Folic Acid Supplementation in Children With Sickle Cell Disease

Sponsor

University of British Columbia (Other)

Overall Status

Recruiting

CT.gov ID

NCT04011345

Collaborator

(none)

Enrollment

Location

Arms

21.3

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Anemia, Sickle Cell	Dietary Supplement: Folic Acid Supplement Dietary Supplement: Placebo	N/A

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

Study Type:

Interventional

Anticipated Enrollment :

36 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.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 :

Nov 23, 2020

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Sep 1, 2022

Arms and Interventions

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

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

Dietary Supplement: Folic Acid Supplement

1 milligram folic acid

Dietary Supplement: Placebo

Placebo

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

Dietary Supplement: Folic Acid Supplement

1 milligram folic acid

Dietary Supplement: Placebo

Placebo

Outcome Measures

Primary Outcome Measures

Red Blood Cell Folate Concentration [12 weeks]
Biochemical folate status marker (nmol/L)
Red Blood Cell Folate Concentration [36 weeks]
Biochemical folate status marker (nmol/L)

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 19 Years

Sexes Eligible for Study:

All

Accepts 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.