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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Anemia, Sickle Cell | Dietary Supplement: Folic Acid Supplement Dietary Supplement: Placebo | Not Applicable |
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 (Clinical Trial) |
| Estimated 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. |
| 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 |
| Estimated Primary Completion Date : | September 2022 |
| Estimated Study Completion Date : | September 2022 |
| 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
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Dietary Supplement: Folic Acid Supplement
1 milligram folic acid
Dietary Supplement: Placebo Placebo
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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
|
- Red Blood Cell Folate Concentration [ Time Frame: 12 weeks ]Biochemical folate status marker (nmol/L)
- Red Blood Cell Folate Concentration [ Time Frame: 36 weeks ]Biochemical folate status marker (nmol/L)
- Serum Folate Concentration [ Time Frame: 12 weeks ]Biochemical folate status marker (nmol/L)
- Serum Folate Concentration [ Time Frame: 36 weeks ]Biochemical folate status marker (nmol/L)
- Plasma Unmetabolized Folic Acid Concentration [ Time Frame: 12 weeks ]Biochemical folate marker (nmol/L)
- Plasma Unmetabolized Folic Acid Concentration [ Time Frame: 36 weeks ]Biochemical folate marker (nmol/L)
- S-adenosyl-methionine Concentration [ Time Frame: 12 weeks ]Biochemical folate metabolite (µmol/L)
- S-adenosyl-methionine Concentration [ Time Frame: 36 weeks ]Biochemical folate metabolite (µmol/L)
- S-adenosyl-homocysteine Concentration [ Time Frame: 12 weeks ]Biochemical folate metabolite (µmol/L)
- S-adenosyl-homocysteine Concentration [ Time Frame: 36 weeks ]Biochemical folate metabolite (µmol/L)
- Total homocysteine Concentration [ Time Frame: 12 weeks ]Biochemical folate metabolite (µmol/L)
- Total homocysteine Concentration [ Time Frame: 36 weeks ]Biochemical folate metabolite (µmol/L)
- Acute Pain Crises [ Time Frame: 12 weeks ]Participant self-reported occurrence (# of episodes, and severity of episodes)
- Acute Pain Crises [ Time Frame: 36 weeks ]Participant self-reported occurrence (# of episodes, and severity of episodes)
- Megaloblastic anemia [ Time Frame: 12 weeks ]Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
- Megaloblastic anemia [ Time Frame: 36 weeks ]Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
| Ages Eligible for Study: | 2 Years to 19 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
| Contact: Brock Williams, MSc, RD | 905-999-3710 | brock.williams@ubc.ca | |
| Contact: Crystal Karakochuk, PhD, RD | 604-710-8496 | crystal.karakochuk@ubc.ca |
| Canada, British Columbia | |
| BC Children's Hospital | Recruiting |
| Vancouver, British Columbia, Canada, V6H 3N1 | |
| Contact: Crystal Karakochuk, PhD, RD 604-822-0421 crystal.karakochuk@ubc.ca | |
| Contact: John Wu, MBBS, MSc 604-875-2406 jwu@cw.bc.ca | |
| Principal Investigator: Crystal Karakochuk, PhD, RD | |
| Sub-Investigator: John Wu, MBBS, MSc | |
| Principal Investigator: | Crystal Karakochuk, PhD, RD | University of British Columbia |
| Tracking Information | |||||||||||||||||||
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| First Submitted Date ICMJE | April 30, 2019 | ||||||||||||||||||
| First Posted Date ICMJE | July 8, 2019 | ||||||||||||||||||
| Last Update Posted Date | April 30, 2021 | ||||||||||||||||||
| Actual Study Start Date ICMJE | November 23, 2020 | ||||||||||||||||||
| Estimated Primary Completion Date | September 2022 (Final data collection date for primary outcome measure) | ||||||||||||||||||
| Current Primary Outcome Measures ICMJE |
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| Original Primary Outcome Measures ICMJE | Same as current | ||||||||||||||||||
| Change History | |||||||||||||||||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||||||||||||||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||||||||||||||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||||||||||||||||
| Descriptive Information | |||||||||||||||||||
| Brief Title ICMJE | Folic Acid Supplementation in Children With Sickle Cell Disease | ||||||||||||||||||
| Official Title ICMJE | Folic Acid Supplementation in Children With Sickle-Cell Disease: A Randomized Double-Blind Cross-Over Trial | ||||||||||||||||||
| 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. |
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| 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. |
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| Study Type ICMJE | Interventional | ||||||||||||||||||
| Study Phase ICMJE | Not Applicable | ||||||||||||||||||
| Study Design ICMJE | 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
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| Condition ICMJE | Anemia, Sickle Cell | ||||||||||||||||||
| Intervention ICMJE |
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| Study Arms ICMJE |
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| Publications * | 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. | ||||||||||||||||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||||||||||||||||
| Recruitment Status ICMJE | Recruiting | ||||||||||||||||||
| Estimated Enrollment ICMJE |
36 | ||||||||||||||||||
| Original Estimated Enrollment ICMJE | Same as current | ||||||||||||||||||
| Estimated Study Completion Date ICMJE | September 2022 | ||||||||||||||||||
| Estimated Primary Completion Date | September 2022 (Final data collection date for primary outcome measure) | ||||||||||||||||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 2 Years to 19 Years (Child, Adult) | ||||||||||||||||||
| Accepts Healthy Volunteers ICMJE | No | ||||||||||||||||||
| Contacts ICMJE |
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| Listed Location Countries ICMJE | Canada | ||||||||||||||||||
| Removed Location Countries | |||||||||||||||||||
| Administrative Information | |||||||||||||||||||
| NCT Number ICMJE | NCT04011345 | ||||||||||||||||||
| Other Study ID Numbers ICMJE | H18-02981 | ||||||||||||||||||
| Has Data Monitoring Committee | Yes | ||||||||||||||||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | Crystal Karakochuk, University of British Columbia | ||||||||||||||||||
| Study Sponsor ICMJE | University of British Columbia | ||||||||||||||||||
| Collaborators ICMJE | Not Provided | ||||||||||||||||||
| Investigators ICMJE |
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| PRS Account | University of British Columbia | ||||||||||||||||||
| Verification Date | April 2021 | ||||||||||||||||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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