A Pilot Study of N-acetylcysteine in Patients With Sickle Cell Disease - Full Text View

Purpose

Two primary processes dominate the complications associated with sickle cell disease (SCD): vasoocclusion and hemolysis. Vasoocclusion is very likely to account for the tissue infarction and pain associated with the disease, while hemolysis liberates hemoglobin into the plasma where it scavenges nitric oxide (NO), producing vascular complications such as pulmonary hypertension and skin ulcers. The plasma and vessel wall adhesive protein von Willebrand factor (VWF) is thought to be involved in both of these processes, so strategies aimed at reducing its secretion or reactivity, which could decrease complications in patients with SCD, are being tested.

Based on prior studies, N-acetylcysteine (NAC) treatment may decrease VWF activity in patients with SCD and may be a useful adjunctive treatment in this disorder.

This is a pilot study in patients with hemoglobin homozygous S (HbSS) or hemoglobin S with beta zero thalassemia(HbS-βo thalassemia), with the aim of examining the effect of NAC treatment on VWF parameters. As a first step, the investigators will examine whether intravenous or oral administration of NAC, in doses used to treat other conditions, changes VWF content, activity, multimer size, or extent of oxidation. In prior studies, investigators have shown that a number of patients followed in the sickle cell clinic at the University of Washington have ultralarge VWF multimers and high VWF:total activity (TA). Only patients with elevated VWF are eligible for this pilot study.

Condition	Intervention	Phase
Sickle Cell Disease Sickle Cell Anemia	Drug: N-Acetylcysteine	Phase 0

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Pilot Study of N-acetylcysteine in Patients With Sickle Cell Disease

Resource links provided by NLM:

Genetics Home Reference related topics: sickle cell disease

MedlinePlus related topics: Anemia Sickle Cell Anemia

Drug Information available for: Acetylcysteine

U.S. FDA Resources

Further study details as provided by Puget Sound Blood Center:

Primary Outcome Measures:

Laboratory measures of VWF activity [ Time Frame: Lab assays of VWF activity will be assessed in blood drawn prior to infusion, at the end of the infusion, 1 and 3 days following the end of the infusion and once a week during oral administration. Percent changes in activity over time will be reported. ] [ Designated as safety issue: No ]
To determine if NAC, given intravenously as a one day infusion, or orally over a period of 4 weeks, effectively decreases VWF levels, VWF Total Activity, ULVWF multimers, VWF functions (ristocetin- and shear-induced platelet agglutination), and the extent of VWF methionine oxidation in the A1-A2-A3 region, at different time points during and following administration.

Secondary Outcome Measures:

Laboratory measures of red blood cell hemolysis and oxidation [ Time Frame: Red blood cell (RBC) lab measures will be drawn prior to infusion, at the end of the infusion, 1 and 3 days following the end of the infusion and once a week during oral administration. Percent changes in measurements will be reported over time. ] [ Designated as safety issue: No ]
To determine effects of NAC treatment on laboratory markers of sickle cell disease by measuring a) lactate dehydrogenase (LDH) B) reticulocyte count, and c) percent dense cells and on oxidation by measuring RBC glutathione.
Adverse events during and following NAC administration [ Time Frame: Adverse events will be collected throughout the study and specifically during infusion, one and 3 days after infusion and once per week during study period. ] [ Designated as safety issue: Yes ]
To assess safety by evaluating subjects for adverse events including vaso-occlusive crises and bleeding symptoms during and at time points following administration.

Estimated Enrollment:	5
Study Start Date:	March 2013
Estimated Primary Completion Date:	December 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Oral N-acetylcysteine (NAC) Eligible subjects who did not participate in Intravenous NAC or subjects who are at least 4 weeks after participation in Intravenous NAC, will be given Oral NAC at a dose of 2400mg daily, in two equally divided doses, for 4 weeks. Subjects will have blood drawn prior to beginning the phase and weekly for 4 weeks. Women will have a pregnancy test at each visit. Subjects will maintain a diary. At each visit interim medical events and adverse events will be collected.	Drug: N-Acetylcysteine Oral and Intravenous administration of NAC
Experimental: Intravenous N-acetylcysteine (NAC) Eligible subjects who did not participate in Oral NAC or subjects who are at least 4 weeks after participation in Oral NAC will be administered NAC by IV infusion at 75mg/Kg loading dose over 60 minutes, followed by a 75mg/Kg dose by continuous infusion over 7 hours. At least four weeks after the first infusion, and if the subject tolerated the first infusion, the subject will receive NAC by IV infusion at a 150mg/Kg loading dose over 60 minutes followed by a 150mg/Kg dose over 7 hours. Blood will be drawn prior to the infusion, at the end of the loading dose, at the conclusion of the infusion, and 24 and 72 hours post infusion. Vital signs will be monitored and adverse events collected. Females will have a negative pregnancy test prior to starting the infusion.	Drug: N-Acetylcysteine Oral and Intravenous administration of NAC

Arms

Assigned Interventions

Experimental: Oral N-acetylcysteine (NAC)

Eligible subjects who did not participate in Intravenous NAC or subjects who are at least 4 weeks after participation in Intravenous NAC, will be given Oral NAC at a dose of 2400mg daily, in two equally divided doses, for 4 weeks. Subjects will have blood drawn prior to beginning the phase and weekly for 4 weeks. Women will have a pregnancy test at each visit. Subjects will maintain a diary. At each visit interim medical events and adverse events will be collected.

Drug: N-Acetylcysteine

Oral and Intravenous administration of NAC

Experimental: Intravenous N-acetylcysteine (NAC)

Eligible subjects who did not participate in Oral NAC or subjects who are at least 4 weeks after participation in Oral NAC will be administered NAC by IV infusion at 75mg/Kg loading dose over 60 minutes, followed by a 75mg/Kg dose by continuous infusion over 7 hours. At least four weeks after the first infusion, and if the subject tolerated the first infusion, the subject will receive NAC by IV infusion at a 150mg/Kg loading dose over 60 minutes followed by a 150mg/Kg dose over 7 hours. Blood will be drawn prior to the infusion, at the end of the loading dose, at the conclusion of the infusion, and 24 and 72 hours post infusion. Vital signs will be monitored and adverse events collected. Females will have a negative pregnancy test prior to starting the infusion.

Drug: N-Acetylcysteine

Oral and Intravenous administration of NAC

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age >= 18 years of age
Diagnosis of homozygous sickle cell (SS) or S-betao thalassemia with at least two episodes of vaso-occlusive crises (VOC) requiring narcotics in each of the past 2 years.
Ultra Low Von Willebrand Factor (ULVWF) multimers on agarose gel analysis of patient's plasma
For females of reproductive age, use of contraception and negative pregnancy test
VWF antigen elevated to >150%

Exclusion Criteria:

An additional hematologic diagnosis
Hemoglobin (Hgb) < 7gm/dL
Asthma
Liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (BilliT) > three times upper normal limit
Chronic transfusion therapy, or transfusion within 2 months of enrollment
VOC requiring narcotic therapy within the prior week or requiring hospitalization with discharge < 2 weeks prior to study enrollment
Pregnancy or nursing
Receiving another investigational drug
Known allergy to NAC
Per subject's physician not medically stable enough to participate
Taking nitroglycerin, carbamazepine, or phosphodiesterase 5 (PDE5) inhibitors
Abnormal baseline coagulation tests (> 1.5 times normal limits)
Platelets <150,000/microliter

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01800526

Contacts

Contact: Barbara A Konkle, M.D.	206-233-3349	barbarak@psbc.org
Contact: Colette Norby-Slycord, R.N., M.N.	206-473-7892	coletten@psbc.org

Locations

United States, Washington
University of Washington	Not yet recruiting
Seattle, Washington, United States, 98106
Contact: Barbara A Konkle, M.D. 206-233-3349 barbarak@psbc.org

Sponsors and Collaborators

Puget Sound Blood Center

University of Washington

Investigators

Principal Investigator:

Barbara A Konkle, M.D.

Univ. of Washington/Puget Sound Blood Center

More Information

No publications provided

Responsible Party:	Barbara A. Konkle, M.D., Director, Clinical and Translational Research, Puget Sound Blood Center
ClinicalTrials.gov Identifier:	NCT01800526 History of Changes
Other Study ID Numbers:	117090
Study First Received:	January 21, 2013
Last Updated:	February 25, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by Puget Sound Blood Center:

Sickle Cell Disease
Sickle Cell Anemia

Additional relevant MeSH terms:

Anemia, Sickle Cell
Anemia
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents

Therapeutic Uses
Pharmacologic Actions
Expectorants
Respiratory System Agents
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Protective Agents
Physiological Effects of Drugs
Antidotes

ClinicalTrials.gov processed this record on May 19, 2013

A Pilot Study of N-acetylcysteine in Patients With Sickle Cell Disease (NACinSCD)