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Folic Acid Supplementation in Children With Sickle Cell Disease

Primary Purpose

Anemia, Sickle Cell

Status
Completed
Phase
Not Applicable
Locations
Canada
Study Type
Interventional
Intervention
Folic Acid Supplement
Placebo
Sponsored by
University of British Columbia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Anemia, Sickle Cell focused on measuring Folic Acid, Unmetabolized Folic Acid, Pediatrics

Eligibility Criteria

2 Years - 19 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • BC Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Folic Acid Supplement [Phase 1]

Placebo [Phase 1]

Arm Description

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

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

Outcomes

Primary Outcome Measures

Red Blood Cell Folate Concentration
Biochemical folate status marker (nmol/L)
Red Blood Cell Folate Concentration
Biochemical folate status marker (nmol/L)

Secondary Outcome Measures

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

Full Information

First Posted
April 30, 2019
Last Updated
August 22, 2023
Sponsor
University of British Columbia
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1. Study Identification

Unique Protocol Identification Number
NCT04011345
Brief Title
Folic Acid Supplementation in Children With Sickle Cell Disease
Official Title
Folic Acid Supplementation in Children With Sickle-Cell Disease: A Randomized Double-Blind Cross-Over Trial
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Completed
Study Start Date
November 23, 2020 (Actual)
Primary Completion Date
October 31, 2022 (Actual)
Study Completion Date
October 31, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of British Columbia

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anemia, Sickle Cell
Keywords
Folic Acid, Unmetabolized Folic Acid, Pediatrics

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
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
ParticipantCare ProviderInvestigatorOutcomes 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.
Allocation
Randomized
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Folic Acid Supplement [Phase 1]
Arm Type
Other
Arm Description
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
Arm Title
Placebo [Phase 1]
Arm Type
Other
Arm Description
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
Intervention Type
Dietary Supplement
Intervention Name(s)
Folic Acid Supplement
Intervention Description
1 milligram folic acid
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Red Blood Cell Folate Concentration
Description
Biochemical folate status marker (nmol/L)
Time Frame
12 weeks
Title
Red Blood Cell Folate Concentration
Description
Biochemical folate status marker (nmol/L)
Time Frame
36 weeks
Secondary Outcome Measure Information:
Title
Serum Folate Concentration
Description
Biochemical folate status marker (nmol/L)
Time Frame
12 weeks
Title
Serum Folate Concentration
Description
Biochemical folate status marker (nmol/L)
Time Frame
36 weeks
Title
Plasma Unmetabolized Folic Acid Concentration
Description
Biochemical folate marker (nmol/L)
Time Frame
12 weeks
Title
Plasma Unmetabolized Folic Acid Concentration
Description
Biochemical folate marker (nmol/L)
Time Frame
36 weeks
Title
S-adenosyl-methionine Concentration
Description
Biochemical folate metabolite (µmol/L)
Time Frame
12 weeks
Title
S-adenosyl-methionine Concentration
Description
Biochemical folate metabolite (µmol/L)
Time Frame
36 weeks
Title
S-adenosyl-homocysteine Concentration
Description
Biochemical folate metabolite (µmol/L)
Time Frame
12 weeks
Title
S-adenosyl-homocysteine Concentration
Description
Biochemical folate metabolite (µmol/L)
Time Frame
36 weeks
Title
Total homocysteine Concentration
Description
Biochemical folate metabolite (µmol/L)
Time Frame
12 weeks
Title
Total homocysteine Concentration
Description
Biochemical folate metabolite (µmol/L)
Time Frame
36 weeks
Title
Acute Pain Crises
Description
Participant self-reported occurrence (# of episodes, and severity of episodes)
Time Frame
12 weeks
Title
Acute Pain Crises
Description
Participant self-reported occurrence (# of episodes, and severity of episodes)
Time Frame
36 weeks
Title
Megaloblastic anemia
Description
Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
Time Frame
12 weeks
Title
Megaloblastic anemia
Description
Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
Time Frame
36 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Crystal Karakochuk, PhD, RD
Organizational Affiliation
University of British Columbia
Official's Role
Principal Investigator
Facility Information:
Facility Name
BC Children's Hospital
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V6H 3N1
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
32600389
Citation
Williams BA, McCartney H, Adams E, Devlin AM, Singer J, Vercauteren S, Wu JK, Karakochuk CD. Folic acid supplementation in children with sickle cell disease: study protocol for a double-blind randomized cross-over trial. Trials. 2020 Jun 29;21(1):593. doi: 10.1186/s13063-020-04540-7.
Results Reference
background
Links:
URL
https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04540-7
Description
Study protocol

Learn more about this trial

Folic Acid Supplementation in Children With Sickle Cell Disease

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