Imatinib and Carvedilol for High Blood Pressure in the Lungs in Adults With Sickle Cell Disease

NCT01568645 | Withdrawn Phase 1

• 2 other identifiers: 12009312-H-0093
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Background: \- About one-tenth of adults with sickle cell disease have pulmonary hypertension (high blood pressure in the lungs). This condition can cause shortness of breath, pain crisis, and congestive heart failure. It may even lead to death. Researchers want to test the drugs imatinib and carvedilol to see if they can treat high blood pressure in the lungs. Both drugs have been used to treat other types of heart problems, but they have not been tested as a treatment for high blood pressure related to sickle cell disease. Objectives: \- To see if imatinib and carvedilol are safe and effective treatments for high blood pressure in the lungs in adults with sickle cell disease. Eligibility: \- Adults at least 18 years of age who have sickle cell disease and have or may have high blood pressure in the lungs. Design:

• Participants will be screened with a physical exam and medical history. They will also have different tests of heart and lung function, including a walking test and imaging studies. Blood and urine samples will also be collected.
• Participants who meet specific criteria will take one of two possible study drugs. Those who receive imatinib will take it daily. Those who receive carvedilol will take it twice a day.
• Participants will have weekly study visits for blood tests and other exams. The study drug dose will be adjusted at each weekly visit. It will be increased slowly to reach a target dose(based on the participant s weight) or to find a stable effective dose.
• Participants may continue to take their study drug for up to 24 weeks, with weekly study visits. Regular blood samples and heart and lung function tests will be performed.
• After 24 weeks, qualified participants may continue to take their study drug for up to 6 more months. They will have regular study visits to monitor the treatment.

Conditions

Pulmonary Hypertension

Keywords

Sickle Cell Anemia; Tyrosine Kinase Inhibitor; Platelet Derived Growth Factor; Beta Adrenergic Receptor Blocker; Pulmonary Vascular Disease; Sickle Cell Disease; Pulmonary Hypertension

Outcome Measures

Primary Outcomes (1)

• An open-label non-controlled pilot study, to determine the safety and tolerability of 24-weeks of oral imatinib in SCD associated PAH and of oral carvedilol therapy in SCD associated PVH.

Secondary Outcomes (3)

• Assess the efficacy and impact of imatinib and carvedilol on maximum exercise capacity as measured by peak oxygen consumption during a maximal CPET in SCD-PH subjects.

• Assess toxicity associated with concurrent use of study drugs and hydroxyurea.

• To determine appropriate monitoring, visit frequency and intensity, and to select a subject population and develop projections of statistical power for clinical efficacy endpoints.

Interventions

Carvedilol DRUG

Imatinib DRUG

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Arm A (Imatinib)
• Satisfaction of screening criteria
• Subjects 18 years of age or older
• Women of childbearing potential and male subjects must agree to use reliable methods of birth control (oral contraceptives, other hormonal contraceptives including vaginal contraceptive rings and contraceptive patches, barrier contraceptives such as condoms, an intra uterine device (IUD) or abstinence). This is because the effects of imatinib mesylate on the developing human fetus are not fully known.
• Diagnosis of sickle cell disease (electrophoresis or HPLC)
• Documentation of SS, SC, S-Beta thalassemia or other major sickling phenotypes)
• Diagnosis of sickle cell disease associated pulmonary hypertension by right heart catheterization (mean PAP greater than or equal to 25 mmHg AND PCWP less than or equal to 15 mmHg with PVR greater than or equal to 3.0 Wood s Units)
• WHO functional class II or III symptoms
• Arm B (Carvedilol)
• Satisfaction of screening criteria
• Right heart catheterization (mean PAP greater than or equal to 25 mmHg AND PCWP \> 15 mmHg
• Clinically stable for at least 6 weeks prior to enrollment. PAH treatments must be stable for three months prior to study drug initiation. Prostacyclin analogs, type 5 phosphodiesterase inhibitors and endothelin-1 receptor antagonists are all allowed, alone or in combinations
• Diagnosis of sickle cell disease (electrophoresis or HPLC documentation of SS, SC, S-Beta thalassemia or other major sickling phenotypes)
• Women of childbearing potential and male subjects must agree to use reliable methods of birth control (oral contraceptives, other hormonal contraceptives including vaginal contraceptive rings and contraceptive patches, barrier contraceptives such as condoms, an intra uterine device (IUD) or abstinence). This is because the effects of Carvedilol in pregnancy is unknown (pregnancy risk factor C).
• Subjects 18 years of age or older

You may not qualify if:

• Arm A (Imatinib):
• Current pregnancy and lactation.
• Life expectancy less than 6 months.
• WHO functional class IV symptoms or NYHA-IV dyspnea.
• Presence of any of the medical conditions that are considered to be the cause of subject s pulmonary hypertension by subject s physician, including but not limited to:
• \<TAB\>- Scleroderma.
• \<TAB\>- Known significant obstructive or restrictive respiratory disease with FEV1, FVC or TLC below 60 percent of predicted normal.
• \<TAB\>- Known diagnosis of Obesity-Hypoventilation Syndrome.
• \<TAB\>- Portal hypertension or Child Class B or C cirrhosis.
• \<TAB\>- Significant left ventricular dysfunction (LVEF below 50 percent), significant ischemic, valvular, constrictive or restrictive heart disease.
• Persistently uncontrolled severe systemic hypertension (SBP above 160 mmHg or DBP above 100 mmHg)
• Clinical diagnosis of decompensated congestive heart failure
• Any initiation of new therapeutic intervention within the last 90 days or a dose change within 30 days, that is expected to have an impact on pulmonary hypertension, including but not limited to:
• \<TAB\>Specific pulmonary hypertension medication (e.g. prostacyclin analogues, endothelin receptor antagonists or phosphodiestrase-5 inhibitors)
• \<TAB\>Hydroxyurea

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Related Publications (3)

• Califf RM, Mark DB. Our vision for the American Heart Journal. Am Heart J. 1997 Jan;133(1):137-8. doi: 10.1016/s0002-8703(97)70261-8. No abstract available.

  PMID: 9006304 BACKGROUND

• Sachdev V, Machado RF, Shizukuda Y, Rao YN, Sidenko S, Ernst I, St Peter M, Coles WA, Rosing DR, Blackwelder WC, Castro O, Kato GJ, Gladwin MT. Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease. J Am Coll Cardiol. 2007 Jan 30;49(4):472-9. doi: 10.1016/j.jacc.2006.09.038. Epub 2007 Jan 16.

  PMID: 17258093 BACKGROUND

• Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, Krowka MJ, Langleben D, Nakanishi N, Souza R. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009 Jun 30;54(1 Suppl):S43-S54. doi: 10.1016/j.jacc.2009.04.012.

  PMID: 19555858 BACKGROUND

MeSH Terms

Conditions

Hypertension, Pulmonary; Anemia, Sickle Cell

Interventions

Carvedilol; Imatinib Mesylate

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring; Benzamides; Amides; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Pyrimidines

Study Officials

• Gregory J Kato, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 30, 2012
• First Posted: April 2, 2012
• Study Start: March 2, 2012
• Primary Completion: December 11, 2012
• Study Completion: December 11, 2012
• Last Updated: July 5, 2018

Record last verified: 2012-12-11