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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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04011345
Recruitment Status : Active, not recruiting
First Posted : July 8, 2019
Last Update Posted : April 24, 2023
Sponsor:
Information provided by (Responsible Party):
Crystal Karakochuk, University of British Columbia

Study Description
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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.


Condition or disease Intervention/treatment Phase
Anemia, Sickle Cell Dietary Supplement: Folic Acid Supplement Dietary Supplement: Placebo Not Applicable

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 Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
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
Official Title: Folic Acid Supplementation in Children With Sickle-Cell Disease: A Randomized Double-Blind Cross-Over Trial
Actual Study Start Date : November 23, 2020
Actual Primary Completion Date : November 1, 2022
Estimated Study Completion Date : June 1, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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
 Dietary Supplement: Folic Acid Supplement
1 milligram folic acid

Dietary Supplement: Placebo
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
 Dietary Supplement: Folic Acid Supplement
1 milligram folic acid

Dietary Supplement: Placebo
Placebo


Outcome Measures
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Primary Outcome Measures :
  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 Outcome Measures :
  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


Eligibility Criteria
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Ages Eligible for Study:   2 Years to 19 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04011345


Locations
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Canada, British Columbia
BC Children's Hospital
Vancouver, British Columbia, Canada, V6H 3N1
Sponsors and Collaborators
University of British Columbia
Investigators
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Principal Investigator: Crystal Karakochuk, PhD, RD University of British Columbia
More Information
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Additional Information:

Publications:

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Responsible Party: Crystal Karakochuk, Associate Professor, University of British Columbia
ClinicalTrials.gov Identifier: NCT04011345    
Other Study ID Numbers: H18-02981
First Posted: July 8, 2019    Key Record Dates
Last Update Posted: April 24, 2023
Last Verified: April 2023
Individual Participant Data (IPD) Sharing Statement:
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
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Crystal Karakochuk, University of British Columbia:
Folic Acid
Unmetabolized Folic Acid
Pediatrics
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
 Folic Acid
Hematinics
Vitamin B Complex
Vitamins
Micronutrients
Physiological Effects of Drugs