Clinical trial NCT00832507: Study of Cicletanine for Pulmonary Arterial Hypertension (PAH)
Official title: A Phase 2, Randomized, Double-blind, Placebo-controlled, Multicenter, Dose-ranging Study of Cicletanine in Subjects With Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Keywords: PAH
pulmonary hypertension
cicletanine
cicletanine HCL
cardiovascular
endothelin receptor antagonist
ERA
monotherapy
combination therapy
phosphodiesterase type-5 inhibitor
PDE5i
parenteral prostanoid
PH
pulmonary
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2009-01-30
Enrollment: 162
Sex: ALL
Minimum age (years): 16
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change from baseline in six-minute walk distance (6MWD) evaluated after 12 weeks of treatment
timeFrame: Baseline to Week 12
Secondary outcomes:
measure: 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.
timeFrame: Baseline to Week 60
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama
state: Alabama
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists
state: Arizona
city: Los Angeles
country: United States
facility: VA Greater LA Healthcare System
state: California
city: San Diego
country: United States
facility: University of California San Diego Medical Center
state: California
city: San Jose
country: United States
facility: Harish H. K. Murthy, MD
state: California
city: Torrance
country: United States
facility: UCLA Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Farmington
country: United States
facility: University of Connecticut Health Center
state: Connecticut
city: Ft. Lauderdale
country: United States
facility: Cleveland Clinic
state: Florida
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Augusta
country: United States
facility: Medical College of Georgia
state: Georgia
city: Chicago
country: United States
facility: University of Chicago Hospital
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: New Orleans
country: United States
facility: Louisiana State University
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Tufts-New England Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Beth Israel Medical Center
state: New York
city: New York
country: United States
facility: Cornell University
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Cincinnati
country: United States
facility: The Lindner Clinical Trial Center
state: Ohio
city: Cleveland
country: United States
facility: Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: Davis Heart and Lung Research Institute
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Charlottesville
country: United States
facility: University Of Virginia
state: Virginia
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital
state: New South Wales
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Graz
country: Austria
facility: University Klinik Graz
city: Wien
country: Austria
facility: University Klinik Wien
city: Bruxelles
country: Belgium
facility: ULB Hôpital Erasme
city: Calgary
country: Canada
facility: Peter Lougheed Centre
state: Alberta
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Muenchen
country: Germany
facility: Ludwig-Maximilians-Universitaet
state: BY
city: Giessen
country: Germany
facility: Universitaetsklinikum Giessen und Marburg
state: HE
city: Petach Tikva
country: Israel
facility: Rabin Medical Center
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Monterrey
country: Mexico
facility: Unidad de Investigación Clínica en Medicina S.C.
state: NL
city: Mexico City
country: Mexico
facility: Instituto Nacional de Cardiologia Ignacio Chavez
city: Barcelona
country: Spain
facility: H Clinic i Provincial
city: Madrid
country: Spain
facility: HU 12 de Octubre
city: London
country: United Kingdom
facility: Royal Free Hospital
state: Gt Lon
Study officials:
affiliation: Senior Clinical Research Scientist, Gilead Sciences
name: Gennyne Walker, PhD
role: STUDY_CHAIR
References: