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Folic Acid Supplementation in Children With Sickle Cell Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04011345
Recruitment Status : Recruiting
First Posted : July 8, 2019
Last Update Posted : January 18, 2020
Sponsor:
Information provided by (Responsible Party):
Crystal Karakochuk, University of British Columbia

Tracking Information
First Submitted Date  ICMJE April 30, 2019
First Posted Date  ICMJE July 8, 2019
Last Update Posted Date January 18, 2020
Actual Study Start Date  ICMJE January 3, 2020
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2019)
  • Red Blood Cell Folate Concentration [ Time Frame: 12 weeks ]
    Biochemical folate status marker (nmol/L)
  • Red Blood Cell Folate Concentration [ Time Frame: 36 weeks ]
    Biochemical folate status marker (nmol/L)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 3, 2019)
  • Serum Folate Concentration [ Time Frame: 12 weeks ]
    Biochemical folate status marker (nmol/L)
  • Serum Folate Concentration [ Time Frame: 36 weeks ]
    Biochemical folate status marker (nmol/L)
  • Plasma Unmetabolized Folic Acid Concentration [ Time Frame: 12 weeks ]
    Biochemical folate marker (nmol/L)
  • Plasma Unmetabolized Folic Acid Concentration [ Time Frame: 36 weeks ]
    Biochemical folate marker (nmol/L)
  • S-adenosyl-methionine Concentration [ Time Frame: 12 weeks ]
    Biochemical folate metabolite (µmol/L)
  • S-adenosyl-methionine Concentration [ Time Frame: 36 weeks ]
    Biochemical folate metabolite (µmol/L)
  • S-adenosyl-homocysteine Concentration [ Time Frame: 12 weeks ]
    Biochemical folate metabolite (µmol/L)
  • S-adenosyl-homocysteine Concentration [ Time Frame: 36 weeks ]
    Biochemical folate metabolite (µmol/L)
  • Total homocysteine Concentration [ Time Frame: 12 weeks ]
    Biochemical folate metabolite (µmol/L)
  • Total homocysteine Concentration [ Time Frame: 36 weeks ]
    Biochemical folate metabolite (µmol/L)
  • Acute Pain Crises [ Time Frame: 12 weeks ]
    Participant self-reported occurrence (# of episodes, and severity of episodes)
  • Acute Pain Crises [ Time Frame: 36 weeks ]
    Participant self-reported occurrence (# of episodes, and severity of episodes)
  • Megaloblastic anemia [ Time Frame: 12 weeks ]
    Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
  • Megaloblastic anemia [ Time Frame: 36 weeks ]
    Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Folic Acid Supplementation in Children With Sickle Cell Disease
Official Title  ICMJE Folic Acid Supplementation in Children With Sickle-Cell Disease: A Randomized Double-Blind Cross-Over Trial
Brief Summary

Folic acid supplementation (1mg/d) is the standard recommendation for Canadian children with Sickle cell disease (SCD), even though it can provide up to six times the recommended intake amount for healthy children. There is growing concern that too much folic acid can be detrimental to health as high folate levels and circulating unmetabolized folic acid (UMFA), which occurs in blood with doses of folic acid as low as 0.2mg/d, have been associated with accelerated growth of some pre-cancerous cells, and altered DNA methylation and gene expression.

To inform the efficacy and potential harm of high-dose folic acid supplementation in Canadian children with SCD, a double-blind randomized controlled cross-over trial is proposed. Children with SCD (n=36, aged 2-19 y) will be recruited from BC Children's Hospital and randomized to initially receive 1 mg/d folic acid or a placebo for 12-weeks (wk). After a 12-wk washout period, treatments will be reversed.

Detailed Description

Blood samples will be collected at baseline and 12-wk of each treatment period (weeks 12, 24, and 36).

Serum and RBC concentrations of total folate, different folate forms and clinical outcomes will be measured at baseline and after each treatment period. Dietary folate intake will be assessed at baseline.

The objective of this study is to determine efficacy and potential harm of folic acid supplementation, versus no supplementation, in Canadian children with sickle cell disease.

It is hypothesized that: (1) there will be no difference in mean RBC folate concentrations across folic acid and placebo groups after 12-wk, (2) none of the participants will have folate deficiency, and (3) compared to periods of no supplementation, during periods of high-dose folic acid supplementation participants will show no difference in clinical outcomes, but have higher plasma unmetabolized folic acid concentrations.

Significance: There is a need to determine if the current clinical practice of high-dose folic acid supplementation is efficacious, and warranted.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:
This research project will consist of a clinical trial in which children with SCD are randomly selected to initially receive 1 mg per day of folic acid (the current standard dose) or a placebo for a 12-week period. Following that, each participant will have a 12 week wash-out period and then treatments are reversed (folic acid supplement or placebo) for 12 weeks. No controls are included in the study as each participant serves as their own control during periods of no supplementation.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:
This is a double-blind clinical trials, so neither participants nor medical care providers will be aware of the participants group assignment in order to limit bias, changes in dietary habits, or medical treatment. The outcomes assessor will also be unaware of participant assignment in order to limit bias in analysis of samples.
Primary Purpose: Supportive Care
Condition  ICMJE Anemia, Sickle Cell
Intervention  ICMJE
  • Dietary Supplement: Folic Acid Supplement
    1 milligram folic acid
  • Dietary Supplement: Placebo
    Placebo
Study Arms  ICMJE
  • Folic Acid Supplement [Phase 1]
    Phase 1: Folic acid supplement (1 mg per day) for 12 weeks; Phase 2: Wash-out period (no supplement or placebo) for 12 weeks; Phase 3: Placebo for 12 weeks
    Interventions:
    • Dietary Supplement: Folic Acid Supplement
    • Dietary Supplement: Placebo
  • Placebo [Phase 1]
    Phase 1: Placebo for 12 weeks; Phase 2: Wash-out period (no supplement or placebo) for 12 weeks; Phase 3: Folic acid supplement (1 mg per day) for 12 weeks
    Interventions:
    • Dietary Supplement: Folic Acid Supplement
    • Dietary Supplement: Placebo
Publications * Williams BA, McCartney H, Adams E, Devlin AM, Singer J, Vercauteren S, Wu JK, Karakochuk CD. Folic acid supplementation in children with sickle cell disease: study protocol for a double-blind randomized cross-over trial. Trials. 2020 Jun 29;21(1):593. doi: 10.1186/s13063-020-04540-7.

*   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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 3, 2019)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2022
Estimated Primary Completion Date January 1, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Individuals with SCD aged 2-19 y attending British Columbia Children's Hospital
  • Individuals having received routine daily supplementation of folic acid for the prior 12-weeks

Exclusion Criteria:

  • Individuals receiving a blood transfusion in the prior 12-weeks
  • Individuals allergic to any components of the supplement (cellulose, methylcellulose, magnesium stearate, and/or titanium dioxide)
  • Individuals presenting with megaloblastic anemia in the prior 12-weeks
  • Individuals with pulmonary, renal and/or cardiac complications (severe or recurrent acute chest syndrome)
  • Individuals routinely taking medications known to interfere with B vitamin metabolism (chloramphenicol, methotrexate, metformin, sulfasalazine, phenobarbital, primidone, triamterene, barbiturates)
  • Individuals who are currently pregnant, planning to become pregnant in the next 9-months, or currently breastfeeding
  • Individuals who have participated in a clinical research trial in the previous 30 days
  • Individuals who have donated blood in the previous 30 days
  • Individuals with unstable medical conditions or unstable laboratory results.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 19 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Brock Williams, MSc, RD 905-999-3710 brock.williams@ubc.ca
Contact: Crystal Karakochuk, PhD, RD 604-710-8496 crystal.karakochuk@ubc.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04011345
Other Study ID Numbers  ICMJE H18-02981
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results reported in the published articles, after de-identification (text, tables, figures, and appendices).
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: Access will be available starting within 3 months of the publication of results and up to a period of 5 years
Access Criteria: Researchers who provide a methodologically sound proposal may gain access following receipt of a signed data access agreement.
Responsible Party Crystal Karakochuk, University of British Columbia
Study Sponsor  ICMJE University of British Columbia
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Crystal Karakochuk, PhD, RD University of British Columbia
PRS Account University of British Columbia
Verification Date January 2020

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