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Completed

NCT Number: NCT04011345

Folic Acid Supplementation in Children With Sickle Cell Disease

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.

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Key information

Conditions

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

Age range

2 year–19 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

BC Children's Hospital

Vancouver, British Columbia, V6H 3N1, Canada

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Folic Acid Supplement

Dietary Supplement

1 milligram folic acid

Placebo

Dietary Supplement

Placebo

Primary outcomes

  1. Red Blood Cell Folate Concentration

    Time frame: 12 weeks

    Biochemical folate status marker (nmol/L)

  2. Red Blood Cell Folate Concentration

    Time frame: 36 weeks

    Biochemical folate status marker (nmol/L)

Secondary outcomes

  1. Serum Folate Concentration

    Time frame: 12 weeks

    Biochemical folate status marker (nmol/L)

  2. Serum Folate Concentration

    Time frame: 36 weeks

    Biochemical folate status marker (nmol/L)

  3. Plasma Unmetabolized Folic Acid Concentration

    Time frame: 12 weeks

    Biochemical folate marker (nmol/L)

  4. Plasma Unmetabolized Folic Acid Concentration

    Time frame: 36 weeks

    Biochemical folate marker (nmol/L)

  5. S-adenosyl-methionine Concentration

    Time frame: 12 weeks

    Biochemical folate metabolite (µmol/L)

  6. S-adenosyl-methionine Concentration

    Time frame: 36 weeks

    Biochemical folate metabolite (µmol/L)

  7. S-adenosyl-homocysteine Concentration

    Time frame: 12 weeks

    Biochemical folate metabolite (µmol/L)

  8. S-adenosyl-homocysteine Concentration

    Time frame: 36 weeks

    Biochemical folate metabolite (µmol/L)

  9. Total homocysteine Concentration

    Time frame: 12 weeks

    Biochemical folate metabolite (µmol/L)

  10. Total homocysteine Concentration

    Time frame: 36 weeks

    Biochemical folate metabolite (µmol/L)

  11. Acute Pain Crises

    Time frame: 12 weeks

    Participant self-reported occurrence (# of episodes, and severity of episodes)

  12. Acute Pain Crises

    Time frame: 36 weeks

    Participant self-reported occurrence (# of episodes, and severity of episodes)

  13. Megaloblastic anemia

    Time frame: 12 weeks

    Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs

  14. Megaloblastic anemia

    Time frame: 36 weeks

    Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs

Sponsors and collaborators

Lead sponsor

University of British Columbia

Other

Registry information

Official study title

Folic Acid Supplementation in Children With Sickle-Cell Disease: A Randomized Double-Blind Cross-Over Trial

Important dates

Study start
2020
Primary completion
2022
Study completion
2022
First posted
Jul 8, 2019
Registry last updated
Aug 24, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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