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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
Sponsor:
Collaborator:
GlaxoSmithKline
Information provided by (Responsible Party):
Prof. Dr. med. Ekkehard Gruenig, Heidelberg University

Tracking Information
First Submitted Date  ICMJE October 31, 2014
First Posted Date  ICMJE November 14, 2014
Results First Submitted Date  ICMJE December 18, 2019
Results First Posted Date  ICMJE April 30, 2020
Last Update Posted Date April 30, 2020
Actual Study Start Date  ICMJE July 1, 2014
Actual Primary Completion Date November 27, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 17, 2020)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 10, 2014)
Mean pulmonary arterial pressure change from baseline [ Time Frame: baseline, 6 months ]
Determine whether mPAP 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 17, 2020)
  • 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
    1. Patients with Pulmonary Hypertension but without any resulting limitation of physical activity.
    2. Patients with Pulmonary Hypertension resulting in slight limitation of physical activity.
    3. Patients with Pulmonary Hypertension resulting in marked limitation of physical activity.
    4. 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: November 10, 2014)
  • Mean pulmonary arterial pressure during exercise change from baseline [ Time Frame: baseline, 6 months ]
    Determine whether exercise induced elevated mPAP-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 , 3 months , 6 months ]
  • Borg Dyspnea Index [ Time Frame: baseline , 3 months , 6 months ]
    measured directly after 6 minute walking distance
  • Quality of life (SF-36) Questionnaire [ Time Frame: baseline , 3 months , 6 months ]
  • Lung function [ Time Frame: baseline ,3 months ,6 months ]
    DLCo
  • Lung function [ Time Frame: baseline ,3 months ,6 months ]
    DLCo/VA
  • Lung function [ Time Frame: baseline ,3 months ,6 months ]
    FVC
  • Lung function [ Time Frame: baseline ,3 months ,6 months ]
    FEV1
  • Lung function [ Time Frame: baseline ,3 months ,6 months ]
    TLC
  • Lung function [ Time Frame: baseline ,3 months ,6 months ]
    residual volume
  • Echocardiography [ Time Frame: baseline ,3 months , 6 months ]
    RA-area
  • Echocardiography [ Time Frame: baseline ,3 months , 6 months ]
    RV-area
  • Echocardiography [ Time Frame: baseline ,3 months , 6 months ]
    Tei
  • Echocardiography [ Time Frame: baseline ,3 months , 6 months ]
    TAPSE
  • Echocardiography [ Time Frame: baseline ,3 months , 6 months ]
    sPAP
  • WHO-functional class [ Time Frame: baseline , 3 months, 6 months ]
  • Raynaud-syndrome and skin involvement, assessed by the modified Rodnan-Skin score and Symptoms of Scleroderma [ Time Frame: baseline ,3 months, 6 months ]
  • Hemodynamics [ Time Frame: baseline , 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
  • Hemodynamics [ Time Frame: baseline , 6 months ]
    venous oxygen saturation (SvO2)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Early Treatment of Borderline Pulmonary Arterial Hypertension Associated With Systemic Sclerosis (SSc-APAH)
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Systemic Sclerosis
  • Pulmonary Hypertension
Intervention  ICMJE
  • Drug: 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.

    Other Names:
    • Volibris
    • ATC code: C02KX02
  • Drug: Placebo
    Placebo tablet (one to two tablets corresponding to one to two verum tablets)
    Other Name: Placebo tablet
Study Arms  ICMJE
  • 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).
    Intervention: Drug: Ambrisentan
  • Placebo Comparator: Placebo
    Placebo tablet
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 10, 2014)
38
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE December 31, 2017
Actual Primary Completion Date November 27, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02290613
Other Study ID Numbers  ICMJE 2014-05ED
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Prof. Dr. med. Ekkehard Gruenig, Heidelberg University
Study Sponsor  ICMJE Heidelberg University
Collaborators  ICMJE GlaxoSmithKline
Investigators  ICMJE
Principal Investigator: Ekkehard Grünig, MD Thoraxclinic at the University of Heidelberg
PRS Account Heidelberg University
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP