Efficacy, Safety, Tolerability and Pharmacokinetics (PK) of Nilotinib (AMN107) in Pulmonary Arterial Hypertension (PAH)

Study Overview
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Brief Summary
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The purpose of this trial was to establish the safety, tolerability and PK of nilotinib in this population and to test the hypothesis that 6 months treatment with nilotinib will significantly reduce pulmonary artery resistance.

Detailed Description
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The purpose of this trial was to establish the safety, tolerability and PK of nilotinib in this population and to test the hypothesis that 6 months

Official Title
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A 24 Week, Randomized, Double Blind, Multicenter, Placebocontrolled Efficacy, Safety, Tolerability and PK Trial of Nilotinib (Tasigna®, AMN107) in Pulmonary Arterial Hypertension (PAH)

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Nilotinib
* Drug: Placebo to nilotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: World Health Organization (WHO) Functional Class II or III 6MWD ≥ 150 m and ≤ 450 m at screening Current diagnosis of PAH according to Dana Point 2008 Meeting Inadequate clinical response on one or more class(es) of PAH drug Stabilization of pulmonary hypertension medications for ≥ 2 months on approved therapeutic dose of at least one PAH drug and still symptomatic with WHO functional Class II or III performance. Exclusion Criteria: Women of child-bearing potential not practicing birth control In treatment with chronic nitric oxide therapy Pre-existing lung disease Use of drugs prolonging the QT interval or strong CYP3A4 inhibitors Long QT syndrome or QTc > 450 ms males; > 470 ms females. WHO Class IV Pulmonary capillary wedge pressure > 15 mm Hg Other diagnosis of PAH in WHO Diagnostic Group 1 PAH associated with: venous hypertension (WHO Diagnostic Group II), 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) Thrombocytopenia < 50 x109/L (50 x 103/µL) Uncontrolled systemic arterial hypertension, systolic > 160 mm Hg or diastolic >90 mm Hg Any advanced, severe, or unstable disease of any type that may interfere with the primary and secondary endpoint evaluations. Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib<br>Participants in cohort 1 were assigned to receive nilotinib 50 mg during 14 days, followed by 150 mg during 14 days, followed by 300 mg during 140 days. Participants in cohort 2 were assigned to receive nilotinib 300 mg during 168 days | Drug: Nilotinib<br>* Nilotinib capsules for oral administration at 50 mg, 150 mg twice a day and 300 mg (2 capsules of 150 mg) twice a day.<br>|
| Placebo Comparator: Placebo<br>Participants were assigned to receive placebo to nilotinib to match 50 mg and 150 mg capsules during 168 days. | Drug: Placebo to nilotinib<br>* Placebo to nilotinib capsules for oral administration to match 50 mg, 150 mg and 300 mg capsules twice a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pulmonary Vascular Resistance (PVR) | Change in pulmonary vascular resistance is measured via right heart catheter assessment according to local hospital procedures. It assesses several prognostic hemodynamic variables in pulmonary hypertension, including Pulmonary Vascular Resistance (PVR). Study was prematurely terminated and not powered for efficacy. | 168 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Six-Minute Walk Distance (6MWD) From Baseline | During standardized walk course participants are connected to a portable pulse oximeter via a finger probe and instructed to walk at a comfortable speed for as far as they could manage in 6 minutes. Study was prematurely terminated and efficacy data were not analyzed or summarized | Baseline, 168 days | 
| Total Number of Adverse Events and Serious Adverse Events | Adverse events were summarized by the number of patients having any adverse event overall and presented in the safety section. Study was prematurely terminated. | 168 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension, Nilotinib, 6MWD, Pulmonary Hypertension