Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)

Phase 4

Terminated

• Conditions: Pulmonary Arterial Hypertension
• Interventions: Drug: macitentan; Drug: tadalafil

• Registration Number: NCT02968901
• Lead Sponsor: Actelion

Brief Summary

The purpose of the study is to document the effect of first line dual oral combination therapy with macitentan 10mg and tadalafil 40mg on pulmonary vascular resistance (PVR) in treatment-naïve patients with newly diagnosed pulmonary arterial hypertension (PAH).

Detailed Description

Not available

Study Timeline

• Study Start: 2015-09-01
• Study First Submitted: 2016-11-14
• Study First Submitted QC: 2016-11-17
• Study First Posted: 2016-11-21
• Primary Completion: 2018-09-10
• Study Completion: 2018-09-10
• Status Verified: 2019-10
• Last Update Submitted: 2019-10-04
• Last Update Posted: 2019-10-08

Recruitment & Eligibility

• Status: TERMINATED
• Sex: All
• Target Recruitment: 46

Inclusion Criteria

Not provided

Exclusion Criteria

1. Any PAH-specific drug therapy [e.g. any endothelin receptor antagonist, phosphodiesterase-5 inhibitors (PDE-5i), soluble guanylate cyclase stimulator, prostacyclin, prostacyclin analog, or prostacyclin receptor agonist] at any time prior to Day 1 (single-dose administration for vasoreactivity testing is permitted; previous iloprost used intermittently for the treatment of digital ulcers or Raynaud's phenomenon is permitted if stopped > 6 months prior to Day 1).

2. Subjects who changed the dose or discontinued calcium channel blockers within 1 week prior to Day 1.

3. Initiation of diuretics within 1 week prior to RCH.

4. Subjects on oral diuretics in whom the dose has not been stable for at least 1 week prior to RHC.

5. Treatment with other PDE-5i for erectile dysfunction.

6. Treatment with strong inducers of CYP3A4 (e.g., carbamazepine, rifampin, rifampicin, rifabutin, rifapentin, phenobarbital, phenytoin, and St. John's wort) ≤ 28 days prior to Day 1.

7. Treatment with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, boceprevir, telaprevir, saquinavir, lopinavir, fosamprenavir, darunavir, tipranavir, atazanavir, nelfinavir, amprenavir, indinavir) ≤ 28 days prior to Day 1.

8. History of priapism.

9. Significant aortic and mitral valve disease requiring a specific treatment.

10. Pericardial constriction.

11. Life-threatening arrhythmia.

12. Uncontrolled hypertension.

13. Symptomatic coronary artery disease.

14. Cardio-pulmonary rehabilitation program based on exercise (planned, or started ≤ 12 weeks prior to Day 1).

15. Body mass index (BMI) > 40 kg/m2 at screening.

16. Acute myocardial infarction ≤ 12 weeks prior to Day 1.

17. Known permanent atrial fibrillation.

18. Low blood pressure < 90/50 mmHg at screening or Day 1.

19. Ongoing or planned treatment with nitrates and/or doxazosin.

20. DLCO < 40% of predicted value (eligible only if no sign of veno-occlusive disease according to adjudication committee);

21. Presence of ≥ 1 of the following signs of relevant lung disease at any time prior to Day 1:

    • FEV1/FVC < 70% and FEV1 < 65% of predicted after bronchodilator administration;
    • Total Lung Capacity (TLC) < 60% of predicted.

22. Known or suspicion of pulmonary veno-occlusive disease (PVOD).

23. Severe renal insufficiency (estimated creatinine clearance ≤ 30 mL/min/1.73m²) assessed by central laboratory at screening.

24. Ongoing or planned dialysis.

25. Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin > 3 x ULN accompanied by AST > ULN (assessed by central laboratory at screening) and/or Child-Pugh Class C.

26. Serum AST and/or ALT > 3 x ULN (assessed by central laboratory at screening).

27. Porto-pulmonary hypertension.

28. Hemoglobin < 100 g/L assessed by central laboratory at screening.

29. Hypersensitivity to any active substance or excipient of macitentan or tadalafil formulation.

30. Loss of vision in one eye because of non-arteritic anterior ischemic optic neuropathy (NAION), regardless of whether or not this episode was in connection with previous PDE-5i exposure.

31. Hereditary degenerative retinal disorders, including retinitis pigmentosa.

32. Pregnancy, breast-feeding, intention to become pregnant during the study or woman of childbearing potential not agree to use reliable method of contraception from screening up to 30 days after EOT2.

33. Hereditary problems of galactose intolerance, Lapp lactase deficiency, glucosegalactose malabsorption.

34. Any factor or condition likely to affect protocol compliance of the patient as judged by the investigator.

35. Treatment with another investigational drug (planned, or taken ≤ 12 weeks prior to Day 1).

36. Concomitant life-threatening disease with a life expectancy < 12 months.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
bitherapy	macitentan	Macitentan and tadalafil
bitherapy	tadalafil	Macitentan and tadalafil

Primary Outcome Measures

Name	Time	Method
pulmonary vascular resistance (PVR)	16 weeks	Change from Baseline to Week 16 in percentage of patients with clinically meaningful improvement of PVR (decrease of 30% from baseline to Week 16)

Secondary Outcome Measures

Name	Time	Method
6MWD	Week 16	Change from Baseline to Week 16 in 6MWD
level NT-proBNP	Week 16	Change in NT-proBNP from baseline to Week 16
mean pulmonary arterial pressure (mPAP)	Week 16	Change from Baseline to Week 16 in mean pulmonary arterial pressure (mPAP)
cardiac index (CI)	Week 16	Change from Baseline to Week 16 in cardiac index (CI).
mixed venous oxygen saturation (Sv02)	Week 16	Change from Baseline to Week 16 in mixed venous oxygen saturation (Sv02)
mean right atrial pressure (mRAP)	Week 16	Change from Baseline to Week 16 in mean right atrial pressure (mRAP)
WHO functional class	Week 16	Change from baseline to Week 16 in WHO functional class and Percentage of patients with improvement/worsening of WHO functional class from baseline to Week 16
total pulmonary resistance (TPR)	Week 16	Change from Baseline to Week 16 in total pulmonary resistance (TPR)
Number of treatment goals	Week 16	Number of treatment goals (score 0 or 1 per goal, i.e. total score 0-5) met at Week 16: WHO-FC I or II; Cardiac index \> 2.8 L/min/m²; mRAP \< 8 mmHg; 6MWD \> 400 m; NT-proBNP \< 3xULN

Trial Locations

Locations (18)

Hôpital de Haut Levêque; 🇫🇷 Bordeaux, France

CHU Site du Bocage; 🇫🇷 Dijon, France

Hôpital Louis Pradel; 🇫🇷 Lyon, France

Hôpital Arnaud de Villeneuve; 🇫🇷 Montpellier, France

Hôpital Robert Debré; 🇫🇷 Reims, France

Hôpital Bretonneau; 🇫🇷 Tours, France

Hôpital Jean Minjoz; 🇫🇷 Besançon, France

Hôpital Côte de Nacre; 🇫🇷 Caen, France

Hôpital Albert Michallon; 🇫🇷 Grenoble, France

Hôpital Bicètre; 🇫🇷 Le Kremlin-Bicêtre, France

Hôpital Timone Adultes; 🇫🇷 Marseille, France

Hôpital Pontchaillou; 🇫🇷 Rennes, France

Hôpital Charles Nicolle; 🇫🇷 Rouen, France

Hôpital Dupuytren; 🇫🇷 Limoges, France

CHR La Miletrie; 🇫🇷 Poitiers, France

Hôpital Nord; 🇫🇷 Saint-Priest-en-Jarez, France

Hôpital Larrey; 🇫🇷 Toulouse, France

Hôpital Civil; 🇫🇷 Strasbourg, France