Impact-Cteph

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Trial duration

14 Jun 2021 → 3 Jul 2025

Decision date (initial)

2024-11-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-513672-17-00

EudraCT number

2020-004546-11

ClinicalTrials.gov

NCT04780932

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To compare the effect of an initial dual oral treatment (riociguat, macitentan) vs. standard-of-care initial oral monotherapy (riociguat, placebo) on pulmonary vascular resistance (PVR) prior to BPA in newly diagnosed and treatment-naïve subjects with inoperable CTEPH

Secondary objectives 3

1. To compare the effect of an initial dual oral treatment (riociguat, macitentan) vs. standard-of-care initial oral monotherapy (riociguat, placebo) on : - The change in other clinical measures of pulmonary hypertension prior to BPA - The change in other clinical measures of pulmonary hypertension after potential BPA - Pulmonary vascular resistance after potential BPA - The rate of BPA procedure-related complications - The disease progression. - Quality of life
2. To analyse the safety profile of an initial dual oral treatment (riociguat, macitentan)
3. To analyse health economics aspects of an initial dual oral treatment (riociguat, macitentan)

Conditions and MedDRA coding

Inoperable Chronic thromboembolic pulmonary hyperTension

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Signed informed consent
2. Male or female ≥18 and ≤ 80 years of age at inclusion
3. Newly diagnosed and treatment-naïve subjects with CTEPH judged as inoperable due to surgically inaccessible lesions but eligible for balloon pulmonary angioplasty, riociguat and macitentan by multidisciplinary team assessment and fulfilling the following criteria: a. Symptomatic pulmonary hypertension (PH) in WHO FC ≥ II. b. Confirmation of diagnosis based on 2 of the 3 following methods: i. Ventilation-perfusion lung scan ii. Digital subtraction pulmonary angiography (DSA) iii. CT pulmonary angiography (CTPA)
4. Confirmation of inoperability based on CTPA scan and/or DSA
5. Right-heart catheterization (RHC) in the 12-week period prior to screening visit or during screening period showing the following: a. Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg b. Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg or left ventricular end diastolic pressure ≤ 15 mmHg c. PVR at rest ≥ 400 dyn.sec.cm-5
6. Subject anticoagulated (with either vitamin K antagonists or direct oral anticoagulants [e.g., factor IIa inhibitors, factor Xa inhibitors]), or treated with unfractionated heparin or low molecular weight heparin for at least 3 months prior to baseline RHC.
7. 6MWD ≥ 50m
8. Women of childbearing potential must: a. Have a negative pre-treatment serum pregnancy test b. Agree to use reliable contraception from screening up to 1 month following discontinuation of the last study treatment.

Exclusion criteria 26

1. Previous pulmonary endarterectomy
2. Previous balloon pulmonary angioplasty
3. Any PAH-targeted therapy (e.g., any endothelin receptor antagonist (ERA), phosphodiesterase-5 inhibitor (PDE-5i), soluble guanylate cyclase stimulator, prostacyclin, prostacyclin analog, or prostacyclin receptor agonist) at any time prior to inclusion.
4. Ongoing or planned treatment with organic nitrates
5. Known moderate-to-severe restrictive lung disease (i.e., total lung capacity < 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second [FEV1] < 60% of predicted, with FEV1 / forced vital capacity < 65%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema).
6. Symptomatic coronary artery disease requiring nitrate use or intervention (e.g., Percutaneous Coronary Intervention, Coronary Artery Bypass Graft) anticipated in the 6-month period after inclusion.
7. Acute myocardial infarction ≤ 12 weeks prior to inclusion.
8. Left heart failure with an ejection fraction less than 40%.
9. Cerebrovascular events (e.g., transient ischemic attack, stroke) ≤ 12 weeks prior to inclusion.
10. History of life-threatening hemoptysis (>100 mL in 24 h) or subjects who have previously undergone bronchial arterial embolization for hemoptysis.
11. Hemoglobin < 100 g/L.
12. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 × upper limit of the normal range.
13. Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 × upper limit of the normal range (ULN) accompanied by aspartate aminotransferase (AST) > ULN; and/or Child-Pugh Class C.
14. Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m²).
15. Systolic blood pressure <95mmHg.
16. Treatment with strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., rifabutin, rifampicin, carbamazepine, phenobarbital, phenytoin, St. John’s wort) ≤ 28 days prior to inclusion.
17. Treatment with strong multi pathway P-glycoprotein (P-gp)/ breast cancer resistance protein (BCRP) inhibitors (e.g., lopinavir/ritonavir) ≤ 28 days prior to inclusion
18. Treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or a moderate dual CYP3A4/CYP2C9 inhibitor (e.g., fluconazole, amiodarone) or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors ≤ 28 days prior to inclusion.
19. Known hypersensitivity to riociguat or macitentan or to any excipient of their formulation.
20. History of severe allergic-like reaction to intravascular administration of iodinated contrast media (including diffuse edema or facial edema with dyspnea, diffuse erythema with hypotension, laryngeal edema with stridor and/or hypoxia, bronchospasm, anaphylactic shock with hypotension and tachycardia).
21. Subject who cannot remain in a supine position for at least 120 min for any reason.
22. Pregnancy, breastfeeding, or intention to become pregnant during the study.
23. Subjects with underlying medical disorders and anticipated life expectancy < 12 months (eg active cancer disease with localized and/or metastasized tumor mass).
24. Alcohol abuse (at investigator discretion).
25. Subject not covered by social security service.
26. Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Pulmonary vascular resistance (PVR) at rest at week 16 expressed as a percentage of the baseline resting PVR.

Secondary endpoints 7

1. Change from baseline to week 16 in : - 6-min walk distance (6MWD) - World Health Organisation (WHO) functional class (FC) and Borg dyspnea score - N-terminal pro-brain natriuretic peptide (NT-proBNP) level - Quality of life EQ-5D-3L scale.
2. Change from baseline to week 42 in : - 6MWD - WHO FC and Borg dyspnea score - NT proBNP level - Quality of life EQ-5D-3L scale.
3. Change from baseline to week 42 in PVR.
4. Percentage of subjects reaching PVR<240 dyn.sec.cm-5 at week 42.
5. Frequency and type of BPA procedure-related complications from BPA procedure to end-of-study.
6. Time from randomization to the first PH-related disease progression event up to end-of-study, defined as any of the following : - Death (all causes) - Need for lung transplantation - Hospitalization due to PH - Initiation of parenteral prostanoid therapy due to PH-related disease progression - Clinical worsening defined as a post-baseline decrease in 6MWD by ≥ 15 % combined with WHO FC III or IV).
7. Change from baseline to week 29 in : - 6MWD - WHO FC and Borg dyspnea score - NT proBNP level - Quality of life EQ-5D-3L scale.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Xavier Jais

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Christine Pereira

Locations

1 EU/EEA country · 26 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications