Folic Acid Supplementation in Children With Sickle Cell Disease

NCT04011345 | Completed DMC

• 1 other identifier: H18-02981
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

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.

Conditions

Anemia, Sickle Cell

Keywords

Folic Acid; Unmetabolized Folic Acid; Pediatrics

Outcome Measures

Primary Outcomes (2)

• Red Blood Cell Folate Concentration

  Biochemical folate status marker (nmol/L)

  12 weeks

• Red Blood Cell Folate Concentration

  Biochemical folate status marker (nmol/L)

  36 weeks

Secondary Outcomes (14)

• Serum Folate Concentration

  12 weeks

• Serum Folate Concentration

  36 weeks

• Plasma Unmetabolized Folic Acid Concentration

  12 weeks

• Plasma Unmetabolized Folic Acid Concentration

  36 weeks

• S-adenosyl-methionine Concentration

  12 weeks

Study Arms (2)

Folic Acid Supplement [Phase 1]

OTHER

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

Dietary Supplement: Folic Acid Supplement; Dietary Supplement: Placebo

Placebo [Phase 1]

OTHER

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

Dietary Supplement: Folic Acid Supplement; Dietary Supplement: Placebo

Interventions

Folic Acid Supplement DIETARY_SUPPLEMENT

1 milligram folic acid

Folic Acid Supplement [Phase 1]; Placebo [Phase 1]

Placebo DIETARY_SUPPLEMENT

Placebo

Folic Acid Supplement [Phase 1]; Placebo [Phase 1]

Eligibility Criteria

• Age: 2 Years - 19 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of British Columbia: lead

Study Sites (1)

BC Children's Hospital

Vancouver, British Columbia, V6H 3N1, Canada

Location

Related Publications (2)

• 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.

  PMID: 32600389 BACKGROUND

• Williams BA, McCartney H, Singer J, Devlin AM, Vercauteren S, Amid A, Wu JK, Karakochuk CD. Folic acid supplementation in children with sickle cell disease: a randomized double-blind noninferiority cross-over trial. Am J Clin Nutr. 2025 Apr;121(4):910-920. doi: 10.1016/j.ajcnut.2025.02.001. Epub 2025 Feb 5.

  PMID: 39921095 DERIVED

Related Links

• Study protocol

MeSH Terms

Conditions

Anemia, Sickle Cell

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Crystal Karakochuk, PhD, RD

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: SUPPORTIVE CARE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: 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.

Study Record Dates

• First Submitted: April 30, 2019
• First Posted: July 8, 2019
• Study Start: November 23, 2020
• Primary Completion: October 31, 2022
• Study Completion: October 31, 2022
• Last Updated: August 24, 2023

Record last verified: 2023-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, 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.

Locations

CA (1)