Treprostinil Combined With Tadalafil for Pulmonary Hypertension (T2)

This study has been terminated.
(One subject enrolled and completed this study. The study was stopped due to poor recruitment.)
Sponsor:
Collaborator:
United Therapeutics
Information provided by (Responsible Party):
Rhode Island Hospital
ClinicalTrials.gov Identifier:
NCT01302444
First received: February 16, 2011
Last updated: July 18, 2013
Last verified: April 2012
  Purpose

Objectives: To test whether the combined administration of the medications treprostinil(a prostacycline therapy), and tadalafil(a PDE-5 [ phosphodiesterase type 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 (pulmonary arterial hypertension) 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.


Condition Intervention Phase
Pulmonary Arterial Hypertension
Drug: Tadalafil
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Randomized Placebo Controlled Trial of Treprostinil Infusion Combined With Oral Tadalafil or Placebo in Pulmonary Arterial Hypertension

Resource links provided by NLM:


Further study details as provided by Rhode Island Hospital:

Primary Outcome Measures:
  • All Cause Mortality [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • Adverse Events Are no Greater Than With Treprostinil Infusion Alone [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]
  • WHO Functional Class Will Improve or Remain Stable [ Time Frame: 16 weeks ] [ Designated as safety issue: No ]
  • Hospitalizations [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 6 Minute Walking Distance Change Will Improve [ Time Frame: 16 weeks of therapy ] [ Designated as safety issue: No ]
  • Tei Index Change by Transthoracic Echocardiography [ Time Frame: 16 weeks of therapy ] [ Designated as safety issue: No ]
  • Plasma BNP (Brain Natriuretic Peptide)Level Change [ Time Frame: 16 weeks of therapy ] [ Designated as safety issue: No ]
  • Change From Baseline in Pulmonary Arterial Systolic Pressure (PASP)as Assessed by Transthoracic Echocardiography Using Doppler Ultrasound [ Time Frame: 16 weeks ] [ Designated as safety issue: Yes ]

Enrollment: 1
Study Start Date: March 2011
Study Completion Date: March 2012
Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Tadalafil
first 4 weeks are for adjusting treprostinil dose, then Tadalafil 40mg daily for 12 weeks, Group is randomly chosen from entire cohort
Drug: Tadalafil
Tadalafil 40mg for 12 weeks
Other Name: Adcirca
Placebo Comparator: Placebo
first 4 weeks for adjusting treprostinil dose, then Placebo for 12 weeks
Drug: Placebo
Placebo for 12 weeks
Other Name: sugar pill

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 (cyclic guanosine monophosphate) 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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 (pulmonary arterial pressure)> 25 mmHg and PCWP (pulmonary capillary wedge pressure) < 15 mmHg within 6 months of study entry.

Exclusion Criteria:

  1. Pulmonary hypertension associated with

    a. Portal hypertension b. HIV infection c. Pulmonary venous hypertension defined as PCWP > 15 mmHg d. Chronic lung disease defined as i. FEV1(forced expiratory volume at one second

    )/FVC (forced vital capacity) less than 0.65 ii. TLC < 0.70 iii. Untreated Sleep Apnea with AHI (apnea-hypopnea index )> 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 [Alanine Aminotransferase or AST (Alanine Aminotransferase ) > 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01302444

Locations
United States, Maine
Maine Medical Center
Portland, Maine, United States, 04102
United States, Massachusetts
Tuft's New England Medical Center
Boston, Massachusetts, United States, 02111
Brigham & Womens Hospital
Boston, Massachusetts, United States, 02115
United States, New Jersey
Saint Barnabas Health Care System, Newark Beth Israel Medical Center
Newark, New Jersey, United States, 07112
United States, New York
Weill Cornell Medical Center
New York, New York, United States, 10021
Beth Israel Medical Center
new York, New York, United States, 10003
University of Rochester Medical Center
Rochester, New York, United States, 14642
United States, Rhode Island
Rhode Island Hospital
Providence, Rhode Island, United States, 02903
United States, Virginia
Inova Fairfax Hospital
Falls Church, Virginia, United States, 22042
Sponsors and Collaborators
Rhode Island Hospital
United Therapeutics
Investigators
Study Director: James R Klinger, MD Rhode Island Hospital
  More Information

Additional Information:
No publications provided

Responsible Party: Rhode Island Hospital
ClinicalTrials.gov Identifier: NCT01302444     History of Changes
Other Study ID Numbers: T2 Trial
Study First Received: February 16, 2011
Results First Received: June 7, 2013
Last Updated: July 18, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Rhode Island Hospital:
treprostinil
pulmonary hypertension, tadalafil

Additional relevant MeSH terms:
Hypertension, Pulmonary
Hypertension
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases
Treprostinil
Tadalafil
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents

ClinicalTrials.gov processed this record on April 15, 2014