Folic Acid Supplementation in Children With Sickle Cell Disease

August 22, 2023 updated by: Crystal Karakochuk, University of British Columbia

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

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.

Study Overview

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 Type

Interventional

Enrollment (Actual)

31

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • British Columbia
      • Vancouver, British Columbia, Canada, V6H 3N1
        • BC Children's Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

2 years to 19 years (Child, Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: 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
Placebo
1 milligram folic acid
Other: 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
Placebo
1 milligram folic acid

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Red Blood Cell Folate Concentration
Time Frame: 12 weeks
Biochemical folate status marker (nmol/L)
12 weeks
Red Blood Cell Folate Concentration
Time Frame: 36 weeks
Biochemical folate status marker (nmol/L)
36 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Serum Folate Concentration
Time Frame: 12 weeks
Biochemical folate status marker (nmol/L)
12 weeks
Serum Folate Concentration
Time Frame: 36 weeks
Biochemical folate status marker (nmol/L)
36 weeks
Plasma Unmetabolized Folic Acid Concentration
Time Frame: 12 weeks
Biochemical folate marker (nmol/L)
12 weeks
Plasma Unmetabolized Folic Acid Concentration
Time Frame: 36 weeks
Biochemical folate marker (nmol/L)
36 weeks
S-adenosyl-methionine Concentration
Time Frame: 12 weeks
Biochemical folate metabolite (µmol/L)
12 weeks
S-adenosyl-methionine Concentration
Time Frame: 36 weeks
Biochemical folate metabolite (µmol/L)
36 weeks
S-adenosyl-homocysteine Concentration
Time Frame: 12 weeks
Biochemical folate metabolite (µmol/L)
12 weeks
S-adenosyl-homocysteine Concentration
Time Frame: 36 weeks
Biochemical folate metabolite (µmol/L)
36 weeks
Total homocysteine Concentration
Time Frame: 12 weeks
Biochemical folate metabolite (µmol/L)
12 weeks
Total homocysteine Concentration
Time Frame: 36 weeks
Biochemical folate metabolite (µmol/L)
36 weeks
Acute Pain Crises
Time Frame: 12 weeks
Participant self-reported occurrence (# of episodes, and severity of episodes)
12 weeks
Acute Pain Crises
Time Frame: 36 weeks
Participant self-reported occurrence (# of episodes, and severity of episodes)
36 weeks
Megaloblastic anemia
Time Frame: 12 weeks
Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
12 weeks
Megaloblastic anemia
Time Frame: 36 weeks
Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
36 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Crystal Karakochuk, PhD, RD, University of British Columbia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 23, 2020

Primary Completion (Actual)

October 31, 2022

Study Completion (Actual)

October 31, 2022

Study Registration Dates

First Submitted

April 30, 2019

First Submitted That Met QC Criteria

July 3, 2019

First Posted (Actual)

July 8, 2019

Study Record Updates

Last Update Posted (Actual)

August 24, 2023

Last Update Submitted That Met QC Criteria

August 22, 2023

Last Verified

August 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual participant data that underlie the results reported in the published articles, after de-identification (text, tables, figures, and appendices).

IPD Sharing Time Frame

Access will be available starting within 3 months of the publication of results and up to a period of 5 years

IPD Sharing Access Criteria

Researchers who provide a methodologically sound proposal may gain access following receipt of a signed data access agreement.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF
  • ANALYTIC_CODE
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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