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

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ClinicalTrials.gov Identifier: NCT01849016
Recruitment Status : Completed
First Posted : May 8, 2013
Last Update Posted : July 4, 2016
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)

Tracking Information
First Submitted Date  ICMJE May 6, 2013
First Posted Date  ICMJE May 8, 2013
Last Update Posted Date July 4, 2016
Study Start Date  ICMJE April 2013
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 1, 2016)
The incidence rate of SCD related pain in daily life per patient year [ Time Frame: 6 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 7, 2013)
The frequency of SCD related pain in daily life in patients with Sickle Cell Disease [ Time Frame: 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 1, 2016)
  • 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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
    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 ]
  • Compliance of study medication; proportion of study medication used based on pill counts. [ Time Frame: 6 months ]
    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 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 7, 2013)
  • The severity of SCD related pain in daily life [ Time Frame: 6 months ]
  • The incidence and severity of painful crises [ Time Frame: 6 months ]
  • The frequency and length of hospital admissions [ Time Frame: 6 months ]
  • The health-related Quality of Life [ Time Frame: 6 months ]
  • The SCD-related societal costs [ Time Frame: 6 months ]
  • The tolerability of NAC [ Time Frame: 6 months ]
  • Frequency of use of pain medication at home [ Time Frame: 6 months ]
  • Frequency of SCD complications (e.g. acute chest syndrome) [ Time Frame: 6 months ]
  • The changes in hematological markers of oxidative stress, hemolysis, hypercoagulability, inflammation, erythrocyte adhesion and endothelial dysfunction [ Time Frame: 6 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE N-Acetylcysteine in Patients With Sickle Cell Disease
Official Title  ICMJE N-Acetylcysteine in Patients With Sickle Cell Disease - Reducing the Incidence of Daily Life Pain
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE Sickle Cell Disease
Intervention  ICMJE
  • Drug: N-Acetylcysteine
    Other Names:
    • Acetylcysteine
    • Fluimicil
    • Acetadote
  • Drug: Placebo
Study Arms  ICMJE
  • Experimental: N-Acetylcysteine
    N-Acetylcysteine 600mg 1 oral tablet twice daily during 6 months
    Intervention: Drug: N-Acetylcysteine
  • Placebo Comparator: Placebo
    Placebo 1 oral tablet twice daily during 6 months
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 1, 2016)
96
Original Estimated Enrollment  ICMJE
 (submitted: May 7, 2013)
140
Actual Study Completion Date  ICMJE June 2016
Actual Primary Completion Date June 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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').
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Netherlands,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01849016
Other Study ID Numbers  ICMJE 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) )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party B.J. Biemond, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study Sponsor  ICMJE Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Collaborators  ICMJE
  • 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  ICMJE
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)
PRS Account Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Verification Date June 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP