less than 90mmHg Subject with moderate to severe liver disease Subject with moderate or severe renal impairment Subject receiving lithium within the 2 weeks prior to the Screening Visit Subject requiring intermittent or chronic treatment with nitrates Subject receiving non-anti-arrhythmic drugs Subject has a diagnosis of long QT syndrome Subject with evidence of chronic thromboembolic disease Subject with obstructive lung disease Subject with severe arthritis, musculoskeletal problems, or morbid obesity that would affect the subject's ability to perform or complete the 6MWT Has a history of malignancies within the past 5 years Subject with disease that may adversely affect the safety of the subject and/or efficacy of the study drug or severely limit the lifespan of the subject Female subject who is pregnant or breastfeeding Has demonstrated noncompliance with previous medical regimens Has a recent history of abusing alcohol or illicit drugs Has participated in a clinical study involving another investigational drug or device within 4 weeks before the Screening Visit Has a known hypersensitivity to the study drug, the metabolites, or formulation excipients Receiving an oral arginine supplement within 2 weeks prior to the Screening Visit

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cicletanine 150 mg QD<br>Cicletanine 150 mg administered once daily (QD) | Drug: Cicletanine<br>* Cicletanine capsules 150 mg or 300 mg administered orally once or twice daily<br>|
| Experimental: Cicletanine 150 mg BID<br>Cicletanine 150 mg administered twice daily (BID) | Drug: Cicletanine<br>* Cicletanine capsules 150 mg or 300 mg administered orally once or twice daily<br>|
| Experimental: Cicletanine 300 mg QD<br>Cicletanine 300 mg administered once daily (QD) | Drug: Cicletanine<br>* Cicletanine capsules 150 mg or 300 mg administered orally once or twice daily<br>|
| Placebo Comparator: Placebo<br>Placebo to match cicletanine administered once daily | Drug: Cicletanine<br>* Cicletanine capsules 150 mg or 300 mg administered orally once or twice daily<br>Drug: Cicletanine Placebo<br>* Placebo to match cicletanine administered orally once daily, followed by active cicletanine in the blinded extension period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in six-minute walk distance (6MWD) evaluated after 12 weeks of treatment |  | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in BDI, WHO Functional Class, BNP, cardiac hemodynamics and SF-36 physical functioning scale following 12 weeks of treatment. In addition, time to clinical worsening (TTCW) will be evaluated. |  | Baseline to Week 60 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ERA, PAH, PDE5i, pulmonary hypertension, cicletanine, cicletanine HCL, cardiovascular, endothelin receptor antagonist, monotherapy, combination therapy, phosphodiesterase type-5 inhibitor, parenteral prostanoid, PH, pulmonary