Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

NCT01036802 | Terminated Phase 2 Results DMC

• 2 other identifiers: 09-1596R01HL094592-01A1
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

Sickle cell disease (SCD) is often referred to as a hypercoagulable state. However, the contribution of coagulation activation to the pathogenesis of SCD remains uncertain. Pulmonary hypertension (PHT) is a common complication associated with significant morbidity and mortality. Autopsy studies of SCD patients with PHT show evidence of in situ thrombosis involving pulmonary vessels, similar to findings in non-sickle cell patients with PHT. Anticoagulation has been reported to be of benefit in non-sickle cell patients with PHT. With the evidence of increased coagulation activation in SCD, PHT represents a clinical endpoint that may be used to evaluate the contribution of coagulation activation to the pathophysiology of SCD. The investigators hypothesize that increased thrombin generation, as well as platelet activation are central to the pathophysiology of SCD and contribute to the occurrence of several SCD-related complications, including PHT. As a consequence, treatment modalities that down-regulate thrombin generation would be expected to delay the progression of PHT and result in improved survival in patients with SCD.

Conditions

Pulmonary Hypertension

Keywords

sickle cell disease; pulmonary hypertension; coagulation activation; platelet activation; endothelial activation

Outcome Measures

Primary Outcomes (1)

• Effect of Anticoagulation on Pulmonary Artery Systolic Pressure Was Obtained by Doppler Echocardiography

  We determined the effect of anticoagulation with warfarin on estimated pulmonary artery systolic pressure obtained by Doppler echocardiography. The presented data are average values for the study subjects in the treatment group. When data was missing, the previous value was carried forward.

  Measurements were obtained at Screening, and at Months 3, 6, 9, and 12

Secondary Outcomes (6)

• 6-minute Walk Test

  Measurements were obtained at Screening, Months 3, 6, 9, and 12

• Thrombin Generation

  Measurements were obtained at Screening, and at Months 3, 6, 9, and 12

• Platelet Activation

  Measurements were obtained at Screening, Prior to Run-in, and at Months 3, 6, 9, and 12

• Endothelial Activation

  Measurements were obtained at Screening, and at Months 3, 6, 9, and 12

• All-cause Mortality

  Assessment was obtained until completion of study at 12 months

Study Arms (2)

Warfarin

ACTIVE COMPARATOR

Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin

Drug: Warfarin

Placebo

PLACEBO COMPARATOR

matching active products

Drug: Placebo

Interventions

Warfarin DRUG

Patients on the active treatment arm will receive warfarin to achieve a target international normalized ratio of between 2 and 3

Also known as: Coumadin

Warfarin

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 16 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• At least 16 years of age
• Have a confirmed diagnosis of sickle cell anemia (HbSS) or sickle cell beta zero thalassemia
• Have evidence of persistent elevation of pulmonary artery systolic pressure on Doppler echocardiography (TR jet velocity of 2.5 to 2.9 m/s \[or estimated pulmonary artery systolic pressure above the upper limit of reference adjusted ranges and up to 45 mm Hg\]), but no evidence of moderate or severe diastolic dysfunction on tissue Doppler echocardiography. Mild PHT must be confirmed on repeat evaluation, at least 3 months later
• Have a serum creatinine =/\< 1.5 mg/dl
• Have serum transaminase values (ALT) \< 2 times upper limits of normal
• Have serum albumin =/\> 3.2 g/dl
• Have a platelet count =/\< 150,000 cu/mm
• Have normal baseline coagulation profile (PT/PTT)
• Patients on treatment with hydroxyurea should be on a stable dose for at least 6 months. Doses of hydroxyurea may only be adjusted during the course of the study for safety reasons.
• Be able to understand the requirements of the study and be willing to give informed consent.
• Women of childbearing age must be practicing (and will continue to practice for the course of the study) an adequate method of contraception.

You may not qualify if:

• Have a baseline hemoglobin \< 6.0 gm/dl
• Have congenital heart disease, valvular heart disease, and other identified cause of pulmonary hypertension (including pulmonary fibrosis) unrelated to SCD
• Have an elevated pulmonary capillary wedge pressure, as evidenced by E/Em \> 15 by pulsed wave and tissue Doppler imaging
• Have no measurable tricuspid regurgitant velocity on echocardiography
• Have a history of major gastrointestinal bleeding or a bleeding diathesis
• Have sickle cell complications such as recent vaso-occlusive crisis or acute chest syndrome, 4-weeks prior to commencing the study
• Have a history of clinically overt stroke(s) or seizures
• Have a brain magnetic resonance imaging/magnetic resonance angiography scan with evidence of Moya Moya within the preceding year
• Are pregnant or breastfeeding
• Are on chronic anticoagulant therapy
• Have a history of metastatic cancer
• Are chronically on therapy with aspirin or non-steroidal anti-inflammatory agents
• Are on a chronic transfusion program or have received a blood transfusion in the prior 8 weeks
• Have a positive urine toxicology screen for cocaine and amphetamines
• Have a history of alcohol abuse

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

MeSH Terms

Conditions

Hypertension, Pulmonary; Anemia, Sickle Cell

Interventions

Warfarin

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)

4-Hydroxycoumarins; Coumarins; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

This study was terminated early due to difficulty in accruing subjects.

Results Point of Contact

• Title: Kenneth I. Ataga, MD
• Organization: University of North Carolina, Chapel Hill

kataga@med.unc.edu

919-843-7708

Study Officials

• Kenneth I Ataga, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 18, 2009
• First Posted: December 21, 2009
• Study Start: December 1, 2009
• Primary Completion: September 1, 2012
• Study Completion: September 1, 2012
• Last Updated: May 9, 2016
• Results First Posted: February 21, 2014

Record last verified: 2014-01

Locations

US (1)