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Systemic SclerosisPhase 2EDITANCT02290613

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

A Phase 2 study testing Ambrisentan in people with Systemic Sclerosis and Pulmonary Hypertension, run by Heidelberg University at 1 site in Germany.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Systemic Sclerosis, Pulmonary Hypertension
What is being tested?
Ambrisentan
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
38 participants
Where
1 siteGermany
Study dates
1 Jul 2014to 31 Dec 2017
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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
Show all 22Show fewer
  • 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)
  • Baseline values of hepatic aminotransferases (ALT and/or AST) >3 x upper limit of normal (ULN)
  • Systolic blood pressure <85 mmHg;
  • evidence of inadequately treated blood pressure >160/90 mmHg and/or blood pressure during exercise >220/120 mmHg
  • Patients referred with clinically significant overt heart failure
  • Clinically significant fluid retention
  • 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)
  • Known significant diastolic dysfunction associated with clinical heart failure
  • Known coronary disease or significant valvular heart disease
  • Known congenital heart defects such as single ventricle, transposition, Eisenmenger
  • Known hypertrophic cardiomyopathy or left ventricular hypertrophy (interventricular septum thickness (IVS) or posterior wall thickness (PWD) >1.2 cm)
  • 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
  • Pregnancy or lactation

Trial locations and contacts

1 site in 1 country.

Germany1 site

  • Thoraxclinic at the University of Heidelberg

    Heidelberg, 69126

Other trials in Germany

About this study

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

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.

Read the 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.
Being tested
Ambrisentan, Placebo
Keywords
pulmonary hypertension, systemic sclerosis
Medical subject headings
Scleroderma, Systemic, Hypertension, Pulmonary

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AmbrisentanDrug

    Also called Volibris, ATC code: C02KX02

    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.

  • PlaceboDrug

    Also called Placebo tablet

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

Study groups in NCT02290613
Study groupRoleWhat they receive
Ambrisentan VerumExperimentalStudy medication will be ambrisentan 10 mg (starting with 5 mg in the beginning of the study and then up-titrated to 10 mg/day).
Receives: Drug: Ambrisentan
PlaceboPlacebo comparatorPlacebo tablet
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: baseline, 6 months

Secondary outcomes (21)

  1. 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.

    Measured: baseline, 6 months

  2. 6-Minute-walking Test

    Measured: baseline, 6 months

  3. 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).

    Measured: baseline, 6 months

  4. 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.

    Measured: baseline, 6 months

  5. Lung Function

    DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO))

    Measured: baseline,6 months

  6. Lung Function

    DLCo (diffusing capacity or transfer factor of the lung for carbon monoxide (CO))

    Measured: baseline, 6 months

  7. Lung Function

    FVC (forced vital capacity)

    Measured: baseline, 6 months

  8. Lung Function

    FEV1 (forced expiratory volume in one second)

    Measured: baseline, 6 months

  9. Lung Function

    TLC (total lung capacity)

    Measured: baseline, 6 months

  10. Lung Function

    residual volume

    Measured: baseline, 6 months

  11. Echocardiography

    RA-area (right atrial area)

    Measured: baseline, 6 months

  12. Echocardiography

    RV-area (right ventricular area)

    Measured: baseline, 6 months

  13. Echocardiography

    TAPSE (tricuspid annular plane systolic excursion)

    Measured: baseline, 6 months

  14. Echocardiography

    sPAP (systolic pulmonary arterial pressure)

    Measured: baseline, 6 months

  15. WHO-functional Class

    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.

    Measured: baseline

  16. Hemodynamics

    right atrial pressure

    Measured: change from baseline to 6 months

  17. Hemodynamics

    pulmonary vascular resistance

    Measured: baseline, 6 months

  18. Hemodynamics

    cardiac output (CO)

    Measured: baseline, 6 months

  19. Hemodynamics

    cardiac index (CI)

    Measured: baseline, 6 months

  20. Hemodynamics

    PAWP (pulmonary arterial wedge pressure)

    Measured: baseline , 6 months

  21. Hemodynamics

    venous oxygen saturation (SvO2)

    Measured: baseline, 6 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Nov 2014 (estimated)
  2. Study start1 Jul 2014
  3. Primary completion27 Nov 2017
  4. Study completion31 Dec 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
38 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02290613
Sponsor's protocol ID
2014-05ED
Acronym
EDITA
Status last verified
Apr 2020
First submitted
31 Oct 2014
Last updated
30 Apr 2020
Data monitoring committee
No

Publications

  • 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.

    PubMed 18506008

  • 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.

    PubMed 21545989

  • 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.

    PubMed 31655622

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ambrisentan in people with Systemic Sclerosis and Pulmonary Hypertension, run by Heidelberg University at 1 site in Germany.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Apr 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Apr 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mean Pulmonary Arterial Pressure Change From Baseline (time frame: baseline, 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02290613, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Apr 2020; AzTrials last refreshed its copy on 8 Nov 2026.

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