Pulmonary HypertensionPhase 2NCT01036802
Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease
A Phase 2 study testing Warfarin in people with Pulmonary Hypertension, run by University of North Carolina, Chapel Hill at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 16 to 65 years
- Conditions the study is for
- Pulmonary Hypertension
- What is being tested?
- Warfarin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 3 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2009to Sep 2012
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Show all 11Show fewer
- 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.
Who cannot join
- 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
Show all 17Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of North Carolina
Chapel Hill, North Carolina, 27599
About this study
Official title: An Exploratory Study of Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease
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.
Read the 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.
- Conditions
- Pulmonary Hypertension
- Being tested
- Warfarin, Placebo
- Keywords
- sickle cell disease, pulmonary hypertension, coagulation activation, platelet activation, endothelial activation
- Medical subject headings
- Hypertension, Pulmonary, Anemia, Sickle Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
WarfarinDrug
Also called Coumadin
Patients on the active treatment arm will receive warfarin to achieve a target international normalized ratio of between 2 and 3
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Warfarin | Active comparator | Patients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin Receives: Drug: Warfarin |
| Placebo | Placebo comparator | matching active products Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Measurements were obtained at Screening, and at Months 3, 6, 9, and 12
Secondary outcomes (6)
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.
Measured: Measurements were obtained at Screening, Months 3, 6, 9, and 12
Thrombin Generation
We evaluated the effect of warfarin on a plasma measure of thrombin generation (thrombin-antithrombin complex)
Measured: Measurements were obtained at Screening, and at Months 3, 6, 9, and 12
Platelet Activation
We evaluated the effect of anticoagulation with warfarin on platelet activation assessed by measuring plasma levels of soluble CD40 ligand
Measured: Measurements were obtained at Screening, Prior to Run-in, and at Months 3, 6, 9, and 12
Endothelial Activation
We assessed the effect of warfarin on plasma measures of endothelial activation (soluble vascular cell adhesion molecule-1)
Measured: Measurements were obtained at Screening, and at Months 3, 6, 9, and 12
All-cause Mortality
We assessed the effect of warfarin on mortality in the study subjects
Measured: Assessment was obtained until completion of study at 12 months
Major and Minor Bleeding Complications
We evaluated the safety of warfarin by evaluating for major and minor bleeding complications in study subjects
Measured: Evaluations were obtained at Screening, and at Months 3, 6, 9, and 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Dec 2009 (estimated)
- Study startDec 2009
- Primary completionSep 2012
- Study completionSep 2012
Why it stopped: Difficulty in accruing subjects
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Pulmonary HypertensionStudies of the same condition, open and under way.
- More trials run by University of North Carolina, Chapel HillThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of North Carolina, Chapel Hill
- Sponsor type
- University, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Sponsor
- Investigators
- Kenneth I Ataga, MD, Principal investigator, University of North Carolina, Chapel Hill
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01036802
- Sponsor's protocol ID
- 09-1596
- Other IDs
- R01HL094592-01A1
- Status last verified
- Jan 2014
- First submitted
- 18 Dec 2009
- Last updated
- 9 May 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 9 May 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Exploratory Study of Anticoagulation For Pulmonary Hypertension in Sickle Cell Disease
- ClinicalTrials.gov ID
- NCT01036802
- Acronym / sponsor ID
- 09-1596
- Conditions
- Pulmonary Hypertension
- Keywords
- sickle cell disease, pulmonary hypertension, coagulation activation, platelet activation, endothelial activation
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Difficulty in accruing subjects
- Enrolment
- 3 participants (actual)
- Lead sponsor
- University of North Carolina, Chapel HillUniversity, hospital or other
- Collaborators
- National Heart, Lung, and Blood Institute (NHLBI)
- Study start
- Dec 2009
- Primary completion
- Sep 2012 (actual)
- Study completion
- Sep 2012 (actual)
- First posted
- 21 Dec 2009 (estimated)
- Results
- Posted 21 Feb 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Warfarin | Active comparator | Drug: WarfarinPatients on the active treatment arm will be anticoagulated using the vitamin K antagonist, warfarin |
| Placebo | Placebo comparator | Drug: Placebomatching active products |
Who may qualify
- Ages
- 16 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (11 listed)
- 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
Key exclusion criteria (17 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| WarfarinAlso: CoumadinPatients on the active treatment arm will receive warfarin to achieve a target international normalized ratio of between 2 and 3 | Drug | Warfarin |
| Placebo | Drug | Placebo |
Primary outcome
Effect of Anticoagulation on Pulmonary Artery Systolic Pressure Was Obtained by Doppler Echocardiography
Time frame: Measurements were obtained at Screening, and at Months 3, 6, 9, and 12
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.
6 secondary outcomes
6-minute Walk Test
Time frame: Measurements were obtained at Screening, Months 3, 6, 9, and 12
Thrombin Generation
Time frame: Measurements were obtained at Screening, and at Months 3, 6, 9, and 12
Platelet Activation
Time frame: Measurements were obtained at Screening, Prior to Run-in, and at Months 3, 6, 9, and 12
Endothelial Activation
Time frame: Measurements were obtained at Screening, and at Months 3, 6, 9, and 12
All-cause Mortality
Time frame: Assessment was obtained until completion of study at 12 months
Major and Minor Bleeding Complications
Time frame: Evaluations were obtained at Screening, and at Months 3, 6, 9, and 12
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 May 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kenneth I Ataga, MD principal investigator
University of North Carolina, Chapel Hill
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Warfarin in people with Pulmonary Hypertension, run by University of North Carolina, Chapel Hill at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 9 May 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 21 Feb 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Effect of Anticoagulation on Pulmonary Artery Systolic Pressure Was Obtained by Doppler Echocardiography (time frame: Measurements were obtained at Screening, and at Months 3, 6, 9, and 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 May 2016.