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Pulmonary Vascular Disease |

Cicletanine as Add-on Therapy for Pulmonary Arterial Hypertension

Mardi Gomberg-Maitland*, MD; Ronald Oudiz, MD; Shelley Shapiro, MD; Anne Keogh, MD; David Badesch, MD; Robert Frantz, MD; C. Gregory Elliott, MD; Hunter Gillies, MD; Gennyne Walker, PhD; Aaron Waxman, MD
Author and Funding Information

University of Chicago, Chicago, IL


Chest. 2012;142(4_MeetingAbstracts):806A. doi:10.1378/chest.1386552
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Abstract

SESSION TYPE: Pulmonary Hypertension I

PRESENTED ON: Sunday, October 21, 2012 at 10:30 AM - 11:45 AM

PURPOSE: Cicletanine (CIC) is an antihypertensive with vasorelaxant and diuretic properties. Based on potential efficacy observed with compassionate use of CIC in PAH patients, we performed a safety and efficacy study of CIC for PAH.

METHODS: 162 subjects were randomized to 12 weeks of placebo (n=41) or CIC doses of 150mg qd (n=39), 150mg bid (n=40) or 300mg qd (n=42). Subjects could be on stable doses of an endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE5i), parenteral prostanoid (PG), or any 2-drug combination. The primary analysis was comparison of change in 6-minute walk distance (6MWD) following 12 weeks of treatment with CIC 300mg (150 mg bid+300mg qd; n=82) vs. placebo. Secondary analyses included: dyspnea, World Health Organization functional class (FC), NT proBNP, and a subset analysis of hemodynamics (n=51).

RESULTS: More than half the subjects had idiopathic PAH (57%) vs. associated PAH (43%), with a mean time from diagnosis of 5.3 years. 43% were receiving ERA/PDE5i/PG monotherapy and 51% were receiving 2-drug therapy. Subjects were either FC Class II (39%) or FC Class III (61%), and the mean baseline 6MWD was 370±64 meters (m). For the 300mg combined group, the placebo-adjusted mean and median changes from baseline in 6MWD were +19.4 m (95% CI: 0.3, 38.4) and +7.0 m (95%: CI -8.0, 24.0), respectively (p=0.50). Median change from baseline was +9.0 m with placebo and +14.0 m (150mg qd), + 17.5 m (150mg bid) and +12.0 m (300mg qd) with CIC. There were no clinically relevant improvements in secondary assessments, including pulmonary vascular resistance. Adverse events reported more frequently with CIC, consistent with known properties of diuretics, included nausea, hypokalemia, and fatigue.

CONCLUSIONS: CIC was well-tolerated but did not improve exercise tolerance, symptoms or hemodynamics in patients with PAH after 12 weeks of treatment.

CLINICAL IMPLICATIONS: CIC was not efficacious in a prevalent PAH population receiving approved PAH-specific therapies. The lack of deterioration in the placebo group illustrates the importance of a placebo comparator arm in future PAH “add-on” studies.

DISCLOSURE: Mardi Gomberg-Maitland: Consultant fee, speaker bureau, advisory committee, etc.: Mardi Gomberg-Maitland received consulting fees from Gilead Sciences and is on the Cicletanine Advisory Committee.

Ronald Oudiz: Consultant fee, speaker bureau, advisory committee, etc.: Ron Oudiz received consulting fees from Gilead Sciences and is on the Cicletanine Advisory Committee.

Shelley Shapiro: Consultant fee, speaker bureau, advisory committee, etc.: Shelley Shapiro received consulting fees from Gilead Sciences and is on the Cicletanine Advisory Committee.

Anne Keogh: Consultant fee, speaker bureau, advisory committee, etc.: Anne Keogh received consulting fees from Gilead Sciences and is on the Cicletanine Advisory Committee.

David Badesch: Consultant fee, speaker bureau, advisory committee, etc.: David Badesch received consulting fees from Gilead Sciences and is on the Cicletanine Advisory Committee.

Robert Frantz: Consultant fee, speaker bureau, advisory committee, etc.: Robert Frantz received consulting fees from Gilead Sciences and is on the Cicletanine Advisory Committee.

C. Gregory Elliott: Consultant fee, speaker bureau, advisory committee, etc.: C. Gregory Elliott received consulting fees from Gilead Sciences and is on the Cicletanine Advisory Committee.

Hunter Gillies: Employee: Hunter Gillies is an employee of Gilead Sciences.

Gennyne Walker: Employee: Gennyne Walker is an empoyee and shareholder of Gilead Sciences.

Aaron Waxman: Consultant fee, speaker bureau, advisory committee, etc.: Aaron Waxman received consulting fees from Gilead Sciences and is on the Cicletanine Advisory Committee.

This abstract describes the administration of cicletanine for to patients with pulmonary arterial hypertension (PAH) Cicletanine is not approved for the treatment of PAH.

University of Chicago, Chicago, IL

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