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

• Register: EUCTR
• Last refreshed on: 9 December 2013
• Main ID: EUCTR2010-019883-36-DE
• Date of registration: 13/05/2011
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A 24 week, randomized, double blind, multicenter, placebo-controlled efficacy, safety, tolerability and PK trial of Nilotinib (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 (AMN107) in Pulmonary Arterial Hypertension (PAH)
• Date of first enrolment: 13/10/2011
• Target sample size: 55
• 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

Canada, Germany, Hungary, Italy, Korea, Republic of, Singapore, Switzerland, United States

Contacts

• Name: Medical Competence Center
• Affiliation: Novartis Pharma GmbH

• Name: Medical Competence Center
• Affiliation: Novartis Pharma GmbH

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. 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.
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 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

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 i

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: 14.1 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Intervention(s)

Trade Name: Tasigna® 150 mg

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: 150-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Name: Nilotinib 50 mg
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)

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 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

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 Outcome(s)

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

Secondary ID(s)

2010-019883-36-HU

CAMN107X2201

Source(s) of Monetary Support

Novartis Pharma Services AG