N-Acetylcysteine in Patients With Sickle Cell Disease

NCT01849016 | Completed Phase 3

• 4 other identifiers: NAC trial2012-004892-37171201003NL 41205.018.12
• Study Type: interventional
• Target: 96
• Locations: 3 countries
• Sites: 11

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.

Conditions

Sickle Cell Disease

Keywords

Sickle Cell Disease; Sickle Cell Anemia; Pain; N-Acetylcysteine; Acetylcysteine; Oxidative stress

Outcome Measures

Primary Outcomes (1)

• The incidence rate of SCD related pain in daily life per patient year

  The incidence of pain in daily life will be expressed as the number of pain days in relation to total follow-up time, and transformed to an event rate per patient year with a corresponding rate ratio and its 95% confidence interval. A pain day will be defined as: * When the box "Yes, I have experienced pain" is checked in the daily pain diary. * Days with hospital admission for painful crisis will be included in the total number of pain days and in the total number of diary observation days, irrespective of pain diary reports on these dates.

  6 months

Secondary Outcomes (16)

• The severity of SCD related pain in daily life, using a 0-10 numerical rating scale (NRS) in the study pain diary.

  6 months

• The incidence rate per patient year of painful crises (episodes, based on pain diary observation)

  6 months

• The incidence rate per patient year of days with painful crises (days, based on pain diary observation)

  6 months

• The severity of painful crises. This will be defined using a 0-10 numerical rating scale (NRS) in the pain diary.

  6 months

• The incidence rate per patient year of hospital admissions

  6 months

Study Arms (2)

N-Acetylcysteine

EXPERIMENTAL

N-Acetylcysteine 600mg 1 oral tablet twice daily during 6 months

Drug: N-Acetylcysteine

Placebo

PLACEBO COMPARATOR

Placebo 1 oral tablet twice daily during 6 months

Drug: Placebo

Interventions

N-Acetylcysteine DRUG

Also known as: Acetylcysteine, Fluimicil, Acetadote

N-Acetylcysteine

Placebo DRUG

Placebo

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• Chronic blood transfusion or transfusion in the preceding 3 months
• 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').

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• Erasmus Medical Center: collaborator
• Haga Hospital: collaborator
• University Medical Center Groningen: collaborator
• ZonMw: The Netherlands Organisation for Health Research and Development: collaborator
• Fonds NutsOhra: collaborator
• Stichting Janivo: collaborator
• CHU Brugmann, Brussels: collaborator
• Erasme University Hospital: collaborator
• Centre Hospitalier Régional de la Citadelle: collaborator
• University Hospital St Luc, Brussels: collaborator
• Centre Hospitalier Universitaire Saint Pierre: collaborator
• Queen Fabiola Children's University Hospital: collaborator
• Guy's and St Thomas' NHS Foundation Trust: collaborator

Study Sites (11)

CHU Brugmann

Brussels, Belgium

Location

CHU St. Pierre

Brussels, Belgium

Location

Hôpital Erasme

Brussels, Belgium

Location

Hôpital Universitaire Des Enfants Reine Fabiola (HUDERF)

Brussels, Belgium

Location

UCL St. Luc

Brussels, Belgium

Location

CHR de la Citadelle

Liège, Belgium

Location

Academic Medical Center

Amsterdam, 1105 AZ, Netherlands

Location

University Medical Center Groningen

Groningen, 9713 GZ, Netherlands

Location

Erasmus Medical Center

Rotterdam, 3015 AA, Netherlands

Location

Haga Hospital

The Hague, 2545 CH, Netherlands

Location

Guys' & St. Thomas Hospital

London, United Kingdom

Location

Related Publications (8)

• 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.

  PMID: 18195334 BACKGROUND

• 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.

  PMID: 20678158 BACKGROUND

• 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.

  PMID: 21544855 BACKGROUND

• 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.

  PMID: 21558001 BACKGROUND

• 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.

  PMID: 22318468 BACKGROUND

• 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.

  PMID: 12701116 BACKGROUND

• 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.

  PMID: 15606557 BACKGROUND

• 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.

  PMID: 20575034 BACKGROUND

MeSH Terms

Conditions

Anemia, Sickle Cell; Pain

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Bart Biemond, MD, PhD

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

• Karin Fijnvandraat, MD, PhD

  Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: dr.

Study Record Dates

• First Submitted: May 6, 2013
• First Posted: May 8, 2013
• Study Start: April 1, 2013
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: July 4, 2016

Record last verified: 2016-06

Locations

BE (6); NL (4); GB (1)