Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| GlaxoSmithKline | INDUSTRY |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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:
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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). |
|
| Placebo | Placebo Comparator | Placebo tablet |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Mean Pulmonary Arterial Pressure During Exercise Change From Baseline | 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. | baseline, 6 months |
Not provided
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Ekkehard Grünig, MD | Thoraxclinic at the University of Heidelberg | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Thoraxclinic at the University of Heidelberg | Heidelberg | 69126 | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 18506008 | Background | 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. | |
| 21545989 |
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | 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/die). 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/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake. |
| FG001 | Placebo | Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets) |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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/die). 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/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Posted | Mean | Standard Deviation | mmHg | baseline, 6 months |
|
adverse Events were collected throughout the study from baseline to the 6 month-assessment and 30 days follow-up.
Not provided
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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/die). 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/die. Administration: Ambrisentan and placebo will be administered orally with or without food intake. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Lower jaw fracture | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | Non-systematic Assessment |
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Dr. med. E. Grünig | Thoraxklinik Heidelberg gGmbH at Heidelberg University Hospital | +49 6221 396 | 8053 | ekkehard.gruenig@med.uni-heidelberg.de |
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 29, 2016 | Dec 18, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 12, 2018 | Dec 18, 2019 | SAP_001.pdf |
Not provided
| ID | Term |
|---|---|
| D012595 | Scleroderma, Systemic |
| D006976 | Hypertension, Pulmonary |
| ID | Term |
|---|---|
| D003240 | Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D012871 | Skin Diseases |
| D008171 | Lung Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| C467894 | ambrisentan |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
|
|
| Placebo | Drug | Placebo tablet (one to two tablets corresponding to one to two verum tablets) |
|
|
| 6-Minute-walking Test |
| baseline, 6 months |
| Borg Dyspnea Index | 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). | baseline, 6 months |
| Quality of Life (SF-36) Questionnaire | 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. | baseline, 6 months |
| Lung Function | DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO)) | baseline,6 months |
| Lung Function | DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO)) | baseline, 6 months |
| Lung Function | FVC (forced vital capacity) | baseline, 6 months |
| Lung Function | FEV1 (forced expiratory volume in one second) | baseline, 6 months |
| Lung Function | TLC (total lung capacity) | baseline, 6 months |
| Lung Function | residual volume | baseline, 6 months |
| Echocardiography | RA-area (right atrial area) | baseline, 6 months |
| Echocardiography | RV-area (right ventricular area) | baseline, 6 months |
| Echocardiography | TAPSE (tricuspid annular plane systolic excursion) | baseline, 6 months |
| Echocardiography | sPAP (systolic pulmonary arterial pressure) | baseline, 6 months |
| WHO-functional Class | The World Health Organization functional class includes four categories with
| baseline |
| Hemodynamics | right atrial pressure | change from baseline to 6 months |
| Hemodynamics | pulmonary vascular resistance | baseline, 6 months |
| Hemodynamics | cardiac output (CO) | baseline, 6 months |
| Hemodynamics | cardiac index (CI) | baseline, 6 months |
| Hemodynamics | PAWP (pulmonary arterial wedge pressure) | baseline , 6 months |
| Hemodynamics | venous oxygen saturation (SvO2) | baseline, 6 months |
| 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. |
| 31655622 | Derived | 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. |
| BG001 | Placebo | Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets) |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Type of SSc | Count of Participants | Participants |
|
| OG001 | Placebo | Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets) |
|
|
| Secondary | Mean Pulmonary Arterial Pressure During Exercise Change From Baseline | 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. | Posted | Mean | Standard Deviation | mmHg | baseline, 6 months |
|
|
|
| Secondary | 6-Minute-walking Test | Posted | Mean | Standard Deviation | meters | baseline, 6 months |
|
|
|
| Secondary | Borg Dyspnea Index | 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). | Posted | Mean | Standard Deviation | units on a scale | baseline, 6 months |
|
|
|
| Secondary | Quality of Life (SF-36) Questionnaire | 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. | Posted | Mean | Standard Deviation | units on a scale | baseline, 6 months |
|
|
|
| Secondary | Lung Function | DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO)) | Posted | Mean | Standard Deviation | % of target value | baseline,6 months |
|
|
|
| Secondary | Lung Function | DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO)) | Posted | Mean | Standard Deviation | mmol/min/kPa | baseline, 6 months |
|
|
|
| Secondary | Lung Function | FVC (forced vital capacity) | Posted | Mean | Standard Deviation | % of target | baseline, 6 months |
|
|
|
| Secondary | Lung Function | FEV1 (forced expiratory volume in one second) | Posted | Mean | Standard Deviation | Litres | baseline, 6 months |
|
|
|
| Secondary | Lung Function | TLC (total lung capacity) | Posted | Mean | Standard Deviation | Litres | baseline, 6 months |
|
|
|
| Secondary | Lung Function | residual volume | Posted | Mean | Standard Deviation | Litres | baseline, 6 months |
|
|
|
| Secondary | Echocardiography | RA-area (right atrial area) | Posted | Mean | Standard Deviation | cm^2 | baseline, 6 months |
|
|
|
| Secondary | Echocardiography | RV-area (right ventricular area) | Posted | Mean | Standard Deviation | cm^2 | baseline, 6 months |
|
|
|
| Secondary | Echocardiography | TAPSE (tricuspid annular plane systolic excursion) | Posted | Mean | Standard Deviation | cm | baseline, 6 months |
|
|
|
| Secondary | Echocardiography | sPAP (systolic pulmonary arterial pressure) | Posted | Mean | Standard Deviation | mmHg | baseline, 6 months |
|
|
|
| Secondary | WHO-functional Class | The World Health Organization functional class includes four categories with
| Posted | Count of Participants | Participants | baseline |
|
|
|
| Secondary | Hemodynamics | right atrial pressure | Posted | Mean | Standard Deviation | mmHg | change from baseline to 6 months |
|
|
|
| Secondary | Hemodynamics | pulmonary vascular resistance | Posted | Mean | Standard Deviation | Wood Units | baseline, 6 months |
|
|
|
| Secondary | Hemodynamics | cardiac output (CO) | Posted | Mean | Standard Deviation | L/min | baseline, 6 months |
|
|
|
| Secondary | Hemodynamics | cardiac index (CI) | Posted | Mean | Standard Deviation | L/min/m^2 | baseline, 6 months |
|
|
|
| Secondary | Hemodynamics | PAWP (pulmonary arterial wedge pressure) | Posted | Mean | Standard Deviation | mmHg | baseline , 6 months |
|
|
|
| Secondary | Hemodynamics | venous oxygen saturation (SvO2) | Posted | Mean | Standard Deviation | % saturation | baseline, 6 months |
|
|
|
| 0 |
| 19 |
| 1 |
| 19 |
| 17 |
| 19 |
| EG001 | Placebo | Placebo tablet Placebo: Placebo tablet (one to two tablets corresponding to one to two verum tablets) | 0 | 19 | 5 | 19 | 17 | 19 |
| Angina Pectoris | Cardiac disorders | Non-systematic Assessment |
|
| Coronary artery disease | Cardiac disorders | Non-systematic Assessment |
|
| Gastrointestinal infection | Gastrointestinal disorders | Non-systematic Assessment |
|
| Lymphangitis | Blood and lymphatic system disorders | Non-systematic Assessment |
|
| Raynaud | Musculoskeletal and connective tissue disorders | Non-systematic Assessment |
|
| Edema | Cardiac disorders | Non-systematic Assessment |
|
| Dizziness | Nervous system disorders | Non-systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Non-systematic Assessment |
|
| Paraesthesia | Nervous system disorders | Non-systematic Assessment |
|
| Coronary artery disease | Cardiac disorders | Non-systematic Assessment |
|
| arterial hypotension | Cardiac disorders | Non-systematic Assessment |
|
| Epistaxis | Vascular disorders | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | Non-systematic Assessment |
|
Not provided
Not provided
| D012140 | Respiratory Tract Diseases |
| D006973 | Hypertension |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |