Treatment of Sickle Cell Patients Hospitalized in Pain Crisis With Prophylactic Dose Low-molecular-weight Heparin (LMWH) Versus Placebo

• Sponsor: Duke University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01419977
• Collaborator: Eisai Limited (Industry)
• Enrollment: 34
• Location: 1
• Arms: 2
• Duration (Months): 38
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Sickle cell disease (SCD) is one of the most common inherited diseases worldwide and exhibits highest frequency in people of African descent. Patients with SCD currently have few treatment options, with hydroxyurea being the only medication approved to reduce the frequency of vaso-occlusive crisis (VOC) and prevent other SCD complications such as acute chest syndrome. Once patients develop VOC, hospitalizations aim to alleviate pain; no specific therapy is currently available to otherwise affect the course of the VOC. However, there has been increasing interest in the role of coagulation in the pathogenesis of SCD. The investigators hypothesize that low dose anticoagulant therapy, such as prophylactic dose low-molecular-weight heparin (LMWH), could be a novel way to ameliorate the vaso-occlusive process and thereby hasten the resolution of pain.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Disease; Vaso-occlusive Crisis	Drug: Placebo; Drug: Dalteparin	Phase 2

Detailed Description

This is a double blind prospective randomized placebo controlled study with an enrollment target of 100 patients. All subjects with SCD that meet inclusion criteria while inpatient, will be eligible for the study and randomized to receive prophylactic LMWH or placebo. Treatment with either LMWH (dalteparin 5000 IU subcutaneously daily) or placebo will occur for the initial 7 days of hospitalization. Randomization will occur within Investigational Drug Services, which will dispense and label medications to all patients. All patients will be followed throughout their hospitalization as well as in the outpatient clinic. The initial blood sample will be obtained within 36 hours of admission.

Following randomization, blood will be drawn to perform: D-dimer, prothrombin fragment 1.2, thrombin-antithrombin complex, and Thrombin Generation Assay (TGA). Blood will be drawn as an inpatient (at admission, day 3, and day 5), as well as during a single outpatient follow-up visit two weeks post discharge. Patients with prolonged hospitalization will only have blood drawn on admission, day 3, and day 5, with a final blood draw as an outpatient (at least 14 days after discharge). Treatment by prophylactic LMWH or placebo will occur for the initial 7 days of hospitalization or until discharge.

Clinical pain scores will be performed twice daily throughout for the initial 7 days of hospitalization of all patients. The primary pain assessment tool will be a 10-cm horizontal visual analog scale (VAS), with "0" corresponding to no pain at one end and "10" indicating the worst pain at the other. The VAS test will be administered by the same blinded study coordinator or PI throughout the study, using standardized instructions. Pain will also be assessed during the follow up outpatient visit (to confirm patient's pain has returned to their baseline).

Patients will be recommended to follow up in outpatient clinic approximately 2-4 week following hospitalization. At this time, patients will be examined, have their clinical pain score determined, and have final blood draw for testing as detailed above. Should patients not return within 4 weeks, patient will be contacted by phone to determine their clinical status.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Randomized Double Blind Placebo Controlled Treatment of Sickle Cell Patients Hospitalized in Pain Crisis With Prophylactic Dose LMWH Versus Placebo
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Normal saline solution	Drug: Placebo; Normal saline solution, administered by nursing staff once daily
Experimental: Dalteparin 5000 unites subcutaneously, Other Name: Fragmin	Drug: Dalteparin; Low molecular weight heparin (LMWH), 5000 unites subcutaneously, administered by nursing staff once daily, Other Name: Fragmin

Outcome Measures

Primary Outcome Measures

1. Change in D-dimer [Day 1 and Day 3]

   Patients will have D-dimer,for samples drawn on Day 1 and Day 3

2. Change in Clinical Pain Scores [Baseline to day 1]

   The primary pain assessment tool will be a 10-cm horizontal visual analog scale (VAS), with "0" corresponding to no pain at one end and "10" indicating the worst pain at the other.

3. Change in Thrombin Generation Assay - Endogenous Thrombin Potential [Day 1 and Day 3]

   Patients will have thrombin generation assay samples drawn on Day 1 and 3

4. Change in Clinical Pain Scores [Baseline to day 3]

   The primary pain assessment tool will be a 10-cm horizontal visual analog scale (VAS), with "0" corresponding to no pain at one end and "10" indicating the worst pain at the other.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Documented HgbSS or HgbS-beta0 thalassemia by previous hemoglobin electrophoresis,

• age greater than 18 years old, and

• admit diagnosis of vaso-occlusive crisis.

Labs must be drawn within 36 hours of admission and randomization to treatment arm must occur during this time.

Exclusion Criteria:

• End stage renal disease (creatinine >3.0 mg/dL),

• use of antiplatelet or anticoagulation medication for an alternative indication,

• use of steroids or immunosuppressive medications,

• platelet count less than 100 X 109/L,

• history or development of heparin induced thrombocytopenia, packed red blood cell transfusion in the past one month, or

• recent hospitalization with discharge within the past 1 week.

Patients with re-admissions will not be enrolled again and will have no further samples drawn.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University
• Eisai Limited

Investigators

• Principal Investigator: Nirmish Shah, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT01419977
• Other Study ID Numbers: Pro00023305
• First Posted: Aug 19, 2011
• Last Update Posted: Feb 16, 2015
• Last Verified: Jan 1, 2015

• Keywords provided by Duke University: sickle cell disease; vaso-occlusive crisis; anticoagulation
• Additional relevant MeSH terms: Anemia, Sickle Cell; Dalteparin; Tinzaparin; Heparin, Low-Molecular-Weight

Study Results

Participant Flow

Pre-assignment Detail	Of the 34 subjects were consented, 29 are received drug and had the day 1 blood draw. 2 subjects withdrew prior to receiving study drug. In addition, 2 subjects were discharged and 1 subject received a transfusion prior to the blood draw on day 1.

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, administered by nursing staff once daily	Dalteparin: Low molecular weight heparin (LMWH), 5000 units subcutaneously, administered by nursing staff once daily, Other Name: Fragmin
Period Title: Overall Study
STARTED	16	13
COMPLETED	16	13
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Placebo	Dalteparin	Total
Arm/Group Description	Placebo: Normal saline solution, administered by nursing staff once daily	Dalteparin: Low molecular weight heparin (LMWH), 5000 units subcutaneously, administered by nursing staff once daily, Other Name: Fragmin	Total of all reporting groups
Overall Participants	16	13	29
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	16 100%	13 100%	29 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	4 25%	7 53.8%	11 37.9%
Male	12 75%	6 46.2%	18 62.1%
Region of Enrollment (participants) [Number]
United States	16 100%	13 100%	29 100%

Outcome Measures

1. Primary Outcome

Title	Change in D-dimer
Description	Patients will have D-dimer,for samples drawn on Day 1 and Day 3
Time Frame	Day 1 and Day 3

Outcome Measure Data

Analysis Population Description

9 subjects were discharged prior to day 3 so the day 3 blood sample was not obtained.

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, administered by nursing staff once daily	Dalteparin: Low molecular weight heparin (LMWH), 5000 units subcutaneously, administered by nursing staff once daily, Other Name: Fragmin
Measure Participants	11	9
Mean (Standard Deviation) [ng/mL]	478.8 (312.4)	260.1 (200.3)

2. Primary Outcome

Title	Change in Clinical Pain Scores
Description	The primary pain assessment tool will be a 10-cm horizontal visual analog scale (VAS), with "0" corresponding to no pain at one end and "10" indicating the worst pain at the other.
Time Frame	Baseline to day 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, administered by nursing staff once daily	Dalteparin: Low molecular weight heparin (LMWH), 5000 units subcutaneously, administered by nursing staff once daily, Other Name: Fragmin
Measure Participants	16	13
Mean (Standard Deviation) [units on a scale]	-0.3 (0.5)	-1.6 (0.4)

3. Primary Outcome

Title	Change in Thrombin Generation Assay - Endogenous Thrombin Potential
Description	Patients will have thrombin generation assay samples drawn on Day 1 and 3
Time Frame	Day 1 and Day 3

Outcome Measure Data

Analysis Population Description

9 subjects were discharged prior to day 3 so the day 3 blood sample was not obtained.

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, administered by nursing staff once daily	Dalteparin: Low molecular weight heparin (LMWH), 5000 units subcutaneously, administered by nursing staff once daily, Other Name: Fragmin
Measure Participants	11	9
Mean (Standard Deviation) [nM]	13.4 (34.5)	-45.98 (47.31)

4. Primary Outcome

Title	Change in Clinical Pain Scores
Description	The primary pain assessment tool will be a 10-cm horizontal visual analog scale (VAS), with "0" corresponding to no pain at one end and "10" indicating the worst pain at the other.
Time Frame	Baseline to day 3

Outcome Measure Data

Analysis Population Description

9 subjects were discharged prior to obtaining day 3 VAS score.

Arm/Group Title	Placebo	Dalteparin
Arm/Group Description	Placebo: Normal saline solution, administered by nursing staff once daily	Dalteparin: Low molecular weight heparin (LMWH), 5000 units subcutaneously, administered by nursing staff once daily, Other Name: Fragmin
Measure Participants	11	9
Mean (Standard Deviation) [units on a scale]	-0.9 (0.2)	-2.4 (0.9)

Adverse Events

Arm/Group Title	Placebo		Dalteparin
Arm/Group Description	Placebo: Normal saline solution, administered by nursing staff once daily		Dalteparin: Low molecular weight heparin (LMWH), 5000 units subcutaneously, administered by nursing staff once daily, Other Name: Fragmin
All Cause Mortality
	Placebo		Dalteparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Dalteparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Dalteparin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/16 (0%)		0/13 (0%)

Limitations/Caveats

Limitations to our pilot study include the small study sample size, which leads to difficulty in determining significant differences in the outcome measurements.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.