E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Arterial Hypertension (PAH) Class II or III patients remaining symptomatic despite at least one PAH-specific therapy. |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To evaluate the effect of nilotinib on pulmonary vascular resistance (PVR) compared to placebo after 24 weeks of therapy |
|
E.2.2 | Secondary objectives of the trial |
• To test the effect of nilotinib on 6 min walk distance (6MWD) relative to baseline and compared to placebo after 24 weeks of therapy in patients able to perform the test.
• Establish the safety and tolerability of nilotinib in patients with PAH including effects on QTc and platelet activation
• To test the effect of nilotinib on pulmonary vascular resistance relative to baseline after 24 weeks of therapy
• To test the effect of nilotinib on other hemodynamic parameters, including cardiac output/index (CO/CI), pulmonary artery pressure (PaP), pulmonary capillary wedge pressure (PCWP), systemic pressure (SAP) and resistance (SVR)
• To test the effect of nilotinib on time to clinical worsening (TTCW) compared to placebo
• To assess change in Borg dyspnea score during 6-min walk testing, with nilotinib as compared to placebo
• To assess the pharmacokinetics of nilotinib in this patient population
For list of Exploratory objectives, please refer to CAMN107X2201 protocol |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained before any assessment is performed
2. Male or female 18 years of age or older who are unable to bear children and females of child bearing potential not disqualified as per Exclusion Criterion 1 (below)
3. WHO Functional Class II or III
4. PVR > 800 dyn.s/cm5 at screening
5. A current diagnosis of Pulmonary Arterial Hypertension according to the Dana Point 2008 Meeting: WHO Diagnostic Group I, idiopathic or heritable (familial or sporadic) PAH, PAH associated with collagen vascular disease including systemic sclerosis, rheumatoid arthritis, mixed connective tissue diseases, and overlap syndrome. PAH following one year repair of congenital heart defect (ASD, VSD or PDA), or PAH associated with diet therapies or other drugs
6. Inadequate clinical response despite stabilization on one or more class(es) of PAH drug [e.g., PDE5 inhibitor, endothelin receptor blocker, vasodilator prostaglandin (systemic, inhaled or oral)]
7. Stabilization of pulmonary hypertension medications defined as observed for ≥ 2 months on approved therapeutic dose of at least one PAH drug and still symptomatic with WHO functional Class II or III performance. |
|
E.4 | Principal exclusion criteria |
1. Other diagnosis of PAH in WHO Diagnostic Group 1 including congenital systemic to
pulmonary shunts
2. A diagnosis of PAH associated with: venous hypertension (WHO Diagnostic Group II, including LVEF < 45%), hypoxia (WHO Diagnostic Group III), chronic pulmonary thromboembolic disease (WHO Diagnostic Group IV) or other miscellaneous causes (WHO Diagnostic Class V, which includes sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels, glycogen storage disease, Gaucher’s disease, myeloproliferative disorders)
3. Diagnosis of pulmonary artery or vein stenosis
4. Pre-existing lung disease including parasitic diseases affecting lungs, congenital abnormalities of the lungs, COPD, thorax or diaphragm or bronchial asthma
5. WHO Class IV
6. Previous therapeutic radiation of lungs or mediastinum
7. In treatment with chronic nitric oxide therapy
8. An advanced, severe, or unstable disease of any type that may interfere with the primary and secondary endpoint evaluations
9. Having undergone atrial septostomy in the 3 months prior to the screening visit
10. Previously undergone radiofrequency catheter ablation for atrial or sinus arrhythmias in the 3 months prior to screening visit
11. History of ventricular tachycardia, ventricular fibrillation or ventricular flutter
12. History of left-heart disease.
13. Atrial fibrillation or history of atrial fibrillation in the previous 3 months
14. Having syncope in the 3 months prior to the screening visit
15. History of previous myocardial infarction, unstable angina, or clinically significant bradycardia (<60 bpm and accompanied by clinical symptoms)
16. QRS > 120 ms or > 140 ms in the presence of bundle branch block
17. Current or history of consistently prolonged QTcF (2 or more ECGs in the prior 12 months in the absence of a right bundle branch block or QTcF>450 ms for males and > 470 ms for females at screening); family history of long QT syndrome
18. History of Torsades de Pointes
19. Use of drugs known to prolong the QT interval or known to be strong CYP3A4 inhibitors
20. Untreated or inadequately controlled hypokalemia (<3.5 mmol/L) or hypomagnesemia (<0.65 mmol/L) at the screening visit (Visit 1)
21. Uncontrolled systemic arterial hypertension, systolic > 160 mm Hg or diastolic >90 mm Hg
22. Evidence of clinically significant hepatic impairment
23. Diagnosis of Hepatitis B or C
24. Hemoglobin < 100 g/L (10 g/dL) at the screening visit (Visit 1)
25. History of sickle cell anemia
26. Deficient thrombocyte function, thrombocytopenia < 50 x109/L (50 x 103/μL)
27. Deficiencies of blood coagulation, inherited or acquired blood coagulation disorders, factor XII, factor XIII
28. Disseminated intravascular coagulation (DIC)
29. Evidence of major bleeding or intracranial hemorrhage
30. History of latent bleeding risk such as diabetic retinopathy, gastrointestinal bleeding due to gastric or duodenal ulcers, or colitis ulcerosa
31. History of elevated intracranial pressure
32. History of immunodeficiency diseases, including HIV
33. History of pancreatitis or serum amylase or lipase ≥ 1.5 x ULN at screening or baseline visits
34. Previous treatment with nilotinib
35. Use of other investigational drugs (including study drug) at the time of enrollment, of within 30 days or 5 half-lives of enrollment, whichever is longer
36. History of hypersensitivity to nilotinib or to drugs of similar chemical classes
37. Medically diagnosed symptomatic lactose intolerance.
38. Disability that may prevent the patient from completing all study requirements, with the exception of the 6MWT.
39. Life expectancy of 6 months or less
40. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases
41. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. UNLESS they are:
• women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner
• women whose partners have been sterilized by vasectomy or other means
• using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent
42. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test
43. History of alcohol abuse within 6 months of screening
44. History of illicit drug abuse within 6 months of screening |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Pulmonary vascular resistance (PVR) |
|
E.5.2 | Secondary end point(s) |
6 MWT (Minutes Walking Test)
Safety & Tolerability
Other hemodynamic parameters other than PVR
TTCW (Time to Clinical worsening)
Borg Dyspnea scale
Pharmacokinetics |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Germany |
Hungary |
Italy |
Korea, Republic of |
Singapore |
Switzerland |
United States |
|
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of the trial is defined in the protocol |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |