Pulmonary Hypertension and Imatinib

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Kewal Asosingh, Ph.D, The Cleveland Clinic
ClinicalTrials.gov Identifier:
NCT01092897
First received: March 24, 2010
Last updated: February 3, 2014
Last verified: February 2014
  Purpose

The purpose of the study is to determine whether circulating molecular and cellular biomarkers are predictive of imatinib effect on pulmonary artery hypertension.


Condition
PAH

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Biomarkers in Pulmonary Arterial Hypertension Treated With Imatinib

Resource links provided by NLM:


Further study details as provided by The Cleveland Clinic:

Primary Outcome Measures:
  • Measuring circulating biomarkers of imatinib affect [ Time Frame: within one year of the end of the study ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Evaluate effect of imatinib on the activation of mast cells [ Time Frame: within one year of the end of the study ] [ Designated as safety issue: No ]

Estimated Enrollment: 130
Study Start Date: March 2010
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Groups/Cohorts
Subjects with PAH treated with Imatinib

Detailed Description:

We 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, we hypothesize that anti cKit tyrosine kinase inhibitor (TKI), imatinib, provides clinical benefit to patients through inhibition of mast cell progenitor proliferation, mobilization and differentiation. To test this, we will determine if mast cell progenitors and mast cell biomarkers are related to imatinib clinical response. This will be an ancillary study, part of a placebo-controlled, double-blind multi center clinical trial of imatinib in pulmonary arterial hypertension.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

Patients diagnosed with PAH that are enrolled in the Imatinib clinical trial.

Criteria

Inclusion Criteria:

from Imatinib Trial

  • Male or Female 18 years or older
  • A current diagnosis or 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
  • A PVR>1000dynes.sec.cm-5(as assess by RHC at screening or in the 2 months preceding the screening visit despite treatment with two or more specific PAH therapies, including endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5), or inhaled, intravenous or oral prostacyclin analogues for ≥3 months. On stable background therapy doses for ≥ 30 days except for warfarin (≥30 days but doses can vary even within the mouth before enrollment)
  • WHO Functional Class II-IV. For WHO Functional Class IV, one of the 2 or more specific PAH therapies must be an inhaled, intravenous or oral prostacyclin analogue, unless the subject has been shown to be intolerant of prostacyclin analogues.
  • 6MWD≥150meters and ≥450meters at screening. Distances of two consecutive 6MWTs should be within 15% of one another.
  • Ability to provide written informed consent

Exclusion Criteria: from Imatinib Trial

  • Women of childbearing potential who are not practicing birth control methods.
  • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of positive hCG laboratory test (> 5 mIU/MI)
  • Have previously received treatment with imatinib
  • In treatment with chronic nitric oxide therapy
  • Pre-existing lung disease including parasitic diseases affecting lungs, congenital abnormalities of the lungs, thorax or diaphragm or bronchial asthma associated with chronic hypoxia that may contribute to severity of PAH
  • With a pulmonary capillary wedge pressure >15 mm Hg to rule out PAH secondary to left ventricular dysfunction
  • With a diagnosis of pulmonary artery or vein stenosis
  • With other diagnosis of PAH in WHO Diagnostic Group 1 re excluded including congenital systemic to pulmonary shunts (large, small that not surgically repaired, portal hypertension, HIV infection, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopthaies, myeloproliferative disorders)
  • With a diagnosis of 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, lympangiomatosis, compression of pulmonary vessels).
  • With deficient thrombocyte function, thrombocytopenia >50x109/L(50x103/µL)
  • With a history of acute heart failure or chronic left sided heart failure
  • With uncontrolled systemic arterial hypertension, systolic >160mmHg or diastolic >90mmHg
  • With hemoglobin <100g/L (10 g/dl)
  • With deficiencies of blood coagulation, inherited or acquired blood 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
  • With disseminated intravascular coagulation (DIC)
  • With evidence of major bleeding or intracranial hemorrhage
  • With a history of latent bleeding risk such as diabetic retinopathy, gastrointestinal bleeding due to gastric or duodenal ulcers, or colitis ulcerosa
  • With a history of moderate or greater hepatic insufficiency transaminase levels >4times the upper limit or normal or a bilirubin >2times the upper limit of normal
  • With a history of renal insufficiency (serum creatinine >200µmol/1or 2.6mg/dl)
  • Previous therapeutic radiation of lungs mediastinum
  • With a history of sickle cell anemia
  • With a QTcF>450msec for males and >470 msec for females at screening
  • With a history of ventricular tachycardia, ventricular fibrillation or ventricular flutter
  • Having syncope in the 3 months prior to the screening visit
  • With a history of Torsades de Pointes
  • With a history of long QT syndrome
  • Having undergone atrial septostomy in the 3 months prior to screening visit
  • Having undergone radiofrequency catheter ablation for atrial or sinus arrhythmias in the 3 months prior to screening visit
  • With an advanced, sever, or unstable disease of any type that may interfere with the primary and secondary endpoint evaluations
  • With a history of immunodeficiency diseases, including HIV
  • With a known hypersensitivity to QTI571 or drugs similar to the study drug
  • With a disability that may prevent the patient from competing all study requirements and in particular, interfere with the 6MWT assessment
  • With a life expectancy of 6months or less
  • Having used other investigational drugs at the time of enrollment, within 30 days or 5 half-lives of enrollment, whichever is longer
  • With a history of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
  • With a diagnosis of Hepatitis B or C
  • With a history of alcohol abuse within 6 months of screening
  • With a history of illicit drug abuse within 6 months of screening
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01092897

Locations
United States, Colorado
University of Colorado Denver
Aurora, Colorado, United States
United States, Florida
Cleveland Clinic Florida
Weston, Florida, United States
United States, Maryland
Johns Hopkins
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
United States, Texas
UT Southwestern Medical Center of Dallas
Dallas, Texas, United States, 75390-8550
Sponsors and Collaborators
The Cleveland Clinic
Investigators
Principal Investigator: Kewal Asosingh, M.S., Ph.D The Cleveland Clinic
  More Information

Publications:
Responsible Party: Kewal Asosingh, Ph.D, Associate Staff, The Cleveland Clinic
ClinicalTrials.gov Identifier: NCT01092897     History of Changes
Other Study ID Numbers: 09-782
Study First Received: March 24, 2010
Last Updated: February 3, 2014
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Imatinib
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 19, 2014