Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH)

NCT02290613 | Completed Phase 2 Results

• 1 other identifier: 2014-05ED
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

Trial Design Patients with borderline PAH indicated by borderline mPAP values will be included in this single centre study. This clinical investigation is performed as a Proof-of-Concept (PoC) investigator initiated trial (IIT) using a prospective, randomized, double-blind, parallel group, placebo-controlled, phase IIA clinical study design. On their first visit their medical history will be obtained and physical examination will be conducted. Moreover, an electrocardiogram (ECG), laboratory testing (NT-proBNP, uric acid and other laboratory tests), echocardiography at rest and right heart catheterization will be carried out. If patients have been identified within the last 6 months before screening investigations by right heart catheterization, the measurements are considered valid as baseline investigations and will not be repeated. If patients fulfill the inclusion criteria and still suffer from borderline mPAP values they will be invited to join the study. The clinical investigations will begin within 28 days. The prospective study will comprise a 6 months study period (180 ±2 weeks) plus the screening phase up to 28 days and a follow-up phase of 30 ±7 days.

Conditions

Systemic Sclerosis; Pulmonary Hypertension

Keywords

pulmonary hypertension; systemic sclerosis

Outcome Measures

Primary Outcomes (1)

• Mean Pulmonary Arterial Pressure Change From Baseline

  Determine whether mean pulmonary arterial pressure of SSc patients with borderline - PAH (mPAP 21 24 mmHg, TPG \>11 mmHg) can be reduced by 3 mm Hg (absolute change baseline vs. 6 months; equals 15%) following treatment with ambrisentan 10 mg/die (initiated with 5 mg/die and elevated up to 10 mg/die) over 6 months (primary endpoint) compared to baseline and placebo.

  baseline, 6 months

Secondary Outcomes (21)

• Mean Pulmonary Arterial Pressure During Exercise Change From Baseline

  baseline, 6 months

• 6-Minute-walking Test

  baseline, 6 months

• Borg Dyspnea Index

  baseline, 6 months

• Quality of Life (SF-36) Questionnaire

  baseline, 6 months

• Lung Function

  baseline,6 months

Study Arms (2)

Ambrisentan Verum

EXPERIMENTAL

Study medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/day).

Drug: Ambrisentan

Placebo

PLACEBO COMPARATOR

Placebo tablet

Drug: Placebo

Interventions

Ambrisentan DRUG

Titration: As common practice of the clinic, the patient will adapt the dose from 5 mg to 10 mg after 1 to 4 weeks according to tolerability and after consultation (by phone or personally) with one of the investigators. Additionally, at each study visit the investigator needs to decide, based on the patient's well-being, patients´ assessment, safety parameters, and tolerance of ambrisentan, if the study medication should be modified. The respective decision (increase, maintain or decrease dose) must be documented. Maximum dose allowed: not to exceed 10 mg/day. Administration: Ambrisentan and placebo will be administered orally with or without food intake.

Also known as: Volibris, ATC code: C02KX02

Ambrisentan Verum

Placebo DRUG

Placebo tablet (one to two tablets corresponding to one to two verum tablets)

Also known as: Placebo tablet

Placebo

Eligibility Criteria

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

You may qualify if:

• mPAP 21-24 mmHg, TPG \> 11mmHg, PAWP \<15 mmHg and/or
• Exercise induced elevated mPAP-values \>30 mmHg, PAWP \<18 mmHg; TPG \>15 mmHg, as defined in Saggar et al. (2012) without left heart or severe lung disease or systemic arterial hypertension
• Adult patients having completed his/her 18th birthday
• Patients with definite diagnosis of Systemic Sclerosis using the scleroderma criteria of the American Rheumatism Association
• SSc-disease duration \>3 years
• Able to understand and willing to sign the Informed Consent Form
• Negative pregnancy test at the start of the trial and appropriate contraception throughout the study for women with child-bearing potential.

You may not qualify if:

• Any connective tissue diseases (CTD) other than SSc
• Pulmonary hypertension (PH) confirmed by right heart catheter (RHC) before enrolment, i.e. mPAP ≥25 mmHg at rest
• Patients presenting normal mPAP values, that is mPAP\<21 mmHg at rest, ≤30 mmHg during exercise, PAWP \>=15 mmHg at rest or \<=18 mmHg during exercise
• Ongoing or a history of \>2 weeks of continued use of therapies that are considered definitive PH treatment: endothelin receptor antagonists (ERA; e.g. bosentan, ambrisentan), phosphodiesterase type 5 inhibitors (PDE5; e.g. sildenafil, tadalafil, vardenafil), prostanoids (e.g. epoprostenol, treprostinil, iloprost, beraprost) and soluble guanylate cyclase stimulator (e.g. Riociguat). Intermittent use of PDE5 inhibitors for male erectile dysfunction is permitted.
• Known intolerance to ambrisentan or one of its excipients
• Clinically significant anemia (hemoglobin concentration of less than 75% of the lower limit of normal, LLN)
• Forced vital capacity (FVC) \<60%, forced expiratory volume in first second (FEV1) \<65%
• Severe interstitial lung disease, idiopathic pulmonary fibrosis
• Renal insufficiency (glomerular filtration rate \[GFR\] \<60 mL/min/1.73m2 for at least 3 months)
• Baseline values of hepatic aminotransferases (ALT and/or AST) \>3 x upper limit of normal (ULN)
• Systolic blood pressure \<85 mmHg;
• evidence of inadequately treated blood pressure \>160/90 mmHg and/or blood pressure during exercise \>220/120 mmHg
• Patients referred with clinically significant overt heart failure
• Clinically significant fluid retention
• Previous evidence or diagnosis of clinically relevant left heart disease, i.e. at least one of the following: Previous echocardiography with estimated left ventricular (LV) ejection fraction \<50%, previous history of cardiogenic pulmonary edema, increased size of left atrium (\>50 mm)

Sponsors & Collaborators

• Heidelberg University: lead
• GlaxoSmithKline: collaborator

Study Sites (1)

Thoraxclinic at the University of Heidelberg

Heidelberg, 69126, Germany

Location

Related Publications (3)

• Galie N, Olschewski H, Oudiz RJ, Torres F, Frost A, Ghofrani HA, Badesch DB, McGoon MD, McLaughlin VV, Roecker EB, Gerber MJ, Dufton C, Wiens BL, Rubin LJ; Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group. Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. Circulation. 2008 Jun 10;117(23):3010-9. doi: 10.1161/CIRCULATIONAHA.107.742510. Epub 2008 May 27.

  PMID: 18506008 BACKGROUND

• Klinger JR, Oudiz RJ, Spence R, Despain D, Dufton C. Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension. Am J Cardiol. 2011 Jul 15;108(2):302-7. doi: 10.1016/j.amjcard.2011.03.037. Epub 2011 May 3.

  PMID: 21545989 BACKGROUND

• Pan Z, Marra AM, Benjamin N, Eichstaedt CA, Blank N, Bossone E, Cittadini A, Coghlan G, Denton CP, Distler O, Egenlauf B, Fischer C, Harutyunova S, Xanthouli P, Lorenz HM, Grunig E. Early treatment with ambrisentan of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: a randomized, controlled, double-blind, parallel group study (EDITA study). Arthritis Res Ther. 2019 Oct 26;21(1):217. doi: 10.1186/s13075-019-1981-0.

  PMID: 31655622 DERIVED

MeSH Terms

Conditions

Scleroderma, Systemic; Hypertension, Pulmonary

Interventions

ambrisentan

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Prof. Dr. med. E. Grünig
• Organization: Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital

ekkehard.gruenig@med.uni-heidelberg.de

+49 6221 396

Study Officials

• Ekkehard Grünig, MD

  Thoraxclinic at the University of Heidelberg

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med. Ekkehard Grünig

Study Record Dates

• First Submitted: October 31, 2014
• First Posted: November 14, 2014
• Study Start: July 1, 2014
• Primary Completion: November 27, 2017
• Study Completion: December 31, 2017
• Last Updated: April 30, 2020
• Results First Posted: April 30, 2020

Record last verified: 2020-04

Locations

DE (1)