N-Acetylcysteine in Patients With Sickle Cell Disease (NAC)

N-Acetylcysteine in Patients With Sickle Cell Disease - Reducing the Incidence of Daily Life Pain

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease
• Intervention / Treatment: Drug: Placebo; Drug: N-Acetylcysteine

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • Hopital Erasme
  • Brussels, Belgium
    • Hopital Universitaire des Enfants Reine Fabiola (HUDERF)
  • Brussels, Belgium
    • CHU Brugmann
  • Brussels, Belgium
    • Chu St. Pierre
  • Brussels, Belgium
    • UCL St. Luc
  • Liège, Belgium
    • CHR de la Citadelle
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academic Medical Center
  • Groningen, Netherlands, 9713 GZ
    • University Medical Center Groningen
  • Rotterdam, Netherlands, 3015 AA
    • Erasmus Medical Center
  • The Hague, Netherlands, 2545 CH
    • Haga Hospital
• United Kingdom
  • London, United Kingdom
    • Guys' & St. Thomas Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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').

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: N-Acetylcysteine; N-Acetylcysteine 600mg 1 oral tablet twice daily during 6 months	Drug: N-Acetylcysteine; Other Names: Acetylcysteine; Acetadote; Fluimicil
Placebo Comparator: Placebo; Placebo 1 oral tablet twice daily during 6 months	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
The severity of SCD related pain in daily life, using a 0-10 numerical rating scale (NRS) in the study pain diary.	The average intensity of pain indicated on pain days in daily life will be compared between the two groups. The intensity of pain will be calculated as the average pain score over all pain days, using the highest scores indicated per day (either score over night or over day). Hospital days will be excluded from the analysis, as these scores often have not been completed fully during admission and the analysis is targeted at pain in daily life. Pain scores will be considered as continuous data with a normal distribution.	6 months
The incidence rate per patient year of painful crises (episodes, based on pain diary observation)	The number of patient-indicated painful crises in relation to total follow-up time will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval. Also, the average number of crisis days per patient in relation to total follow-up time will be evaluated (including hospital admission days, see below). A painful crisis will be defined as either (overlap is possible): When the box "Yes, I was in a crisis" is checked in a daily diary.; Missing diary days that are immediately preceded and followed by crisis days or by hospital admission.; A visit or admission to a hospital that lasted more than 4 hours for acute sickling-related pain, which was treated with orally or parenterally administered narcotics.; An acute chest syndrome	6 months
The incidence rate per patient year of days with painful crises (days, based on pain diary observation)	The number of days with patient-indicated painful crises in relation to total follow-up time will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval. A painful crisis will be defined as either (overlap is possible): When the box "Yes, I was in a crisis" is checked in a daily diary.; Missing diary days that are immediately preceded and followed by crisis days or by hospital admission.; A visit or admission to a hospital that lasted more than 4 hours for acute sickling-related pain, which was treated with orally or parenterally administered narcotics.; An acute chest syndrome	6 months
The severity of painful crises. This will be defined using a 0-10 numerical rating scale (NRS) in the pain diary.	The average intensity of pain indicated on crisis days in daily life will be compared between the two groups. The intensity of pain will be calculated as the average pain score over all crisis days, using the highest scores indicated per day (either score over night or over day). Hospital days will be excluded from the analysis, as these scores often have not been completed fully during admission and the analysis is targeted at pain in daily life. Pain scores will be considered as continuous data with a normal distribution. Painful crisis definition as above.	6 months
The incidence rate per patient year of hospital admissions	The number of sickle cell related hospital admissions in relation to total follow-up diary observation time will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval. Admissions will be verified using hospital medical records, if available. Hospital admission will be defined as: • Every visit to a hospital that lasted more than 4 hours for acute sickling-related disease, which was treated with orally or parenterally administered narcotics.	6 months
The incidence rate per patient year of hospital admission days	The number of sickle cell related hospital admission days in relation to total follow-up diary observation time will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval. Admissions will be verified using hospital medical records, if available. Hospital admission will be defined as: • Every visit to a hospital that lasted more than 4 hours for acute sickling-related disease, which was treated with orally or parenterally administered narcotics.	6 months
Time in days to first painful crisis (as defined above)	The time in days from randomization to first painful crisis (patient-defined) and hospital admission for painful crisis will be expressed in cumulative event rates, estimated by Kaplan-Meier analysis.	6 months
Time in days to first hospital admission for painful crisis (as defined above)	The time in days from randomization to first painful crisis (patient-defined) and hospital admission for painful crisis will be expressed in cumulative event rates, estimated by Kaplan-Meier analysis.	6 months
The health-related Quality of Life, as measured by use of validated questionnaires.	In adults this will be assessed with SF36-forms, a short-form health survey that has been proven to be valid and reliable in the black population.46 In children from 12 to 18 years old, we will use the PedsQL questionnaire, often used to assess quality of life in children, also validated in SCD patients	6 months
The SCD-related societal costs, assessed by a prospective cost-effectiveness analysis	The societal costs of pain care with the use of NAC, in the intervention group, will be compared to the societal costs of current pain care in the control group. Estimates of unit costs will be based on calculation of real costs of pain care. Generated direct medical costs will be recorded in the case record forms and by means of the Medical Cost Questionnaire (see appendix). Indirect costs arising from losses in productivity will be assessed by means of the Productivity Cost Questionnaire (see appendix) and will be calculated by means of the friction cost method.	6 months
The tolerability of NAC, defined as the number of participants with adverse events.	This will be assessed via the monthly adverse events reports. The frequency of registered adverse events and/or a serious adverse events will be reported per treatment arm, and compared between the two intervention groups.	6 months
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.	The incidence rate of analgesic usage will be defined as the proportion of pain days with reported analgesic use on the total number of pain days (excluding observation days with no reported pain). This proportion will be transformed to an event rate per patient year, with a corresponding rate ratio and it's 95% confidence interval.	6 months
Incidence of SCD complications.	The number of patients with sickle cell related complications (i.e. acute chest syndrome, stroke etc.) will be reported per treatment arm, and compared between the two intervention groups. The related incidence of SCD complications; Acute chest syndrome; Priapism; Hepatic sequestration; Splenic sequestration; Cerebrovascular accident; Leg ulcer; Symptomatic avascular osteonecrosis These complications will be assessed monthly by using hospital medical records.	6 months
The changes in blood markers of oxidative stress, hemolysis, hypercoagulability, inflammation, erythrocyte adhesion and endothelial dysfunction		6 months
Compliance of study medication; proportion of study medication used based on pill counts.	Compliance of use of study medication will primarily be checked by pill counts (number administered versus number returned). Compliance will be expressed as the proportion of tablets remaining, compared to the number of tablets that should have been taken based on a prescription of 2 tablets per day and the total number of observation days per patient.	6 months
Compliance of study medication; N-acetylcysteine plasma concentrations	We additionally aim to evaluate compliance by N-acetylcysteine plasma concentration measurements in blood samples drawn at T0, T3 and T6 in the intervention group, and assess mean change from baseline in the intervention group. This outcome may be used as alternative parameter for patient compliance if pill counts do not suffice.	6 months

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: May 6, 2013
• First Submitted That Met QC Criteria: May 7, 2013
• First Posted (Estimate): May 8, 2013

Study Record Updates

• Last Update Posted (Estimate): July 4, 2016
• Last Update Submitted That Met QC Criteria: June 30, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: Oxidative stress; Pain; N-Acetylcysteine; Sickle Cell Disease; Acetylcysteine; Sickle Cell Anemia
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: NAC trial; 2012-004892-37 (EudraCT Number); 171201003 (Other Grant/Funding Number: ZonMw); NL 41205.018.12 (Other Identifier: Central Committee on Research Involving Human Subjects (known by its Dutch initials, CCMO))

Plan for Individual participant data (IPD)

Study Data/Documents

1. Statistical Analysis Plan
   Information identifier: Version 7.0 - 5/31/2016