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Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

Primary Purpose

Pulmonary Hypertension

Status

Terminated

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Warfarin

Placebo

About this trial

This is an interventional treatment trial for Pulmonary Hypertension focused on measuring sickle cell disease, pulmonary hypertension, coagulation activation, platelet activation, endothelial activation

Eligibility Criteria

16 Years - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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.

Exclusion Criteria:

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
Are currently receiving treatment with epoprostenol (or similar prostacyclin analog), sildenafil (or similar phosphodiesterase 5 inhibitor), bosentan or arginine
Have ingested any investigational drugs within the past 4 weeks.

Sites / Locations

University of North Carolina

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Warfarin

Placebo

Arm Description

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

matching active products

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

6-minute Walk Test

We evaluated the distance walked over 6 minutes. The presented data are average values for the study subjects in the treatment group. When data was missing, the previous value was carried forward.

Thrombin Generation

We evaluated the effect of warfarin on a plasma measure of thrombin generation (thrombin-antithrombin complex)

Platelet Activation

We evaluated the effect of anticoagulation with warfarin on platelet activation assessed by measuring plasma levels of soluble CD40 ligand

Endothelial Activation

We assessed the effect of warfarin on plasma measures of endothelial activation (soluble vascular cell adhesion molecule-1)

All-cause Mortality

We assessed the effect of warfarin on mortality in the study subjects

Major and Minor Bleeding Complications

We evaluated the safety of warfarin by evaluating for major and minor bleeding complications in study subjects

Full Information

NCT ID

NCT01036802

First Posted

December 18, 2009

Last Updated

April 5, 2016

Sponsor

University of North Carolina, Chapel Hill

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT01036802

Brief Title

Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

Official Title

An Exploratory Study of Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

Study Type

Interventional

2. Study Status

Record Verification Date

January 2014

Overall Recruitment Status

Terminated

Why Stopped

Difficulty in accruing subjects

Study Start Date

December 2009 (undefined)

Primary Completion Date

September 2012 (Actual)

Study Completion Date

September 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of North Carolina, Chapel Hill

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

Detailed Description

As a result of the presence of large vessel thrombotic complications, as well as the biochemical evidence of ongoing coagulation activation, 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. While the majority of clinical studies using anticoagulants have shown no convincing benefit in the prevention or treatment of acute pain episodes, most of these studies were small and poorly controlled. Furthermore, because the acute pain episode appears to result from the occlusion of postcapillary venules by the interaction of red blood cells and other cellular elements with the vascular endothelium and subendothelial matrix proteins, it may not be the ideal clinical endpoint for assessing the effect of anticoagulation in SCD patients. Pulmonary hypertension (PHT), a common complication associated with significant morbidity and mortality, and with histopathologic findings of in situ thrombosis involving pulmonary vessels, represents a clinical endpoint that is likely due, at least in part, to increased thrombin generation, and may therefore be used to evaluate the contribution of coagulation activation to the pathophysiology of SCD. Twenty patients with sickle cell anemia (HbSS) or sickle beta zero thalassemia (Sickle beta zero thalassemia) and mild PHT who meet the eligibility requirements will be enrolled, 10 patients to receive anticoagulation with warfarin and 10 to receive placebo rfor 12 months of treatment.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Hypertension

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

3 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Warfarin

Arm Type

Active Comparator

Arm Description

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

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

matching active products

Intervention Type

Drug

Intervention Name(s)

Warfarin

Other Intervention Name(s)

Coumadin

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

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

Description

Time Frame

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

Secondary Outcome Measure Information:

Title

6-minute Walk Test

Description

We evaluated the distance walked over 6 minutes. The presented data are average values for the study subjects in the treatment group. When data was missing, the previous value was carried forward.

Time Frame

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

Title

Thrombin Generation

Description

We evaluated the effect of warfarin on a plasma measure of thrombin generation (thrombin-antithrombin complex)

Time Frame

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

Title

Platelet Activation

Description

We evaluated the effect of anticoagulation with warfarin on platelet activation assessed by measuring plasma levels of soluble CD40 ligand

Time Frame

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

Title

Endothelial Activation

Description

We assessed the effect of warfarin on plasma measures of endothelial activation (soluble vascular cell adhesion molecule-1)

Time Frame

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

Title

All-cause Mortality

Description

We assessed the effect of warfarin on mortality in the study subjects

Time Frame

Assessment was obtained until completion of study at 12 months

Title

Major and Minor Bleeding Complications

Description

We evaluated the safety of warfarin by evaluating for major and minor bleeding complications in study subjects

Time Frame

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

16 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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. Exclusion Criteria: 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 Are currently receiving treatment with epoprostenol (or similar prostacyclin analog), sildenafil (or similar phosphodiesterase 5 inhibitor), bosentan or arginine Have ingested any investigational drugs within the past 4 weeks.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kenneth I Ataga, MD

Organizational Affiliation

University of North Carolina, Chapel Hill

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of North Carolina

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599

Country

United States

12. IPD Sharing Statement

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Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease

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