A 24 week, randomized, double blind, multicenter, placebo-controlled efficacy, safety, tolerability and PK trial of Nilotinib (Tasigna®, AMN107) in Pulmonary Arterial Hypertension (PAH)

• Register: EUCTR
• Last refreshed on: 10 July 2012
• Main ID: EUCTR2010-019883-36-HU
• Date of registration: 08/07/2010
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma AG
• Public title: A 24 week, randomized, double blind, multicenter, placebo-controlled efficacy, safety, tolerability and PK trial of Nilotinib (Tasigna®, AMN107) in Pulmonary Arterial Hypertension (PAH)
• Scientific title: A 24 week, randomized, double blind, multicenter, placebo-controlled efficacy, safety, tolerability and PK trial of Nilotinib (Tasigna®, AMN107) in Pulmonary Arterial Hypertension (PAH)
• Date of first enrolment: 31/08/2010
• Target sample size: 66
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2010-019883-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Germany, Hungary

Key inclusion & exclusion criteria

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. 6MWD = 150 m and = 450 m at screening. Distances of two consecutive 6MWTs should be within 15% of one another
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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. UNLESS they are:
a)women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner
b)women whose partners have been sterilized by vasectomy or other means
c)using two birth control methods.
2. Pregnant or nursing (lactating) women
3. History of ventricular tachycardia, ventricular fibrillation or ventricular flutter
4. Use of drugs known to prolong the QT interval or known to be strong CYP3A4 inhibitors
5. Untreated or inadequately controlled hypokalemia or hypomagnesemia at Visit 1
6. Evidence of clinically significant left ventricular dysfunction.
7. Evidence of clinically significant hepatic impairment
8. Atrial fibrillation or history of atrial fibrillation in the previous 3 months
9. Having syncope in the 3 months prior to the screening visit
10. History of previous myocardial infarction or unresolved ischemia
11. QRS > 120 ms or > 140 ms in the presence of bundle branch block
12. Current or history of long QT syndrome or QTc > 450 ms for males and > 470 ms for females at screening or baseline
13. WHO Class IV
14. History of Torsades de Pointes
15. In treatment with chronic nitric oxide therapy
16. Pre-existing lung disease
17. With a pulmonary capillary wedge pressure > 15 mm Hg to rule out PAH secondary to left ventricular dysfunction
18. Diagnosis of pulmonary artery or vein stenosis
19. With other diagnosis of PAH in WHO Diagnostic Group 1 are excluded
20. With a diagnosis of PAH associated with venous hypertension, hypoxia, chronic pulmonary thromboembolic disease or other miscellaneous causes
21. Thrombocytopenia < 50 x109/L (50 x 103/µL)
22. History of acute left sided heart failure or chronic left sided heart failure present at screening
23. Uncontrolled systemic arterial hypertension, systolic > 160 mm Hg or diastolic >90 mm Hg
24. Hemoglobin < 100 g/L (10 g/dL) at the screening visit (Visit 1)
25. Deficiencies of blood coagulation, inherited or acquired blood coagulation disorders, factor XII, factor XIII; decreased generation of coagulation factors due to acute or chronic liver diseases, efficient coagulation due to auto-antibodies against coagulation factors such as in lupus anticoagulant
26. Disseminated intravascular coagulation
27. Evidence of major bleeding or intracranial hemorrhage
28. History of elevated intracranial pressure
29. History of latent bleeding risk
30. Previous therapeutic radiation of lungs or mediastinum
31. History of sickle cell anemia
32. Having undergone atrial septostomy in the 3 months prior to the screening visit
33. Previously undergone radiofrequency catheter ablation for atrial or sinus arrhythmias in the 3 months prior to screening visit
34. An advanced, severe, or unstable disease of any type that may interfere with the primary and secondary endpoint evaluations
35. History of immunodeficiency diseases, including HIV
36. History of pancreatitis.
37. History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes
38. Disability that may prevent the patient from completing all study requirements
39. Life expectancy of 6 months or less
40. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
41. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years
42. D

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension (PAH) Class II or III patients remaining symptomatic despite at least one PAH-specific therapy.
MedDRA version: 12.1 Level: LLT Classification code 10064911 Term: Pulmonary arterial hypertension

Intervention(s)

Trade Name: Tasigna®
Product Name: Tasigna
Product Code: AMN107
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: nilotinib
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: nilotinib
Product Code: AMN107
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: nilotinib
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: Nilotinib
Product Code: AMN107
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: nilotinib
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: • To evaluate the effect of nilotinib on pulmonary vascular resistance (PVR) compared to placebo after 24 weeks of therapy

Primary end point(s): Pulmonary vascular resistance (PVR)

Secondary Objective: • To test the effect of nilotinib on 6 min walk distance (6MWD) relative to baseline and compared to placebo after 24 weeks of therapy
• 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

Secondary ID(s)

CAMN107X2201