A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis

NCT01042158 | Completed Phase 4 Results DMC

• 2 other identifiers: TAD-PH-001P50HL084946
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

This will be a 36-week, single group, open label study assessing the effects of Tadalafil plus Ambrisentan combination therapy in patients with pulmonary arterial hypertension associated with the scleroderma spectrum of disease (PAH-SSD). Standard outcome measures such as six-minute walk distance (6MWD), New York heart Association (NYHA) classification, and hemodynamic measurements will be assessed, as well as novel functional measures of RV-PV function including the transthoracic echocardiogram parameter tricuspid annular plane systolic ejection (TAPSE), contrast-enhanced cardiac MRI and heart rate variability assessed by Holter monitoring. This design (excluding a placebo arm) was selected for ethical concerns and to provide optimal efficiency and active therapy to all study subjects. It also allows for comparisons between the two monotherapies and with combination therapy.

Conditions

Pulmonary Arterial Hypertension; Systemic Sclerosis; Scleroderma Spectrum of Diseases; Connective Tissue Disease; Pulmonary Hypertension

Keywords

Tadalafil; Ambrisentan; Quality of Life

Outcome Measures

Primary Outcomes (2)

• Right Ventricular (RV) Mass

  Assessment of change in Right ventricular mass was done via standard volumetric cine images of the right heart at baseline and comparing it to that at the end of 36 weeks using Cardiac Magnetic Resonance Imaging studies.

  baseline and 36 weeks

• Pulmonary Vascular Resistance (PVR)

  Change in Pulmonary Vascular Resistance (PVR) was ascertained via Right Heart Catheterization (RHC) measurement of the difference between the PVR at baseline and 36 weeks

  baseline 36 weeks

Secondary Outcomes (2)

• Tricuspid Annular Plane Systolic Excursion (TAPSE)

  baseline and 36 weeks

• 6-minute Walk Distance

  baseline and 36 weeks

Study Arms (1)

Tadalafil and ambrisentan upfront therapy

OTHER

This will be a 36-week, single group, open label study assessing the effects of Tadalafil plus Ambrisentan combination therapy in patients with pulmonary arterial hypertension associated with the scleroderma spectrum of disease (PAH-SSD).

Drug: tadalafil and ambrisentan upfront combination therapy

Interventions

tadalafil and ambrisentan upfront combination therapy DRUG

tadalafil 20 mg qd and ambrisentan 5 mg qd. Up-titration of study medications will occur at week 4 (ambrisentan 10 mgs daily and tadalafil 40 mg qd). If a subject experiences an intolerable adverse event as a result of an uptitration in the study drug dose, the dose of study drug maybe down titrated to 20 mg of tadalafil and/or 5mg of ambrisentan. If the subject is still experiencing an intolerable adverse event, then the investigator will withdraw the subject from the study.

Also known as: Adcirca, Letairis

Tadalafil and ambrisentan upfront therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A right heart catheterization done at baseline with a mean pulmonary artery pressure (mPAP) ≥ 25mmHg, pulmonary artery wedge pressure (PAWP) ≤ 15mmHg, and pulmonary vascular resistance (PVR) ≥3 Woods units.
• Scleroderma defined as systemic sclerosis with diffuse or limited scleroderma meeting the American College of Rheumatology (ACR) criteria (33). Cases will be included if they meet clinical features that satisfy ACR criteria for a diagnosis of scleroderma or the presence of three of five features of the CREST syndrome are identified; or there is the presence of definite Raynaud's phenomenon, abnormal nail fold capillaries typical of scleroderma and the presence of a specific scleroderma related auto-antibody. Limited skin involvement is defined as skin tightening distal to elbows and knees with or without facial involvement; and diffuse skin involvement, tightening proximal to these joints or truncal involvement.
• Subjects will be older than 18 years of age with a diagnosis of PAH-SSc.
• Subjects will be NYHA functional class II or III.
• minute walk distance ≥ 100 meters and ≤ 500 meters at screening and baseline.
• Negative urine pregnancy test for women of childbearing age at screening and baseline visits.
• Ability and willingness to provide written informed consent

You may not qualify if:

• Right heart catheterization reveals evidence of pulmonary venous hypertension (pulmonary capillary wedge pressure \> 15 mm Hg).
• Significant chronic obstructive: Forced expiratory volume in 1 second to forced expiratory volume ratio \< 70% and a forced expiratory volume in 1 second less than 60% of predicted.
• Interstitial lung disease
• Based on a combination of pulmonary function tests and chest radiography.
• Patients will be excluded if they have a total lung capacity less than 60% of predicted and included if the total lung capacity was ≥ 70%. Patients with a total lung capacity between 60 and 70% of predicted are included if their computed tomography scan demonstrates only minimal interstitial fibrosis
• Portal hypertension.
• Severe obstructive sleep apnea.
• Chronic thromboembolic disease.
• Positive antibodies to the human immunodeficiency virus.
• History of anorexigen use including fen-phen.
• Any other disease known to be associated with pulmonary hypertension.
• Subjects with other etiology for pulmonary hypertension besides PAH-SSc.
• Subjects with liver function abnormalities (ALT or Aspartate Aminotransferase (AST) \> 3 times the upper limit of normal at screening or at baseline) or chronic liver disease.
• Advanced kidney failure (GFR \< 30 ml/min at screening or at baseline).
• Acute decompensation of underlying illness or hospitalization for pulmonary hypertension within 4 weeks prior to enrollment.

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Institutes of Health (NIH): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Eli Lilly and Company: collaborator
• United Therapeutics: collaborator
• The Cleveland Clinic: collaborator
• University of Texas: collaborator
• Stanford University: collaborator

Study Sites (1)

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Related Publications (2)

• Sato T, Ambale-Venkatesh B, Lima JAC, Zimmerman SL, Tedford RJ, Fujii T, Hulme OL, Pullins EH, Corona-Villalobos CP, Zamanian RT, Minai OA, Girgis RE, Chin K, Khair R, Damico RL, Kolb TM, Mathai SC, Hassoun PM. The impact of ambrisentan and tadalafil upfront combination therapy on cardiac function in scleroderma associated pulmonary arterial hypertension patients: cardiac magnetic resonance feature tracking study. Pulm Circ. 2018 Jan-Mar;8(1):2045893217748307. doi: 10.1177/2045893217748307. Epub 2017 Dec 18.

  PMID: 29251556 DERIVED

• Hassoun PM, Zamanian RT, Damico R, Lechtzin N, Khair R, Kolb TM, Tedford RJ, Hulme OL, Housten T, Pisanello C, Sato T, Pullins EH, Corona-Villalobos CP, Zimmerman SL, Gashouta MA, Minai OA, Torres F, Girgis RE, Chin K, Mathai SC. Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2015 Nov 1;192(9):1102-10. doi: 10.1164/rccm.201507-1398OC.

  PMID: 26360334 DERIVED

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Scleroderma, Systemic; Connective Tissue Diseases; Hypertension, Pulmonary

Interventions

Tadalafil; ambrisentan

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Skin and Connective Tissue Diseases; Skin Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Limitations and Caveats

1. An open-label study with no placebo group 2. Relatively small number of patients and therefore vulnerable to confounding natural history with treatment effects 3. Measurements performed at four different institutions 4. Few missing data

Results Point of Contact

• Title: Paul Hassoun, MD
• Organization: Johns Hopkins University

phassoun@jhmi.edu

410-614-5158

Study Officials

• Paul Hassoun, MD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2010
• First Posted: January 5, 2010
• Study Start: January 1, 2010
• Primary Completion: November 1, 2014
• Study Completion: November 1, 2014
• Last Updated: September 12, 2017
• Results First Posted: September 12, 2017

Record last verified: 2017-08

Locations

US (1)