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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2015 by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor:
Collaborators:
Erasmus Medical Center
Haga Hospital
University Medical Centre Groningen
ZonMw: The Netherlands Organisation for Health Research and Development
Fonds NutsOhra
Stichting Janivo
CHU Brugmann, Brussels
Hôpital Erasme, Brussels
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: March 17, 2015
Last verified: March 2015
  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 frequency of SCD related pain in daily life in days per patient [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    Frequency of pain will be expressed in days per patient in proportion to the total time of intervention (6 months) per treatment group.

    A pain day will be defined as:

    • When the box "Yes, I have experienced pain" is checked in the daily pain diary.



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 incidence of painful crises. The rate of painful crises will be defined as the number of crises and crisis days per patient in proportion to the total time of intervention (6 months) per treatment group. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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. The number of painful crises will be defined as the number of groups of consecutive days that box is checked.
    • A visit to a hospital that lasted more than 4 hours for acute sickling-related pain, which was treated with orally or parenterally administered narcotics.
    • Acute chest syndrome, defined as an episode of chest wall pain in association with findings of a new pulmonary infiltrate on chest x-ray or computerized tomography, and fever.

  • 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 ]

    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. The number of painful crises will be defined as the number of groups of consecutive days that box is checked.
    • A visit to a hospital that lasted more than 4 hours for acute sickling-related pain, which was treated with orally or parenterally administered narcotics.
    • Acute chest syndrome, defined as an episode of chest wall pain in association with findings of a new pulmonary infiltrate on chest x-ray or computerized tomography, and fever.

  • The frequency of hospital admissions, defined as the number of admissions per patient in proportion to total time of intervention. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    Admissions will be verified using hospital medical records, if available. The length of admission will be measured in days, from day of admission to day of discharge, in proportion to total time of intervention (6 months). The rate of admissions will be defined as the number of admissions per patient in proportion to total time of intervention.

    Hospital admission will be defined as:

    • When the box "Yes, I was (admitted) in the hospital the last 24 hours because of sickle cell pain" is checked in a daily diary.
    • 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 length of hospital admissions, measured in days, from day of admission to day of discharge, in proportion to total time of intervention (6 months). [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    Admissions will be verified using hospital medical records, if available. The length of admission will be measured in days, from day of admission to day of discharge, in proportion to total time of intervention (6 months). The rate of admissions will be defined as the number of admissions per patient in proportion to total time of intervention.

    Hospital admission will be defined as:

    • When the box "Yes, I was (admitted) in the hospital the last 24 hours because of sickle cell pain" is checked in a daily diary.
    • 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 ]
  • Time in days to first hospital admission for painful crisis (as defined above) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Time in days to second painful crisis (as defined above) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Time in days to second hospital admission (as defined above) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • 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, defined as events that are classified as 'definitely' or 'probably' related to the use of study medication, as determined by the investigators.

  • Frequency of use of pain medication at home. 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 ]
  • Incidence of SCD complications. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

    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 ]

Estimated Enrollment: 116
Study Start Date: April 2013
Estimated Primary Completion Date: March 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
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

Contacts
Contact: Bart Biemond, MD, PhD +31-20-5665785 b.j.biemond@amc.nl
Contact: Karin Fijnvandraat, MD, PhD +31-20-5662727 c.j.fijnvandraat@amc.nl

Locations
Belgium
Hôpital Erasme Not yet recruiting
Brussels, Belgium
Contact: F. Benghiat, MD         
CHU St. Pierre Not yet recruiting
Brussels, Belgium
Contact: P. Hermans, MD         
Contact: A. Vanderfaeillie, MD         
CHU Brugmann Recruiting
Brussels, Belgium
Contact: M Azerad, MD         
Contact: T Besse-Hammer, MD         
Hôpital Universitaire Des Enfants Reine Fabiola (HUDERF) Not yet recruiting
Brussels, Belgium
Contact: A. Ferster, MD         
UCL St. Luc Not yet recruiting
Brussels, Belgium
Contact: A van Damme, MD         
CHR de la Citadelle Not yet recruiting
Liège, Belgium
Contact: M. Dresse, MD         
Netherlands
Academic Medical Center Recruiting
Amsterdam, Netherlands, 1105 AZ
Contact: Joep Sins, MD    +31-20-5661693    j.w.sins@amc.nl   
Contact: Marjolein Spiering    +31-20-5665785    m.spiering@amc.nl   
Principal Investigator: Bart Biemond, MD, PhD         
Principal Investigator: Karin Fijnvandraat, MD, PhD         
Sub-Investigator: Joep Sins, MD         
Sub-Investigator: Harriët Heijboer, MD, PhD         
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713 GZ
Principal Investigator: Marco de Groot, MD, PhD         
Erasmus Medical Center Recruiting
Rotterdam, Netherlands, 3015 AA
Principal Investigator: Anita Rijneveld, MD, PhD         
Principal Investigator: Marjon Cnossen, MD, PhD         
Haga Hospital Recruiting
The Hague, Netherlands, 2545 CH
Principal Investigator: Jean-Louis Kerkhoffs, MD, PhD         
Principal Investigator: Alfred van Meurs, MD, PhD         
United Kingdom
Guys' & St. Thomas Hospital Not yet recruiting
London, United Kingdom
Contact: R. Kesse-Adu, MD         
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Erasmus Medical Center
Haga Hospital
University Medical Centre Groningen
ZonMw: The Netherlands Organisation for Health Research and Development
Fonds NutsOhra
Stichting Janivo
CHU Brugmann, Brussels
Hôpital Erasme, Brussels
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:

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: March 17, 2015
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
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Acetylcysteine
N-monoacetylcystine
Anti-Infective Agents
Antidotes
Antioxidants
Antiviral Agents
Expectorants
Free Radical Scavengers
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protective Agents
Respiratory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on March 26, 2015