Study of Cicletanine for Pulmonary Arterial Hypertension (PAH)

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

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.

Study Overview

• Status: Terminated
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Cicletanine; Drug: Cicletanine Placebo

Detailed Description

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:

1. To compare the change in other clinical measures of PAH following treatment with cicletanine HCl or placebo in subjects with PAH
2. 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.

• Study Type: Interventional
• Enrollment (Actual): 162
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Royal Perth Hospital
• Austria
  • Graz, Austria, 8036
    • University Klinik Graz
  • Wien, Austria, 1090
    • University Klinik Wien
• Belgium
  • Bruxelles, Belgium, 1070
    • ULB Hopital Erasme
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y6J4
      • Peter Lougheed Centre
  • Ontario
    • London, Ontario, Canada, N6A5W9
      • London Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H3T1E2
      • Jewish General Hospital
• Germany
  • BY
    • Muenchen, BY, Germany, 80336
      • Ludwig-Maximilians-Universitaet
  • HE
    • Giessen, HE, Germany, 35392
      • Universitaetsklinikum Giessen und Marburg
• Israel
  • Petach Tikva, Israel, 49100
    • Rabin Medical Center
  • Ramat Gan, Israel, 52621
    • Chaim Sheba Medical Center
• Mexico
  • Mexico City, Mexico
    • Instituto Nacional de Cardiologia Ignacio Chavez
  • NL
    • Monterrey, NL, Mexico, 64718
      • Unidad de Investigacion Clinica en Medicina S.C.
• Spain
  • Barcelona, Spain, 8036
    • H Clinic i Provincial
  • Madrid, Spain, 28041
    • HU 12 de Octubre
• United Kingdom
  • Gt Lon
    • London, Gt Lon, United Kingdom, NW32QG
      • Royal Free Hospital
• United States
  • Alabama
    • Mobile, Alabama, United States, 36617
      • University of South Alabama
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Arizona Pulmonary Specialists
  • California
    • Los Angeles, California, United States, 90073
      • VA Greater LA Healthcare System
    • San Diego, California, United States, 92037
      • University of California San Diego Medical Center
    • San Jose, California, United States, 95124
      • Harish H. K. Murthy, MD
    • Torrance, California, United States, 90502
      • UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connecticut Health Center
  • Florida
    • Ft. Lauderdale, Florida, United States, 33331
      • Cleveland Clinic
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Louisiana State University
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
    • Boston, Massachusetts, United States, 02111
      • Tufts-New England Medical Center
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10032
      • New York Presbyterian Hospital
    • New York, New York, United States, 10021
      • Cornell University
    • Rochester, New York, United States, 14623
      • University of Rochester
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Clinical Trial Center
    • Cleveland, Ohio, United States, 44106
      • Case Medical Center
    • Columbus, Ohio, United States, 43210-1252
      • Davis Heart and Lung Research Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center at Dallas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Utah
    • Murray, Utah, United States, 84157
      • Intermountain Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Gilead Sciences
• Investigators: Study Chair: Gennyne Walker, PhD, Senior Clinical Research Scientist, Gilead Sciences

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: January 29, 2009
• First Submitted That Met QC Criteria: January 29, 2009
• First Posted (Estimate): January 30, 2009

Study Record Updates

• Last Update Posted (Estimate): February 4, 2014
• Last Update Submitted That Met QC Criteria: January 3, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: combination therapy; pulmonary hypertension; monotherapy; PAH; cardiovascular; endothelin receptor antagonist; PH; pulmonary; ERA; PDE5i; cicletanine; cicletanine HCL; phosphodiesterase type-5 inhibitor; parenteral prostanoid
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Antihypertensive Agents; Natriuretic Agents; Diuretics; Cicletanine
• Other Study ID Numbers: GS-US-235-0101