Clinical trial NCT01849016: N-Acetylcysteine in Patients With Sickle Cell Disease
Official title: N-Acetylcysteine in Patients With Sickle Cell Disease - Reducing the Incidence of Daily Life Pain
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sickle Cell Disease
Keywords: Sickle Cell Disease
Sickle Cell Anemia
Pain
N-Acetylcysteine
Acetylcysteine
Oxidative stress
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: Haga Hospital
name: University Medical Center Groningen
name: ZonMw: The Netherlands Organisation for Health Research and Development
name: Fonds NutsOhra
name: Stichting Janivo
name: CHU Brugmann, Brussels
name: Erasme University Hospital
name: Centre Hospitalier Régional de la Citadelle
name: University Hospital St Luc, Brussels
name: Centre Hospitalier Universitaire Saint Pierre
name: Queen Fabiola Children's University Hospital
name: Guy's and St Thomas' NHS Foundation Trust
First posted: 2013-05-08
Enrollment: 96
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The primary aim of this study is to evaluate the effect of the drug N-Acetylcysteine on the frequency of pain in daily life in patients with Sickle Cell Disease (SCD).

Pain is an invalidating hallmark of this disease and has a considerable impact on the Quality of Life of patients and the medical health care system. Oxidative stress is hypothesized to play a central role in its pathophysiology. In pilot studies the administration of N-Acetylcysteine (NAC) resulted in a reduction of oxidative stress. Moreover, administration of NAC seemed to decrease hospitalization for painful crises in a small pilot study in patients with SCD.

This study will be performed as a multicenter, randomized, controlled trial where patients will be treated with either NAC or placebo for a period of 6 months. The investigators expect that NAC can reduce the frequency of pain in patients with SCD, thereby improving their quality of life and participation in society.


Eligibility criteria: Inclusion Criteria:

* Age 12 years or older
* Sickle cell disease, either homozygous sickle cell disease (HbSS), compound heterozygous sickle cell disease (HbSC), HbSβ0 or HbSβ+ thalassemia
* History of at least 1.0 painful crisis per year in the past 3 years (visit to medical facility is not required)

Exclusion Criteria:

* Chronic blood transfusion or transfusion in the preceding 3 months
* Painful crisis in the last 4 weeks (with respect to the moment of inclusion)
* Pregnancy, breast feeding or the desire to get pregnant in the following 7 months
* Known active gastric/duodenal ulcers
* Hydroxycarbamide (HC) treatment with unstable dose in the last 3 months or started on HC shorter then 6 months prior to study
* Known poor compliance in earlier trials regarding the completion of pain diaries
* Insufficient compliance in run-in period
* Known hypersensitivity to acetylcysteine or one of the other components of the study medication
* Use of pain medication for sickle-cell related pains on more than 15 days per month in the past 6 months ('chronic pain').

Primary outcomes:
measure: The incidence rate of SCD related pain in daily life per patient year
timeFrame: 6 months
Secondary outcomes:
measure: The severity of SCD related pain in daily life, using a 0-10 numerical rating scale (NRS) in the study pain diary.
timeFrame: 6 months
measure: The incidence rate per patient year of painful crises (episodes, based on pain diary observation)
timeFrame: 6 months
measure: The incidence rate per patient year of days with painful crises (days, based on pain diary observation)
timeFrame: 6 months
measure: The severity of painful crises. This will be defined using a 0-10 numerical rating scale (NRS) in the pain diary.
timeFrame: 6 months
measure: The incidence rate per patient year of hospital admissions
timeFrame: 6 months
measure: The incidence rate per patient year of hospital admission days
timeFrame: 6 months
measure: Time in days to first painful crisis (as defined above)
timeFrame: 6 months
measure: Time in days to first hospital admission for painful crisis (as defined above)
timeFrame: 6 months
measure: The health-related Quality of Life, as measured by use of validated questionnaires.
timeFrame: 6 months
measure: The SCD-related societal costs, assessed by a prospective cost-effectiveness analysis
timeFrame: 6 months
measure: The tolerability of NAC, defined as the number of participants with adverse events.
timeFrame: 6 months
measure: The incidence rate per patient year of use of home pain medication (based on pain diary observation). This information will be recorded by subjects in their daily pain diary, including type and dosage of pain medication.
timeFrame: 6 months
measure: Incidence of SCD complications.
timeFrame: 6 months
measure: The changes in blood markers of oxidative stress, hemolysis, hypercoagulability, inflammation, erythrocyte adhesion and endothelial dysfunction
timeFrame: 6 months
measure: Compliance of study medication; proportion of study medication used based on pill counts.
timeFrame: 6 months
measure: Compliance of study medication; N-acetylcysteine plasma concentrations
timeFrame: 6 months
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: CHU Brugmann
city: Brussels
country: Belgium
facility: CHU St. Pierre
city: Brussels
country: Belgium
facility: Hôpital Erasme
city: Brussels
country: Belgium
facility: Hôpital Universitaire Des Enfants Reine Fabiola (HUDERF)
city: Brussels
country: Belgium
facility: UCL St. Luc
city: Liège
country: Belgium
facility: CHR de la Citadelle
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: The Hague
country: Netherlands
facility: Haga Hospital
city: London
country: United Kingdom
facility: Guys' & St. Thomas Hospital
Study officials:
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Bart Biemond, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
name: Karin Fijnvandraat, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Smith WR, Penberthy LT, Bovbjerg VE, McClish DK, Roberts JD, Dahman B, Aisiku IP, Levenson JL, Roseff SD. Daily assessment of pain in adults with sickle cell disease. Ann Intern Med. 2008 Jan 15;148(2):94-101. doi: 10.7326/0003-4819-148-2-200801150-00004.
citation: Nur E, Brandjes DP, Schnog JJ, Otten HM, Fijnvandraat K, Schalkwijk CG, Biemond BJ; CURAMA Study Group. Plasma levels of advanced glycation end products are associated with haemolysis-related organ complications in sickle cell patients. Br J Haematol. 2010 Oct;151(1):62-9. doi: 10.1111/j.1365-2141.2010.08320.x. Epub 2010 Jul 30.
citation: Nur E, Biemond BJ, Otten HM, Brandjes DP, Schnog JJ; CURAMA Study Group. Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management. Am J Hematol. 2011 Jun;86(6):484-9. doi: 10.1002/ajh.22012. Epub 2011 May 4.
citation: Nur E, Verwijs M, de Waart DR, Schnog JJ, Otten HM, Brandjes DP, Biemond BJ, Elferink RP; CURAMA Study Group. Increased efflux of oxidized glutathione (GSSG) causes glutathione depletion and potentially diminishes antioxidant defense in sickle erythrocytes. Biochim Biophys Acta. 2011 Nov;1812(11):1412-7. doi: 10.1016/j.bbadis.2011.04.011. Epub 2011 May 3.
citation: Nur E, Brandjes DP, Teerlink T, Otten HM, Oude Elferink RP, Muskiet F, Evers LM, ten Cate H, Biemond BJ, Duits AJ, Schnog JJ; CURAMA study group. N-acetylcysteine reduces oxidative stress in sickle cell patients. Ann Hematol. 2012 Jul;91(7):1097-105. doi: 10.1007/s00277-011-1404-z. Epub 2012 Feb 10.
citation: Pace BS, Shartava A, Pack-Mabien A, Mulekar M, Ardia A, Goodman SR. Effects of N-acetylcysteine on dense cell formation in sickle cell disease. Am J Hematol. 2003 May;73(1):26-32. doi: 10.1002/ajh.10321.
citation: Somjee SS, Warrier RP, Thomson JL, Ory-Ascani J, Hempe JM. Advanced glycation end-products in sickle cell anaemia. Br J Haematol. 2005 Jan;128(1):112-8. doi: 10.1111/j.1365-2141.2004.05274.x.
citation: van Tuijn CF, van Beers EJ, Schnog JJ, Biemond BJ. Pain rate and social circumstances rather than cumulative organ damage determine the quality of life in adults with sickle cell disease. Am J Hematol. 2010 Jul;85(7):532-5. doi: 10.1002/ajh.21731. No abstract available.