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

This study has been completed.
Sponsor:
Collaborators:
Erasmus Medical Center
Haga Hospital
University Medical Center Groningen
ZonMw: The Netherlands Organisation for Health Research and Development
Fonds NutsOhra
Stichting Janivo
CHU Brugmann, Brussels
Erasme University Hospital
Centre Hospitalier Régional de la Citadelle
University Hospital St Luc, Brussels
Centre Hospitalier Universitaire Saint Pierre
Queen Fabiola Children's University Hospital
Guy's and St Thomas' NHS Foundation Trust
Information provided by (Responsible Party):
B.J. Biemond, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier:
NCT01849016
First received: May 6, 2013
Last updated: June 30, 2016
Last verified: June 2016
  Purpose

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.


Condition Intervention Phase
Sickle Cell Disease
Drug: N-Acetylcysteine
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: N-Acetylcysteine in Patients With Sickle Cell Disease - Reducing the Incidence of Daily Life Pain

Resource links provided by NLM:


Further study details as provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Primary Outcome Measures:
  • The incidence rate of SCD related pain in daily life per patient year [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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.


Secondary Outcome Measures:
  • The severity of SCD related pain in daily life, using a 0-10 numerical rating scale (NRS) in the study pain diary. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.

  • The incidence rate per patient year of painful crises (episodes, based on pain diary observation) [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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

  • The incidence rate per patient year of days with painful crises (days, based on pain diary observation) [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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

  • The severity of painful crises. This will be defined using a 0-10 numerical rating scale (NRS) in the pain diary. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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.


  • The incidence rate per patient year of hospital admissions [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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.


  • The incidence rate per patient year of hospital admission days [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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.


  • Time in days to first painful crisis (as defined above) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.

  • Time in days to first hospital admission for painful crisis (as defined above) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.

  • The health-related Quality of Life, as measured by use of validated questionnaires. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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

  • The SCD-related societal costs, assessed by a prospective cost-effectiveness analysis [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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.


  • The tolerability of NAC, defined as the number of participants with adverse events. [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    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.

  • 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. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.

  • Incidence of SCD complications. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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.


  • The changes in blood markers of oxidative stress, hemolysis, hypercoagulability, inflammation, erythrocyte adhesion and endothelial dysfunction [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Compliance of study medication; proportion of study medication used based on pill counts. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.

  • Compliance of study medication; N-acetylcysteine plasma concentrations [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    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.


Enrollment: 96
Study Start Date: April 2013
Study Completion Date: June 2016
Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: N-Acetylcysteine
N-Acetylcysteine 600mg 1 oral tablet twice daily during 6 months
Drug: N-Acetylcysteine
Other Names:
  • Acetylcysteine
  • Fluimicil
  • Acetadote
Placebo Comparator: Placebo
Placebo 1 oral tablet twice daily during 6 months
Drug: Placebo

  Eligibility

Ages Eligible for Study:   12 Years and older   (Child, Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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').
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01849016

Locations
Belgium
CHU Brugmann
Brussels, Belgium
CHU St. Pierre
Brussels, Belgium
Hôpital Erasme
Brussels, Belgium
Hôpital Universitaire Des Enfants Reine Fabiola (HUDERF)
Brussels, Belgium
UCL St. Luc
Brussels, Belgium
CHR de la Citadelle
Liège, Belgium
Netherlands
Academic Medical Center
Amsterdam, Netherlands, 1105 AZ
University Medical Center Groningen
Groningen, Netherlands, 9713 GZ
Erasmus Medical Center
Rotterdam, Netherlands, 3015 AA
Haga Hospital
The Hague, Netherlands, 2545 CH
United Kingdom
Guys' & St. Thomas Hospital
London, United Kingdom
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Erasmus Medical Center
Haga Hospital
University Medical Center Groningen
ZonMw: The Netherlands Organisation for Health Research and Development
Fonds NutsOhra
Stichting Janivo
CHU Brugmann, Brussels
Erasme University Hospital
Centre Hospitalier Régional de la Citadelle
University Hospital St Luc, Brussels
Centre Hospitalier Universitaire Saint Pierre
Queen Fabiola Children's University Hospital
Guy's and St Thomas' NHS Foundation Trust
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)
  More Information

Publications:

Study Data/Documents: Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: Version 7.0 - 5/31/2016

Responsible Party: B.J. Biemond, dr., Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01849016     History of Changes
Other Study ID Numbers: NAC trial  2012-004892-37  171201003  NL 41205.018.12 
Study First Received: May 6, 2013
Last Updated: June 30, 2016
Health Authority: Netherlands: Dutch Health Care Inspectorate
Netherlands: Medical Ethics Review Committee (METC)
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Sickle Cell Disease
Sickle Cell Anemia
Pain
N-Acetylcysteine
Acetylcysteine
Oxidative stress

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Acetylcysteine
N-monoacetylcystine
Antiviral Agents
Anti-Infective Agents
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 August 25, 2016