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Treprostinil Combined With Tadalafil for Pulmonary Hypertension (T2)

Primary Purpose

Pulmonary Arterial Hypertension

Status
Terminated
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Tadalafil
Placebo
Sponsored by
Rhode Island Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring treprostinil, pulmonary hypertension, tadalafil

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Maine Medical Center
  • Tuft's New England Medical Center
  • Brigham & Womens Hospital
  • Saint Barnabas Health Care System, Newark Beth Israel Medical Center
  • Beth Israel Medical Center
  • Weill Cornell Medical Center
  • University of Rochester Medical Center
  • Rhode Island Hospital
  • Inova Fairfax Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Tadalafil

Placebo

Arm Description

first 4 weeks are for adjusting treprostinil dose, then Tadalafil 40mg daily for 12 weeks, Group is randomly chosen from entire cohort

first 4 weeks for adjusting treprostinil dose, then Placebo for 12 weeks

Outcomes

Primary Outcome Measures

All Cause Mortality
Adverse Events Are no Greater Than With Treprostinil Infusion Alone
WHO Functional Class Will Improve or Remain Stable
Hospitalizations

Secondary Outcome Measures

6 Minute Walking Distance Change Will Improve
Tei Index Change by Transthoracic Echocardiography
Plasma BNP (Brain Natriuretic Peptide)Level Change
Change From Baseline in Pulmonary Arterial Systolic Pressure (PASP)as Assessed by Transthoracic Echocardiography Using Doppler Ultrasound

Full Information

First Posted
February 16, 2011
Last Updated
July 18, 2013
Sponsor
Rhode Island Hospital
Collaborators
United Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT01302444
Brief Title
Treprostinil Combined With Tadalafil for Pulmonary Hypertension
Acronym
T2
Official Title
Randomized Placebo Controlled Trial of Treprostinil Infusion Combined With Oral Tadalafil or Placebo in Pulmonary Arterial Hypertension
Study Type
Interventional

2. Study Status

Record Verification Date
April 2012
Overall Recruitment Status
Terminated
Why Stopped
One subject enrolled and completed this study. The study was stopped due to poor recruitment.
Study Start Date
March 2011 (undefined)
Primary Completion Date
March 2012 (Actual)
Study Completion Date
March 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Rhode Island Hospital
Collaborators
United Therapeutics

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension
Keywords
treprostinil, pulmonary hypertension, tadalafil

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
1 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tadalafil
Arm Type
Active Comparator
Arm Description
first 4 weeks are for adjusting treprostinil dose, then Tadalafil 40mg daily for 12 weeks, Group is randomly chosen from entire cohort
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
first 4 weeks for adjusting treprostinil dose, then Placebo for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Tadalafil
Other Intervention Name(s)
Adcirca
Intervention Description
Tadalafil 40mg for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
sugar pill
Intervention Description
Placebo for 12 weeks
Primary Outcome Measure Information:
Title
All Cause Mortality
Time Frame
16 weeks
Title
Adverse Events Are no Greater Than With Treprostinil Infusion Alone
Time Frame
16 weeks
Title
WHO Functional Class Will Improve or Remain Stable
Time Frame
16 weeks
Title
Hospitalizations
Time Frame
16 weeks
Secondary Outcome Measure Information:
Title
6 Minute Walking Distance Change Will Improve
Time Frame
16 weeks of therapy
Title
Tei Index Change by Transthoracic Echocardiography
Time Frame
16 weeks of therapy
Title
Plasma BNP (Brain Natriuretic Peptide)Level Change
Time Frame
16 weeks of therapy
Title
Change From Baseline in Pulmonary Arterial Systolic Pressure (PASP)as Assessed by Transthoracic Echocardiography Using Doppler Ultrasound
Time Frame
16 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult patients 18-80 years of age World Health Organization Group 1 PAH Idiopathic PAH Heritable PAH PAH associated with connective tissue disease PAH associated with surgical repair of congenital left to right shunt PAH associated with anorectic drug use WHO functional Class III-IV 6 minute walking distance > 150-meters and < 450 meters 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: 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) Concomitant use of nitrates (any form) either regularly or intermittently. Concomitant use of potent CYP3A inhibitors (e.g., ritonavir, ketoconazole, itraconazole) Vascular disease of the retina including retinitis pigmentosa, any sudden vision loss, including any damage to the optic nerve or NAION low blood pressure or high blood pressure that is not controlled Postural hypotension Inability to manage home infusion therapy Pulmonary vasodilator therapy with any phosphodiesterase inhibitor or endothelin receptor antagonist within 30 days of study entry Participation in a clinical investigational study within previous 30 days Renal failure defined as: estimated creatinine clearance < 30 ml/min serum creatinine > 2.5 mg/dl 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 History of hypersensitivity reaction or adverse effect related to tadalafil Life expectancy < 12 months History of deformed penis shape, an erection that lasted more than 4 hours, or Peyronie's disease. Blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia Pregnant or planning to become pregnant or breast feed.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
James R Klinger, MD
Organizational Affiliation
Rhode Island Hospital
Official's Role
Study Director
Facility Information:
Facility Name
Maine Medical Center
City
Portland
State/Province
Maine
ZIP/Postal Code
04102
Country
United States
Facility Name
Tuft's New England Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02111
Country
United States
Facility Name
Brigham & Womens Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Saint Barnabas Health Care System, Newark Beth Israel Medical Center
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07112
Country
United States
Facility Name
Beth Israel Medical Center
City
new York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
Facility Name
Weill Cornell Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
University of Rochester Medical Center
City
Rochester
State/Province
New York
ZIP/Postal Code
14642
Country
United States
Facility Name
Rhode Island Hospital
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02903
Country
United States
Facility Name
Inova Fairfax Hospital
City
Falls Church
State/Province
Virginia
ZIP/Postal Code
22042
Country
United States

12. IPD Sharing Statement

Links:
URL
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2515411/
Description
treprostinil

Learn more about this trial

Treprostinil Combined With Tadalafil for Pulmonary Hypertension

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