Biomarkers in Pulmonary Arterial Hypertension Treated With Nilotinib

The investigators hypothesize that bone marrow progenitor cells are mobilized into the circulation in PAH, home to the lungs and differentiate into mast cells, which promote vascular remodeling and vasoconstriction through release of renin and chymase. As a corollary to this, the investigators hypothesize that anti cKit tyrosine kinase inhibitor (TKI), nilotinib, provides clinical benefit to patients through inhibition of mast cell progenitor proliferation, mobilization and differentiation. To test this, the investigators will determine if mast cell progenitors and mast cell biomarkers are related to nilotinib clinical response. This will be an ancillary study, part of a placebo-controlled, double-blind multi center clinical trial of nilotinib in pulmonary arterial hypertension.

Study Overview

• Status: Withdrawn
• Conditions: PAH

• Study Type: Observational

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Patients diagnosed with PAH that are enrolled in the Nilotinib clinical trial. http://clinicaltrials.gov/ct2/show/NCT01179737?term=tasigna+and+pulmonary+hypertension&rank=1

Description

Inclusion Criteria:

This study is a substudy and subjects must be enrolled in the main trial:

See Study Efficacy, Safety, Tolerability and Pharmacokinetics (PK) of Nilotinib (AMN107) in Pulmonary Arterial Hypertension (PAH) In clinical trials. (clinical Trial ID NCT01179737)

http://clinicaltrials.gov/ct2/show/NCT01179737?

Exclusion Criteria:

Subjects are not enrolled in the main study:

See Study Efficacy, Safety, Tolerability and Pharmacokinetics (PK) of Nilotinib (AMN107) in Pulmonary Arterial Hypertension (PAH) In clinical trials. (clinical Trial ID NCT01179737)

http://clinicaltrials.gov/ct2/show/NCT01179737?term=tasigna+and+pulmonary+hypertension&rank=1

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Subjects with PAH treated with nilotinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measuring circulating markers of Nilotinib affect	We will measure markers of mast cell activation in blood and urine before and during treatment with nilotinib.	within one year of the end of the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate effect of Nilotinib on the activation of mast cells.	We will measure markers of mast cell activation in blood and urine before and during treatment with nilotinib. We will also look at the proliferation of mast cell progenitors and correlate this to clinical markers used to monitor this disease.	within one year of the end of the study

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Investigators: Principal Investigator: Kewal Asosingh, Ph.D, The Cleveland Clinic

Publications and helpful links

General Publications

• Patterson KC, Weissmann A, Ahmadi T, Farber HW. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension. Ann Intern Med. 2006 Jul 18;145(2):152-3. doi: 10.7326/0003-4819-145-2-200607180-00020. No abstract available.
• Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005 Oct;115(10):2811-21. doi: 10.1172/JCI24838.
• Dentelli P, Rosso A, Balsamo A, Colmenares Benedetto S, Zeoli A, Pegoraro M, Camussi G, Pegoraro L, Brizzi MF. C-KIT, by interacting with the membrane-bound ligand, recruits endothelial progenitor cells to inflamed endothelium. Blood. 2007 May 15;109(10):4264-71. doi: 10.1182/blood-2006-06-029603. Epub 2007 Feb 8.
• Heath D, Yacoub M. Lung mast cells in plexogenic pulmonary arteriopathy. J Clin Pathol. 1991 Dec;44(12):1003-6. doi: 10.1136/jcp.44.12.1003.
• Hamada H, Terai M, Kimura H, Hirano K, Oana S, Niimi H. Increased expression of mast cell chymase in the lungs of patients with congenital heart disease associated with early pulmonary vascular disease. Am J Respir Crit Care Med. 1999 Oct;160(4):1303-8. doi: 10.1164/ajrccm.160.4.9810058.

Helpful Links

• See Study: Efficacy, Safety, Tolerabilitiy and PK of AMN 107 in PAH

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (ACTUAL): December 1, 2012
• Study Completion (ACTUAL): December 1, 2012

Study Registration Dates

• First Submitted: March 18, 2011
• First Submitted That Met QC Criteria: March 21, 2011
• First Posted (ESTIMATE): March 23, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): February 4, 2014
• Last Update Submitted That Met QC Criteria: February 3, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Other Study ID Numbers: Novartis AMN-107