Anemia, Sickle CellNCT04011345
Folic Acid Supplementation in Children With Sickle Cell Disease
A study testing Folic Acid Supplement in people with Anemia, Sickle Cell, run by University of British Columbia at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 to 19 years
- Conditions the study is for
- Anemia, Sickle Cell
- What is being tested?
- Folic Acid Supplement
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 31 participants
- Where
- 1 siteCanada
- Study dates
- 23 Nov 2020to 31 Oct 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 19 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 9Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Conditions
- Anemia, Sickle Cell
- Being tested
- Folic Acid Supplement, Placebo
- Keywords
- Folic Acid, Unmetabolized Folic Acid, Pediatrics
- Medical subject headings
- Anemia, Sickle Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Folic Acid SupplementDietary supplement
1 milligram folic acid
PlaceboDietary supplement
Placebo
| Study group | Role | What they receive |
|---|---|---|
| Folic Acid Supplement [Phase 1] | Other | 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 Receives: Dietary Supplement: Folic Acid Supplement; Dietary Supplement: Placebo |
| Placebo [Phase 1] | Other | 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 Receives: Dietary Supplement: Folic Acid Supplement; Dietary Supplement: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Red Blood Cell Folate Concentration
Biochemical folate status marker (nmol/L)
Measured: 12 weeks
Red Blood Cell Folate Concentration
Biochemical folate status marker (nmol/L)
Measured: 36 weeks
Secondary outcomes (14)
Serum Folate Concentration
Biochemical folate status marker (nmol/L)
Measured: 12 weeks
Serum Folate Concentration
Biochemical folate status marker (nmol/L)
Measured: 36 weeks
Plasma Unmetabolized Folic Acid Concentration
Biochemical folate marker (nmol/L)
Measured: 12 weeks
Plasma Unmetabolized Folic Acid Concentration
Biochemical folate marker (nmol/L)
Measured: 36 weeks
S-adenosyl-methionine Concentration
Biochemical folate metabolite (µmol/L)
Measured: 12 weeks
S-adenosyl-methionine Concentration
Biochemical folate metabolite (µmol/L)
Measured: 36 weeks
S-adenosyl-homocysteine Concentration
Biochemical folate metabolite (µmol/L)
Measured: 12 weeks
S-adenosyl-homocysteine Concentration
Biochemical folate metabolite (µmol/L)
Measured: 36 weeks
Total homocysteine Concentration
Biochemical folate metabolite (µmol/L)
Measured: 12 weeks
Total homocysteine Concentration
Biochemical folate metabolite (µmol/L)
Measured: 36 weeks
Acute Pain Crises
Participant self-reported occurrence (# of episodes, and severity of episodes)
Measured: 12 weeks
Acute Pain Crises
Participant self-reported occurrence (# of episodes, and severity of episodes)
Measured: 36 weeks
Megaloblastic anemia
Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
Measured: 12 weeks
Megaloblastic anemia
Determined by hemoglobin and Mean Corpuscular Volume (MCV) concentrations below/above age-specific hematological cut-offs
Measured: 36 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jul 2019
- Study start23 Nov 2020
- Primary completion31 Oct 2022
- Study completion31 Oct 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Anemia, Sickle CellStudies of the same condition, open and under way.
- More trials run by University of British ColumbiaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Crossover
- 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 blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 31 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of British Columbia
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Crystal Karakochuk, University of British Columbia
- Investigators
- Crystal Karakochuk, PhD, RD, Principal investigator, University of British Columbia
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04011345
- Sponsor's protocol ID
- H18-02981
- Status last verified
- Aug 2023
- First submitted
- 30 Apr 2019
- Last updated
- 24 Aug 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie the results reported in the published articles, after de-identification (text, tables, figures, and appendices).
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.
PubMed 32600389Williams BA, McCartney H, Singer J, Devlin AM, Vercauteren S, Amid A, Wu JK, Karakochuk CD. Folic acid supplementation in children with sickle cell disease: a randomized double-blind noninferiority cross-over trial. Am J Clin Nutr. 2025 Apr;121(4):910-920. doi: 10.1016/j.ajcnut.2025.02.001. Epub 2025 Feb 5.
PubMed 39921095
Study at a glance
From the registry record, last updated by the sponsor on 24 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Folic Acid Supplementation in Children With Sickle-Cell Disease: A Randomized Double-Blind Cross-Over Trial
- ClinicalTrials.gov ID
- NCT04011345
- Acronym / sponsor ID
- H18-02981
- Conditions
- Anemia, Sickle Cell
- Keywords
- Folic Acid, Unmetabolized Folic Acid, Pediatrics
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 31 participants (actual)
- Lead sponsor
- University of British ColumbiaUniversity, hospital or other
- Study start
- 23 Nov 2020 (actual)
- Primary completion
- 31 Oct 2022 (actual)
- Study completion
- 31 Oct 2022 (actual)
- First posted
- 8 Jul 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Supportive care
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- 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.
| Arm | Type | Receives |
|---|---|---|
| Folic Acid Supplement [Phase 1] | Other | Dietary Supplement: Folic Acid Supplement, Dietary Supplement: PlaceboPhase 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 [Phase 1] | Other | Dietary Supplement: Folic Acid Supplement, Dietary Supplement: PlaceboPhase 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 |
Who may qualify
- Ages
- 2 to 19 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (2 listed)
- 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
Key exclusion criteria (9 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Folic Acid Supplement1 milligram folic acid | Dietary supplement | Folic Acid Supplement [Phase 1], Placebo [Phase 1] |
| PlaceboPlacebo | Dietary supplement | Folic Acid Supplement [Phase 1], Placebo [Phase 1] |
Primary outcome
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)
14 secondary outcomes
Serum Folate Concentration
Time frame: 12 weeks
Serum Folate Concentration
Time frame: 36 weeks
Plasma Unmetabolized Folic Acid Concentration
Time frame: 12 weeks
Plasma Unmetabolized Folic Acid Concentration
Time frame: 36 weeks
S-adenosyl-methionine Concentration
Time frame: 12 weeks
S-adenosyl-methionine Concentration
Time frame: 36 weeks
S-adenosyl-homocysteine Concentration
Time frame: 12 weeks
S-adenosyl-homocysteine Concentration
Time frame: 36 weeks
Total homocysteine Concentration
Time frame: 12 weeks
Total homocysteine Concentration
Time frame: 36 weeks
Acute Pain Crises
Time frame: 12 weeks
Acute Pain Crises
Time frame: 36 weeks
Megaloblastic anemia
Time frame: 12 weeks
Megaloblastic anemia
Time frame: 36 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Aug 2023.
- Background: PubMed 32600389Williams 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.
- Derived from this study: PubMed 39921095Williams BA, McCartney H, Singer J, Devlin AM, Vercauteren S, Amid A, Wu JK, Karakochuk CD. Folic acid supplementation in children with sickle cell disease: a randomized double-blind noninferiority cross-over trial. Am J Clin Nutr. 2025 Apr;121(4):910-920. doi: 10.1016/j.ajcnut.2025.02.001. Epub 2025 Feb 5.
- Study protocolLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie the results reported in the published articles, after de-identification (text, tables, figures, and appendices).
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Crystal Karakochuk, PhD, RD principal investigator
University of British Columbia
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Folic Acid Supplement in people with Anemia, Sickle Cell, run by University of British Columbia at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Aug 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Red Blood Cell Folate Concentration (time frame: 12 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04011345, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Aug 2023.