Treprostinil Combined With Tadalafil for Pulmonary Hypertension

Condition(s) targeted: Pulmonary Arterial Hypertension

Intervention: Tadalafil (Drug); Placebo (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Rhode Island Hospital

Official(s) and/or principal investigator(s):
James R Klinger, MD, Study Director, Affiliation: Rhode Island Hospital

Overall contact:
James R Klinger, MD, Phone: 401-444-2776, Email: james_klinger@brown.edu

Objectives: To test whether the combined administration of the medications treprostinil(a prostacycline therapy), and tadalafil(a PDE-5 Inhibitor therapy) is better than the administration of treprostinil alone. This treatment would be offered to newly diagnosed patients with pulmonary arterial hypertension who are on no treatment for this disease and are deemed candidates for the medication treprostinil by their physician. The combination therapy will be compared to single therapy with only treprostinil in a double-blind manner.

Current therapy is to begin one treatment, either a PDE5 inhibitor or a prostacycline, depending on the severity of the patient's PAH disease and add additional therapies as deterioration occurs. This treatment could add two agents initially.

Secondary objectives are: To improve pulmonary arterial pressures as measured through a cardiac echocardiogram, improve the subject's 6minute walk distance, delaying the time to clinical worsening, and lowering plasma BNP levels.

Research Procedures: To begin the administration of both treatments at the same time.

Time period is 16 weeks with a one- year follow-up. Cardiac Echocardiograms, clinic

physician exams, and lab work will be followed. Subjects will be between the ages of 18 -

75.

Official title: Randomized Placebo Controlled Trial of Treprostinil Infusion Combined With Oral Tadalafil or Placebo in Pulmonary Arterial Hypertension

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Primary outcome:

All cause mortality

Adverse events are no greater than with Treprostinil infusion alone

WHO functional class will improve or remain stable

Hospitalizations

Secondary outcome:

6 minute walking distance change will improve

Tei index change by transthoracic echocardiography

plasma BNP level change

Change from baseline in pulmonary arterial systolic pressure as assessed by transthoracic echocardiography using Doppler ultrasound

Detailed description: Background: Many cardiovascular diseases such as essential hypertension, coronary artery disease and congestive heart failure respond better to combinations of vasoactive drugs, than to therapy with a single agent. Three categories of pulmonary anti-hypertensive medications have been developed over the last 20 years, but their effect on management of PAH when used in combination are mostly unknown. Two of the pulmonary arterial hypertension (PAH) drug groups are prostacyclines, and PDE5 inhibitors. Although the effects of prostacyclins are mediated via cAMP and the effects of PDE5 inhibitors are mediated via cGMP, there is considerable cross talk between these nucleotides suggesting that adequate levels of both may be needed to maintain normal pulmonary vascular tone and cellular growth responses.

Objective/Hypothesis: This proposal hypothesizes that increasing the levels of both nucleotides (prostacyclines and PDE5 inhibitors), may be more efficacious in the treatment of PAH than increasing either one alone.

Specific Aims: The primary objective of this study is to determine if the combination of treprostinil infusion combined with tadalafil is more efficacious than treprostinil alone in improving the change from baseline in the 6 minute walking distance after 16 weeks of therapy.

Study Design: The proposed study is a multi-center, randomized, double blind, two cohort, parallel group, and 16-week study with 1-year long-term follow-up. The study aims to compare the efficacy of combination therapy with treprostinil infusion and tadalafil to treprostinil infusion alone.

Study Population: All patients who have been newly diagnosed with PAH and who, after consultation with their physician, have elected to be treated with treprostinil infusion will be invited to participate. A total of 66 subjects will be sort to enroll.

Treprostinil dosing will follow a 4 week up-titration schedule with a target 4week dose of 8ng/kg/min minimum, followed by a 12 week randomized tadalafil period.

Minimum age: 18 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Adult patients 18-80 years of age

2. World Health Organization Group 1 PAH

1. Idiopathic PAH

2. Heritable PAH

3. PAH associated with connective tissue disease

4. PAH associated with surgical repair of congenital left to right shunt

5. PAH associated with anorectic drug use

3. WHO functional Class III-IV

4. 6 minute walking distance > 150-meters and < 450 meters

5. Right heart catheterization showing mean PAP > 25 mmHg and PCWP < 15 mmHg within 6 months of study entry.

Exclusion Criteria:

1. Pulmonary hypertension associated with

1. Portal hypertension

2. HIV infection

3. Pulmonary venous hypertension defined as PCWP > 15 mmHg

4. Chronic lung disease defined as

i. FEV1/FVC less than 0. 65 ii. TLC < 0. 70 iii. Untreated Sleep Apnea with AHI > 20 or hemoglobin oxygen saturation nadir < 87% e. Chronic Thromboembolic Disease f. Sarcoidosis g. Pulmonary veno occlusive disease (PVOD)

2. Concomitant use of nitrates (any form) either regularly or intermittently.

3. Concomitant use of potent CYP3A inhibitors (e. g., ritonavir, ketoconazole, itraconazole)

4. Vascular disease of the retina including retinitis pigmentosa, any sudden vision loss, including any damage to the optic nerve or NAION

5. low blood pressure or high blood pressure that is not controlled

6. Postural hypotension

7. Inability to manage home infusion therapy

8. Pulmonary vasodilator therapy with any phosphodiesterase inhibitor or endothelin receptor antagonist within 30 days of study entry

9. Participation in a clinical investigational study within previous 30 days

10. Renal failure defined as:

1. estimated creatinine clearance < 30 ml/min

2. serum creatinine > 2. 5 mg/dl

11. Subjects with liver function abnormalities (ALT or AST > 3 times the upper limit of normal at screening or at baseline) or chronic liver disease

12. History of hypersensitivity reaction or adverse effect related to tadalafil

13. Life expectancy < 12 months

14. History of deformed penis shape, an erection that lasted more than 4 hours, or Peyronie's disease.

15. Blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia

16. Pregnant or planning to become pregnant or breast feed.

James R Klinger, MD, Phone: 401-444-2776, Email: james_klinger@brown.edu

Maine Medical Center, Portland, Maine 04102, United States; Not yet recruiting
Joel A Wirth, MD, Phone: 207-828-1122, Email: wirthj@mmc.org
Tina Manley, RN, Phone: 207-662-4519, Email: manlet@mmc.org
Joel Wirth, MD, Principal Investigator

Tuft's New England Medical Center, Boston, Massachusetts 02111, United States; Not yet recruiting
Nicholas S Hill, MD, Phone: 617-636-4288, Email: nhill@tuftsmedicalcenter.org
Karen Visnaw, RN,BSN, Phone: 617-636-1334, Email: kvisnaw@tuftsmedicalcenter.org
Ioana Preston, MD, Sub-Investigator
Kari Roberts, MD, Sub-Investigator
Aaron B Waxman, MD, Principal Investigator

Brigham & Womens Hospital, Boston, Massachusetts 02115, United States; Not yet recruiting
Aaron Waxman, MD, Phone: 617-525-9733, Email: abwaxman@partners.org
Laurie Lawler, RN, Phone: 617-525-9731, Email: llawler@partners.org
Barbara Cockrill, MD, Sub-Investigator
Arlene Schiro, NP-C, Sub-Investigator

Saint Barnabas Health Care System, Newark Beth Israel Medical Center, Newark, New Jersey 07112, United States; Not yet recruiting
Sean M Studer, MD, Phone: 973-926-4430, Email: sstuder@sbhcs.com
Juliet Williams, CCRC, CMA, Phone: 973-926-8578, Email: juwilliams@sbhcs.com
Sean M Studer, MD, Principal Investigator
Christina Migliore, MD, Sub-Investigator
David Baran, MD, Sub-Investigator

Weill Cornell Medical Center, New York, New York 10021, United States; Not yet recruiting
Evelyn M Horn, MD, Phone: 212-746-2381, Email: horneve@med.cornell.edu
Madeline Yushak, RN, Phone: 212-746-2698, Email: yushakm@nyp.org
Evelyn M Horn, MD, Principal Investigator
Irina Sobol, MD, Sub-Investigator
Rosemarie Gadioma, NP, Sub-Investigator
Nicole Garcia, NP, Sub-Investigator
Neshama Avrahami, NP, Sub-Investigator
Birgit Jorgensen, NP, Sub-Investigator

Beth Israel Medical Center, new York, New York 10003, United States; Not yet recruiting
Roxana Sulica, MD, Phone: 212-844-8824, Email: rsulica@chpnet.org
Rebecca Fenton, RN, Phone: 212-844-8263, Email: rfenton@chpnet.org
Roxana Sulica, MD, Principal Investigator

University of Rochester Medical Center, Rochester, New York 14642, United States; Not yet recruiting
James R White, MD, Phone: 585-486-0147, Ext: 123, Email: jim_white@urmc.rochester.edu
Karen Frutiger, RN, Phone: 585-486-0147, Ext: 123, Email: karen_frutiger@urmc.rochester.edu
James R White, MD, Principal Investigator
Kathleen Wessman, MPA, Sub-Investigator

Rhode Island Hospital, Providence, Rhode Island 02903, United States; Recruiting
James R Klinger, MD, Phone: 401-444-2776, Email: james_klinger@brown.edu
Barbara S Smithson, MSN,RN, Phone: 401-444-9097, Email: bsmithson@lifespan.org
Douglas W Martin, MD, Sub-Investigator
Jeanne E Houtchens, NP-C, Sub-Investigator
James R Klinger, MD, Principal Investigator

Inova Fairfax Hospital, Falls Church, Virginia 22042, United States; Not yet recruiting
Steven Nathan, MD, Phone: 703-776-3610, Email: steven.nathan@inova.org
Edwina Battle, RN, Phone: 703-776-3067, Email: edwinia.battle@inova.org
Shahzad Ahmad, MD, Sub-Investigator
Anne W Brown, MD, Sub-Investigator
Nargues Weir, MD, Sub-Investigator
Steven Nathan, MD, Principal Investigator

Starting date: March 2011
Last updated: June 10, 2011