Folic Acid Supplementation in Children With Sickle Cell Disease

Not Applicable

Completed

• Conditions: Anemia, Sickle Cell
• Interventions: Dietary Supplement: Folic Acid Supplement; Dietary Supplement: Placebo

• Registration Number: NCT04011345
• Lead Sponsor: University of British Columbia

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.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2019-04-30
• Study First Submitted QC: 2019-07-03
• Study First Posted: 2019-07-08
• Study Start: 2020-11-23
• Primary Completion: 2022-10-31
• Study Completion: 2022-10-31
• Status Verified: 2023-08
• Last Update Submitted: 2023-08-22
• Last Update Posted: 2023-08-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 31

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

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Folic Acid Supplement [Phase 1]	Folic Acid Supplement	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
Folic Acid Supplement [Phase 1]	Placebo	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
Placebo [Phase 1]	Folic Acid Supplement	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
Placebo [Phase 1]	Placebo	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

Primary Outcome Measures

Name	Time	Method
Red Blood Cell Folate Concentration	36 weeks	Biochemical folate status marker (nmol/L)

Secondary Outcome Measures

Name	Time	Method
Plasma Unmetabolized Folic Acid Concentration	36 weeks	Biochemical folate marker (nmol/L)
S-adenosyl-methionine Concentration	36 weeks	Biochemical folate metabolite (µmol/L)
S-adenosyl-homocysteine Concentration	36 weeks	Biochemical folate metabolite (µmol/L)
Acute Pain Crises	36 weeks	Participant self-reported occurrence (# of episodes, and severity of episodes)
Megaloblastic anemia	36 weeks	Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
Serum Folate Concentration	36 weeks	Biochemical folate status marker (nmol/L)
Total homocysteine Concentration	36 weeks	Biochemical folate metabolite (µmol/L)

Trial Locations

Locations (1)

BC Children's Hospital; 🇨🇦 Vancouver, British Columbia, Canada