Anemia, Sickle Cell
Conditions
Keywords
Folic Acid, Unmetabolized Folic Acid, Pediatrics
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.
Interventions
DIETARY_SUPPLEMENTFolic Acid Supplement
1 milligram folic acid
DIETARY_SUPPLEMENTPlacebo
Placebo
Sponsors
University of British Columbia
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
SUPPORTIVE_CARE
Masking
QUADRUPLE (Subject, Caregiver, 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.
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.
Eligibility
Sex/Gender
ALL
Age
2 Years to 19 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Red Blood Cell Folate Concentration | 12 weeks | Biochemical folate status marker (nmol/L) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Unmetabolized Folic Acid Concentration | 12 weeks | Biochemical folate marker (nmol/L) |
| S-adenosyl-methionine Concentration | 12 weeks | Biochemical folate metabolite (µmol/L) |
| S-adenosyl-homocysteine Concentration | 12 weeks | Biochemical folate metabolite (µmol/L) |
| Serum Folate Concentration | 12 weeks | Biochemical folate status marker (nmol/L) |
| Acute Pain Crises | 12 weeks | Participant self-reported occurrence (# of episodes, and severity of episodes) |
| Megaloblastic anemia | 12 weeks | Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs |
| Total homocysteine Concentration | 12 weeks | Biochemical folate metabolite (µmol/L) |
Countries
Canada
Outcome results
None listed