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

Randomized Double Blind Placebo Controlled Treatment of Sickle Cell Patients Hospitalized in Pain Crisis With Prophylactic Dose LMWH Versus Placebo

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Vaso-occlusive Crisis
• Intervention / Treatment: Drug: Placebo; Drug: Dalteparin

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 Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in D-dimer	Patients will have D-dimer,for samples drawn on Day 1 and Day 3	Day 1 and Day 3
Change in Clinical Pain Scores	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.	Baseline to day 1
Change in Thrombin Generation Assay - Endogenous Thrombin Potential	Patients will have thrombin generation assay samples drawn on Day 1 and 3	Day 1 and Day 3
Change in Clinical Pain Scores	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.	Baseline to day 3

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: Eisai Limited

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (ACTUAL): July 1, 2013
• Study Completion (ACTUAL): July 1, 2014

Study Registration Dates

• First Submitted: August 17, 2011
• First Submitted That Met QC Criteria: August 18, 2011
• First Posted (ESTIMATE): August 19, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): February 16, 2015
• Last Update Submitted That Met QC Criteria: January 30, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: vaso-occlusive crisis; anticoagulation; sickle cell disease
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin
• Other Study ID Numbers: Pro00023305