Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH) (EDITA)
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|ClinicalTrials.gov Identifier: NCT02290613|
Recruitment Status : Completed
First Posted : November 14, 2014
Results First Posted : April 30, 2020
Last Update Posted : April 30, 2020
|Condition or disease||Intervention/treatment||Phase|
|Systemic Sclerosis Pulmonary Hypertension||Drug: Ambrisentan Drug: Placebo||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||38 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)|
|Official Title:||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|
|Actual Study Start Date :||July 1, 2014|
|Actual Primary Completion Date :||November 27, 2017|
|Actual Study Completion Date :||December 31, 2017|
Experimental: 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).
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.
Ambrisentan and placebo will be administered orally with or without food intake.
Placebo Comparator: Placebo
Placebo tablet (one to two tablets corresponding to one to two verum tablets)
Other Name: Placebo tablet
- 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.
- Mean Pulmonary Arterial Pressure During Exercise Change From Baseline [ Time Frame: baseline, 6 months ]Determine whether exercise induced elevated mean pulmonary arterial pressure-values (>30 mmHg without left heart or severe lung disease or systemic arterial hypertension) can be reduced by ambrisentan 10 mg/die over 6 months.
- 6-Minute-walking Test [ Time Frame: baseline, 6 months ]
- Borg Dyspnea Index [ Time Frame: baseline, 6 months ]measured directly after 6 minute walking distance; The Borg dyspnea index is an standardized scale which reports the subjective feeling of exertion from 0 (no dyspnea) to 10 (maximal feeling of dyspnea).
- Quality of Life (SF-36) Questionnaire [ Time Frame: baseline, 6 months ]SF-36 Questionnaire; physical Summation score; All scores and subscores of the SF-36 questionnaire range from 0 (low quality of life) to 100 (high quality of life). The physical Summation score is a compound score including the physical dimensions of the SF-36.
- Lung Function [ Time Frame: baseline,6 months ]DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO))
- Lung Function [ Time Frame: baseline, 6 months ]DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO))
- Lung Function [ Time Frame: baseline, 6 months ]FVC (forced vital capacity)
- Lung Function [ Time Frame: baseline, 6 months ]FEV1 (forced expiratory volume in one second)
- Lung Function [ Time Frame: baseline, 6 months ]TLC (total lung capacity)
- Lung Function [ Time Frame: baseline, 6 months ]residual volume
- Echocardiography [ Time Frame: baseline, 6 months ]RA-area (right atrial area)
- Echocardiography [ Time Frame: baseline, 6 months ]RV-area (right ventricular area)
- Echocardiography [ Time Frame: baseline, 6 months ]TAPSE (tricuspid annular plane systolic excursion)
- Echocardiography [ Time Frame: baseline, 6 months ]sPAP (systolic pulmonary arterial pressure)
- WHO-functional Class [ Time Frame: baseline ]
The World Health Organization functional class includes four categories with
- Patients with Pulmonary Hypertension but without any resulting limitation of physical activity.
- Patients with Pulmonary Hypertension resulting in slight limitation of physical activity.
- Patients with Pulmonary Hypertension resulting in marked limitation of physical activity.
- Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms.
- Hemodynamics [ Time Frame: change from baseline to 6 months ]right atrial pressure
- Hemodynamics [ Time Frame: baseline, 6 months ]pulmonary vascular resistance
- Hemodynamics [ Time Frame: baseline, 6 months ]cardiac output (CO)
- Hemodynamics [ Time Frame: baseline, 6 months ]cardiac index (CI)
- Hemodynamics [ Time Frame: baseline , 6 months ]PAWP (pulmonary arterial wedge pressure)
- Hemodynamics [ Time Frame: baseline, 6 months ]venous oxygen saturation (SvO2)
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02290613
|Thoraxclinic at the University of Heidelberg|
|Heidelberg, Germany, 69126|
|Principal Investigator:||Ekkehard Grünig, MD||Thoraxclinic at the University of Heidelberg|