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

NCT ID: NCT02290613

Last Updated: 2020-04-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-07-01
• Study Completion Date: 2017-12-31

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.

Detailed Description

Treatment naïve patients with SSc-APAH will be included in the investigator initiated trial (IIT) to assess efficacy and safety of ambrisentan. As patients life-expectancy after diagnosis of untreated patients is only one year we put forward a screening to identify borderline PAH patients and treat them before PH manifests. Therapy with ambrisentan reached a significant improvement in SSc-IPAH patients (Galiè et al. 2008). In PAH mPAP improved about 15% due to ambrisentan (Klinger et al. 2011).

Thus, especially patients with SSc-APAH have a high need for an early diagnosis and therapy. It is important to determine factors predictive of incident SSc-APAH and PH as well as the event rate of PAH and PH occurrence. Early identification and intervention with specific modern therapies as with ambrisentan may improve hemodynamic, symptoms, exercise capacity, quality of life and outcomes in this patient population, in particular in SSc-patients of borderline-PAH. It is considered reasonable that the development of manifest APAH might be preventable in this defined population with SSc and early pulmonary vascular changes. A reliable trial testing this latter hypothesis cannot be performed without critical evidence which defines the response to medical PAH-targeted therapy in borderline-PAH and the associated disease progression of manifest PAH.

Due to the positive results in the treatment of patients with SSc-APAH, the initiation of this proof-of-concept study is justified.

Previously identified patients with borderline PAH indicated by borderline mPAP values will be included in this single centre randomized, controlled, double-blind, parallel group, proof-of-concept (PoC) phase IIa IIT. If assessments necessary for screening have already been made under the screening for PH in Systemic sclerosis trial (non-drug trial, Ethics committee of Heidelberg # S360/2009), these examinations may be used for screening for this trial, as long as they have been performed within the given time frame of the screening period.

On their first visit the patients' 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 during exercise and right heart catheterization will be carried out. If patients fulfill the inclusion criteria and still suffer from borderline mPAP values they will be invited to join the study. Patients will be asked to sign the informed consent form (ICF) before the initial screening will be conducted. Randomization will be performed after a maximum of 28 days and medication or placebo will be provided. If patients have been identified within the last 6 months before baseline by right heart catheterization, the measurements are considered valid for the baseline visit to spare patients a repetition of this invasive procedure. Non-invasive measurements that are out of the time-frame have to be repeated for the study. An 1:1 oral ambrisentan: oral Placebo randomization will be performed.

Patients will be randomized into either:

• A treatment arm with ambrisentan treatment (19 patients)
• A placebo arm (19 patients will receive placebo). Safety and tolerability will be controlled at each study visit until the end of study (day 180 ± 2 weeks). If necessary, the dose will be adapted. As to common practice of the clinic, the patient will adapt the dose according to tolerability and after consultation (by phone or personally) with one of the investigators.

Conditions

Systemic Sclerosis; Pulmonary Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Ambrisentan Verum

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).

Group Type: EXPERIMENTAL

Ambrisentan

Intervention Type: 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.

Placebo

Placebo tablet

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

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

Interventions

Ambrisentan

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.

Intervention Type: DRUG

Placebo

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

Intervention Type: DRUG

Other Intervention Names

Volibris; ATC code: C02KX02; Placebo tablet

Eligibility Criteria

Inclusion Criteria

1. mPAP 21-24 mmHg, TPG > 11mmHg, PAWP <15 mmHg and/or

2. 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

3. Adult patients having completed his/her 18th birthday

4. Patients with definite diagnosis of Systemic Sclerosis using the scleroderma criteria of the American Rheumatism Association

5. SSc-disease duration >3 years

6. Able to understand and willing to sign the Informed Consent Form

7. Negative pregnancy test at the start of the trial and appropriate contraception throughout the study for women with child-bearing potential.

Exclusion Criteria

1. Any connective tissue diseases (CTD) other than SSc

2. Pulmonary hypertension (PH) confirmed by right heart catheter (RHC) before enrolment, i.e. mPAP ≥25 mmHg at rest

3. 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

4. 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.

5. Except for diuretics and corticosteroids medical treatment should not be expected to change 4 weeks prior inclusion into the study and during the entire 12-week study period.

6. Known intolerance to ambrisentan or one of its excipients

7. Clinically significant anemia (hemoglobin concentration of less than 75% of the lower limit of normal, LLN)

8. Forced vital capacity (FVC) <60%, forced expiratory volume in first second (FEV1) <65%

9. Severe interstitial lung disease, idiopathic pulmonary fibrosis

10. Renal insufficiency (glomerular filtration rate [GFR] <60 mL/min/1.73m2 for at least 3 months)

11. Baseline values of hepatic aminotransferases (ALT and/or AST) >3 x upper limit of normal (ULN)

12. Systolic blood pressure <85 mmHg;

13. evidence of inadequately treated blood pressure >160/90 mmHg and/or blood pressure during exercise >220/120 mmHg

14. Patients referred with clinically significant overt heart failure

15. Clinically significant fluid retention

16. 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)

17. Known significant diastolic dysfunction associated with clinical heart failure

18. Known coronary disease or significant valvular heart disease

19. Known congenital heart defects such as single ventricle, transposition, Eisenmenger

20. Known hypertrophic cardiomyopathy or left ventricular hypertrophy (interventricular septum thickness (IVS) or posterior wall thickness (PWD) >1.2 cm)

21. Participation in any clinical drug trial within 4 weeks prior to screening of this study and/or who is scheduled to receive another investigational medicinal product (IMP) during the course of this study

22. Pregnancy or lactation

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: collaborator

Heidelberg University

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dr. med. Ekkehard Gruenig

Prof. Dr. med. Ekkehard Grünig

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ekkehard Grünig, MD

Role: PRINCIPAL_INVESTIGATOR

Thoraxclinic at the University of Heidelberg

Locations

Thoraxclinic at the University of Heidelberg

Heidelberg, , Germany

Countries

Germany

References

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.

Reference Type: BACKGROUND

PMID: 18506008 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21545989 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 31655622 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2014-05ED

Identifier Type: -

Identifier Source: org_study_id