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

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

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.

Study Overview

• Status: Terminated
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Nilotinib; Drug: Placebo to nilotinib

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T6G 2B7
      • Novartis Investigative Site
• Germany
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Marburg, Germany, 35039
    • Novartis Investigative Site
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 120-752
      • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 119074
    • Novartis Investigative Site
  • Singapore, Singapore, 168752
    • Novartis Investigative Site
• Switzerland
  • Zurich, Switzerland, 8091
    • Novartis Investigative Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Novartis Investigative Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0391
      • Novartis Investigative Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Novartis Investigative Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Novartis Investigative Site
  • Tennessee
    • Nashville, Tennessee, United States, 37232-2573
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Nilotinib; 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; Nilotinib capsules for oral administration at 50 mg, 150 mg twice a day and 300 mg (2 capsules of 150 mg) twice a day.
PLACEBO_COMPARATOR: Placebo; Participants were assigned to receive placebo to nilotinib to match 50 mg and 150 mg capsules during 168 days.	Drug: Placebo to nilotinib; Placebo to nilotinib capsules for oral administration to match 50 mg, 150 mg and 300 mg capsules twice a day

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (ACTUAL): January 1, 2013
• Study Completion (ACTUAL): January 1, 2013

Study Registration Dates

• First Submitted: August 3, 2010
• First Submitted That Met QC Criteria: August 10, 2010
• First Posted (ESTIMATE): August 11, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): May 1, 2014
• Last Update Submitted That Met QC Criteria: April 14, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Nilotinib; Pulmonary Arterial Hypertension; 6MWD
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: CAMN107X2201; 2010-019883-36 (EUDRACT_NUMBER)