Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH) A Randomized, Controlled, Double-blind, Parallel Group, Proof-of-concept Trial EDITA
Overview
- Phase
- Phase 2
- Intervention
- Ambrisentan
- Conditions
- Systemic Sclerosis
- Sponsor
- Heidelberg University
- Enrollment
- 38
- Locations
- 1
- Primary Endpoint
- Mean Pulmonary Arterial Pressure Change From Baseline
- Status
- Completed
- Last Updated
- 6 years ago
Overview
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.
Investigators
Prof. Dr. med. Ekkehard Gruenig
Prof. Dr. med. Ekkehard Grünig
Heidelberg University
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •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.
- •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.
- •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)
Arms & Interventions
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).
Intervention: Ambrisentan
Placebo
Placebo tablet
Intervention: Placebo
Outcomes
Primary Outcomes
Mean Pulmonary Arterial Pressure Change From Baseline
Time Frame: baseline, 6 months
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.
Secondary Outcomes
- WHO-functional Class(baseline)
- Borg Dyspnea Index(baseline, 6 months)
- Lung Function(baseline, 6 months)
- Hemodynamics(baseline, 6 months)
- Echocardiography(baseline, 6 months)
- 6-Minute-walking Test(baseline, 6 months)
- Quality of Life (SF-36) Questionnaire(baseline, 6 months)
- Mean Pulmonary Arterial Pressure During Exercise Change From Baseline(baseline, 6 months)