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

Two primary processes dominate the complications associated with sickle cell disease (SCD):
vasoocclusion and hemolysis. 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.

Part 1 enrolls stable outpatients with 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, measures of oxidation and RBC fragments. Patients receive IV NAC first at 150
mg/kg over 8 hours and if tolerated, at a later date at 300 mg/kg over 8 hours in the
University of Washington Clinical Research Center. Blood is collected for laboratory
assessment. Subjects are later offered enrollment in an oral phase.

Part 2, patients with a history of vaso-occlusive crisis (VOC) are approached in the
outpatient setting to discuss the study. When admitted for VOC, subjects receive NAC as an IV
infusion75 mg/kg every 6 hours for up to 5 days. Blood for laboratory assays are collected
each morning and pain assessment is performed prior to and following each NAC infusion.

Inclusion Criteria:

1. Age >= 18 years of age

2. Diagnosis of homozygous sickle cell (SS) or S-beta thalassemia with at least two
episodes of vaso-occlusive crises (VOC) requiring narcotics in each of the past 2
years. For part 2 can include hemoglobin SC disease.

3. For females of reproductive age, use of contraception and negative pregnancy test

Exclusion Criteria:

1. An additional hematologic diagnosis

2. Hemoglobin (Hgb) < 7gm/dL for part 1, < 6 gm/dL for part 2.

3. Asthma requiring medication

4. Liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase
(AST), total bilirubin (BilliT) > three times upper normal limit for Part 1.

5. Chronic transfusion therapy, or transfusion within 2 months of enrollment. For part 2
anticipated need for simple or exchange transfusion during hospitalization.

6. VOC requiring narcotic therapy within the prior week or requiring hospitalization with
discharge < 2 weeks prior to study enrollment for Part 1, for part 2 admission for VOC
within 30 days.

7. Pregnancy or nursing

8. Receiving another investigational drug

9. Known allergy to NAC

10. Per subject's physician not medically stable enough to participate

11. Taking nitroglycerin, carbamazepine, or phosphodiesterase 5 (PDE5) inhibitors

12. Abnormal baseline coagulation tests (> 1.5 times normal limits)

13. Platelets <150,000/microliter for Part 1.

14. For part 2, already enrolled in study twice.