Sickle Cell DiseasePhase 2/3V-FITNCT01718054
Vascular Function Intervention Trial in Sickle Cell Disease
A Phase 2/3 study testing Vascular ready-to-use supplementary food, Regular Ready-to-use supplementary food and Chloroquine in people with Sickle Cell Disease, run by London School of Hygiene and Tropical Medicine at 1 site in Tanzania.
Trial summary
Sickle cell disease (SCD) is the most common inherited disorder worldwide affecting 300,000 births annually, most occuring in sub-Saharan Africa (SSA) where poor detection and care result in high childhood mortality, malnutrition, illness and disability in survivors. Read more about this study
- Who is it for?
- Ages 8 to 11 years
- Conditions the study is for
- Sickle Cell Disease
- What is being tested?
- Vascular ready-to-use supplementary food, Regular Ready-to-use supplementary food and Chloroquine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 120 participants
- Where
- 1 siteTanzania
- Study dates
- Aug 2012to Sep 2017
- Phase
- Phase 2/3
- 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 8 to 11 years
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Aged 8-11 years old at enrolment and resident within urban Dar-es-Salaam
- Enrolled in Muhimbili Sickle Cohort and attending routine Muhimbili National Hospital sickle clinics
- Homozygous for hemoglobin S (HbSS) phenotype confirmed by electrophoresis and high performance liquid chromatography (HPLC)
Who cannot join
- >95th percentile for body mass index (BMI) for age using British 1990 growth standards
- Receiving hydroxyurea therapy or significant other long-term drug therapy
- Diagnosis with clinically significant non-SCD related disease including:
- Stage III or above HIV - or receiving ART therapy regardless of AIDS stage
- Tuberculosis infection
- Blood transfusion within previous 30 days
Show all 10Show fewer
- Previously diagnosed clinical pulmonary hypertension or cardiac dysfunction or clinical signs of pulmonary hypertension (loud pulmonary second heart sound) or heart failure (displaced apex beat, high jugular venous pressure, enlarged liver, peripheral oedema)
- Low visual acuity at baseline (<6/9 using a modified (for Tanzania) Snellen chart or previously diagnosed chronic eye disorder likely to suggest retinopathy or macular degeneration
- Significant hepatic/renal dysfunction assessed by clinical chemistry panel at baseline
- Epilepsy, psoriasis or currently taking any drugs listed as interacting with chloroquine
Trial locations and contacts
1 site in 1 country.
Tanzania1 site
Muhimbili University of Heath and Allied Sciences (MUHAS)
Dar es Salaam
About this study
Official title: Development of a Ready-to-use Nutraceutical Food for Patients With Sickle Cell Disease (SCD): Testing of Vascular Support Components
Sickle cell disease (SCD) is the most common inherited disorder worldwide affecting 300,000 births annually, most occuring in sub-Saharan Africa (SSA) where poor detection and care result in high childhood mortality, malnutrition, illness and disability in survivors. SCD is caused by abnormal haemoglobin, the compound in red blood cells(RBC) that carries oxygen. Much of the disability in SCD may be caused by vascular damage from the breakdown of damaged RBC. Research in high-income countries has led to some effective therapies but these are currently costly and complex. The investigators will test two different formulations of an affordable, ready-to-use supplementary food (RUSF) specifically tailored for children with SCD. As well as containing energy, protein, essential fats, vitamins and minerals, the vascular RUSF (RUSFv) will be fortified with the amino-acids arginine and citrulline and be delivered with a daily chloroquine dose to create a novel "nutraceutical" intervention. Arginine is converted to nitric oxide which is essential for vascular health. Arginine levels are low in SCD because the arginine-degrading enzyme, arginase, is released from RBCs. The investigators propose that by supplying additional arginine (and citrulline which converts to arginine) and suppressing arginase activity (an action of chloroquine) the investigators can improve vascular function. Our study will test this theory, and if provision of RUSF improves growth in children with SCD.
Read the detailed description
Arginine is the substrate of endothelial nitric oxide (NO) synthase. Citrulline converts to arginine and has a greater bioavailability than arginine. Chloroquine is a competitive inhibitor of arginase which is released from lysed red cells and possibly through liver damage. Raised arginase predicts low plasma arginine levels and may predict clinical disease severity.
The interventions being tested are designed to target:
(i) the moderate to severe growth retardation commonly observed in children with SCD especially in low income countries; (ii) endothelial dysregulation secondary to low NO bioavailability, inflammation and oxidant stress, hypothesised to underlie much of the clinical pathology in SCD.
This study will test the following hypotheses:
- That the provision of energy, protein and micronutrients within a ready to use supplementary food will increase linear growth, weight gain and proportion of fat-free mass in children with SCD.
- That the provision of supplementary L-arginine and L-citrulline within the matrix of a twice-daily RUSF plus daily chloroquine (CQ) for 4 months, compared to a standard RUSF and weekly anti-malarial prophylaxis CQ to children with SCD will:
- Increase plasma arginine concentrations and the ratio of plasma arginine: ornithine.
- Decrease or not alter plasma asymmetric dimethylarginine (ADMA) concentrations
- Improve NO-dependent vascular function as detected by an increase in maximum flow mediated dilatation (FMDmax)
- That the provision of daily CQ at a dosage of 2-3mg base/kg/day for 4 months to children with SCD will:
- Decrease the activity of plasma arginase through competitive inhibition
- Decrease levels of plasma inflammatory markers
If successful then larger studies of efficacy and effectiveness would be needed to assess long-term endpoints of hospitalization, stroke, and mortality. Existing evidence suggests that the proposed intervention also has the potential to increase the efficacy of hydroxyurea (HU) therapy. The successful development of an affordable ready-to-use 'nutraceutical' food with proven efficacy in growth promotion and vascular health could represent a major step forward for SCD patients in low-income countries.
- Conditions
- Sickle Cell Disease
- Being tested
- Vascular ready-to-use supplementary food, Regular Ready-to-use supplementary food, Chloroquine
- Keywords
- Vascular function, Ready to use supplementary foods, Chloroquine, Children, Growth, Nitric Oxide
- 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.
Vascular ready-to-use supplementary foodDietary supplement
Daily vascular ready-to-use supplementary food containing protein, energy and fortified with 1 x recommended daily allowance(RDA) of vitamins and minerals except for folic acid = 1mg and with no iron fortificant included and fortified with arginine and citrulline amino acids
Regular Ready-to-use supplementary foodDietary supplement
Daily ready-to-use supplementary food containing protein, energy and fortified with 1 x RDA vitamins and minerals except for folic acid = 1mg and with no iron fortificant included.
ChloroquineDrug
Also called Malaviron syrup
| Study group | Role | What they receive |
|---|---|---|
| vascular | Active comparator | In this intervention period children will receive a vascular ready-to-use supplementary food with added L-Arginine \& L-Citrulline plus daily chloroquine Receives: Dietary Supplement: Vascular ready-to-use supplementary food; Drug: Chloroquine |
| regular | Active comparator | In this intervention period children will receive a regular ready-to-use supplementary food plus weekly dose of chloroquine Receives: Dietary Supplement: Regular Ready-to-use supplementary food; Drug: Chloroquine |
What is being measured
The primary outcome is the main question the study is designed to answer.
ratio of arginine to ornithine concentration & ratio of arginine to ADMA
We will compare the effects of the RUSFv compared to the simple RUSF on:
The ratio of plasma arginine to ornithine \& ratio of arginine to ADMA and adjust for values at baseline
Time frame definition:
0 months = baseline
4 months = after 1st four-month intervention period, before washout 1
8 months = after 1st 4 month washout period before 2nd intervention period
12 months = after 2nd four-month intervention period, before washout 2
16 months = after 2nd 4 month washout period (study end)
Measured: 4 or 12 months
Nitric Oxide dependent endothelial function
Comparison of the effects of the RUSFv to the simple RUSF on vascular function, assessed using flow mediated dilatation (FMDmax), adjusted for baseline values at time 0. Values will also be determined at time point at month 8, in order to check for possible carry-over effect.
Measured: months 4 or 12
Linear Growth and Weight Gain
We will compare the effects of RUSF compared to no RUSF on rates of growth by comparison of the 2 intervention periods combined with the two washout periods combined, by conducting measurements at months 0, 4, 8, 12 \& 16.
Measured: After 8 months of treatment with RUSFv and RUSF
Secondary outcomes (6)
Haemoglobin concentration
Full blood counts (FBC) of ethylenediaminetetraacetic acid (EDTA) whole blood will be conducted
Measured: months 0, 4, 8, 12 & 16
Markers of inflammation and vascular activation
Concentrations of soluble adhesion molecules (VCAM-1, vascular endothelial growth factor-1 (VEGF-1), tumor necrosis factor-alpha (TNF-α) \& e-selectin, tissue factor and IL-6) will be measured in frozen (-80⁰C) plasma aliquots.
C-reactive protein concentrations will be measured in frozen serum samples and leukocyte counts from FBC.
Measured: months 0, 4 & 12
Markers of haemolysis
Plasma haemoglobin will be measured in frozen serum aliquots. Unconjugated bilirubin and lactate dehydrogenase in fresh serum.
Measured: months 0, 4 & 12
Frequency of vaso-occlusive painful episodes
Study personnel will administer detailed questionnaires at weekly home visits to assess the frequency of all sickle and non-sickle associated morbidity and health seeking behaviour, with a focus on painful episodes. Participatory research will be used to determine the likely application and optimal formatting of pain diaries to be completed by patients and families in addition to the standard questionnaire.
Measured: Weekly from month 0-16
liver and kidney function clinical chemistry
aspartate transaminase, alkaline phosphatase, total and direct bilirubin and creatinine will be measured in fresh serum
Measured: months 0, 4 & 12
glomerular filtration rate
glomerular filtration rate will be estimated using an adaptation of the Schwartz equation in which muscle mass measured using bioimpedance will be included in the formula instead of the usual estimate. The outcome will be adjusted for values at baseline.
Measured: months 0, 4 and 12
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Oct 2012 (estimated)
- Study startAug 2012
- Primary completionSep 2016 (estimated)
- Study completionSep 2017 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Sickle Cell DiseaseStudies of the same condition, open and under way.
- 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 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 120 participants (estimated)
Sponsor and investigators
- Lead sponsor
- London School of Hygiene and Tropical Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Wellcome Trust
- Responsible party
- Sponsor
- Investigators
- Sharon Cox, PhD, Principal investigator, London School of Hygiene & Tropical Medicine, UK / Muhimbili Wellcome Programme, Tanzania
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01718054
- Sponsor's protocol ID
- VFIT001
- Other IDs
- WT094780
- Acronym
- V-FIT
- Status last verified
- Jul 2016
- First submitted
- 1 Feb 2012
- Last updated
- 27 Jul 2016
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Cox SE, Ellins EA, Marealle AI, Newton CR, Soka D, Sasi P, Luca Di Tanna G, Johnson W, Makani J, Prentice AM, Halcox JP, Kirkham FJ. Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trial. Lancet Haematol. 2018 Apr;5(4):e147-e160. doi: 10.1016/S2352-3026(18)30020-6. Epub 2018 Mar 13.
PubMed 29548623
Study at a glance
From the registry record, last updated by the sponsor on 27 Jul 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Development of a Ready-to-use Nutraceutical Food for Patients With Sickle Cell Disease (SCD): Testing of Vascular Support Components
- ClinicalTrials.gov ID
- NCT01718054
- Acronym / sponsor ID
- V-FIT / VFIT001
- Conditions
- Sickle Cell Disease
- Keywords
- Vascular function, Ready to use supplementary foods, Chloroquine, Children, Growth, Nitric Oxide
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 120 participants (estimated)
- Lead sponsor
- London School of Hygiene and Tropical MedicineUniversity, hospital or other
- Collaborators
- Wellcome Trust
- Study start
- Aug 2012
- Primary completion
- Sep 2016 (estimated)
- Study completion
- Sep 2017 (estimated)
- First posted
- 31 Oct 2012 (estimated)
- 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.
Sickle cell disease (SCD) is the most common inherited disorder worldwide affecting 300,000 births annually, most occuring in sub-Saharan Africa (SSA) where poor detection and care result in high childhood mortality, malnutrition, illness and disability in survivors. SCD is caused by abnormal haemoglobin, the compound in red blood cells(RBC) that carries oxygen. Much of the disability in SCD may be caused by vascular damage from the breakdown of damaged RBC. Research in high-income countries has led to some effective therapies but these are currently costly and complex. The investigators will test two different formulations of an affordable, ready-to-use supplementary food (RUSF) specifically tailored for children with SCD. As well as containing energy, protein, essential fats, vitamins and minerals, the vascular RUSF (RUSFv) will be fortified with the amino-acids arginine and citrulline and be delivered with a daily chloroquine dose to create a novel "nutraceutical" intervention. Arginine is converted to nitric oxide which is essential for vascular health. Arginine levels are low in SCD because the arginine-degrading enzyme, arginase, is released from RBCs. The investigators propose that by supplying additional arginine (and citrulline which converts to arginine) and suppressing arginase activity (an action of chloroquine) the investigators can improve vascular function. Our study will test this theory, and if provision of RUSF improves growth in children with SCD.
Detailed description
Arginine is the substrate of endothelial nitric oxide (NO) synthase. Citrulline converts to arginine and has a greater bioavailability than arginine. Chloroquine is a competitive inhibitor of arginase which is released from lysed red cells and possibly through liver damage. Raised arginase predicts low plasma arginine levels and may predict clinical disease severity.
The interventions being tested are designed to target:
(i) the moderate to severe growth retardation commonly observed in children with SCD especially in low income countries; (ii) endothelial dysregulation secondary to low NO bioavailability, inflammation and oxidant stress, hypothesised to underlie much of the clinical pathology in SCD.
This study will test the following hypotheses:
- That the provision of energy, protein and micronutrients within a ready to use supplementary food will increase linear growth, weight gain and proportion of fat-free mass in children with SCD.
- That the provision of supplementary L-arginine and L-citrulline within the matrix of a twice-daily RUSF plus daily chloroquine (CQ) for 4 months, compared to a standard RUSF and weekly anti-malarial prophylaxis CQ to children with SCD will:
- Increase plasma arginine concentrations and the ratio of plasma arginine: ornithine.
- Decrease or not alter plasma asymmetric dimethylarginine (ADMA) concentrations
- Improve NO-dependent vascular function as detected by an increase in maximum flow mediated dilatation (FMDmax)
- That the provision of daily CQ at a dosage of 2-3mg base/kg/day for 4 months to children with SCD will:
- Decrease the activity of plasma arginase through competitive inhibition
- Decrease levels of plasma inflammatory markers
If successful then larger studies of efficacy and effectiveness would be needed to assess long-term endpoints of hospitalization, stroke, and mortality. Existing evidence suggests that the proposed intervention also has the potential to increase the efficacy of hydroxyurea (HU) therapy. The successful development of an affordable ready-to-use 'nutraceutical' food with proven efficacy in growth promotion and vascular health could represent a major step forward for SCD patients in low-income countries.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| vascular | Active comparator | Dietary Supplement: Vascular ready-to-use supplementary food, Drug: ChloroquineIn this intervention period children will receive a vascular ready-to-use supplementary food with added L-Arginine \& L-Citrulline plus daily chloroquine |
| regular | Active comparator | Dietary Supplement: Regular Ready-to-use supplementary food, Drug: ChloroquineIn this intervention period children will receive a regular ready-to-use supplementary food plus weekly dose of chloroquine |
Who may qualify
- Ages
- 8 to 11 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (3 listed)
- Aged 8-11 years old at enrolment and resident within urban Dar-es-Salaam
- Enrolled in Muhimbili Sickle Cohort and attending routine Muhimbili National Hospital sickle clinics
- Homozygous for hemoglobin S (HbSS) phenotype confirmed by electrophoresis and high performance liquid chromatography (HPLC)
Key exclusion criteria (10 listed)
- >95th percentile for body mass index (BMI) for age using British 1990 growth standards
- Receiving hydroxyurea therapy or significant other long-term drug therapy
- Diagnosis with clinically significant non-SCD related disease including:
- Blood transfusion within previous 30 days
- Previously diagnosed clinical pulmonary hypertension or cardiac dysfunction or clinical signs of pulmonary hypertension (loud pulmonary second heart sound) or heart failure (displaced apex beat, high jugular venous pressure, enlarged liver, peripheral oedema)
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 |
|---|---|---|
| Vascular ready-to-use supplementary foodDaily vascular ready-to-use supplementary food containing protein, energy and fortified with 1 x recommended daily allowance(RDA) of vitamins and minerals except for folic acid = 1mg and with no iron fortificant included and fortified with arginine and citrulline amino acids | Dietary supplement | vascular |
| Regular Ready-to-use supplementary foodDaily ready-to-use supplementary food containing protein, energy and fortified with 1 x RDA vitamins and minerals except for folic acid = 1mg and with no iron fortificant included. | Dietary supplement | regular |
| ChloroquineAlso: Malaviron syrup | Drug | regular, vascular |
Primary outcome
ratio of arginine to ornithine concentration & ratio of arginine to ADMA
Time frame: 4 or 12 months
We will compare the effects of the RUSFv compared to the simple RUSF on: The ratio of plasma arginine to ornithine \& ratio of arginine to ADMA and adjust for values at baseline Time frame definition: 0 months = baseline 4 months = after 1st four-month intervention period, before washout 1 8 months = after 1st 4 month washout period before 2nd intervention period 12 months = after 2nd four-month intervention period, before washout 2 16 months = after 2nd 4 month washout period (study end)
Nitric Oxide dependent endothelial function
Time frame: months 4 or 12
Comparison of the effects of the RUSFv to the simple RUSF on vascular function, assessed using flow mediated dilatation (FMDmax), adjusted for baseline values at time 0. Values will also be determined at time point at month 8, in order to check for possible carry-over effect.
Linear Growth and Weight Gain
Time frame: After 8 months of treatment with RUSFv and RUSF
We will compare the effects of RUSF compared to no RUSF on rates of growth by comparison of the 2 intervention periods combined with the two washout periods combined, by conducting measurements at months 0, 4, 8, 12 \& 16.
6 secondary outcomes
Haemoglobin concentration
Time frame: months 0, 4, 8, 12 & 16
Markers of inflammation and vascular activation
Time frame: months 0, 4 & 12
Markers of haemolysis
Time frame: months 0, 4 & 12
Frequency of vaso-occlusive painful episodes
Time frame: Weekly from month 0-16
liver and kidney function clinical chemistry
Time frame: months 0, 4 & 12
glomerular filtration rate
Time frame: months 0, 4 and 12
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Jul 2016.
- Derived from this study: PubMed 29548623Cox SE, Ellins EA, Marealle AI, Newton CR, Soka D, Sasi P, Luca Di Tanna G, Johnson W, Makani J, Prentice AM, Halcox JP, Kirkham FJ. Ready-to-use food supplement, with or without arginine and citrulline, with daily chloroquine in Tanzanian children with sickle-cell disease: a double-blind, random order crossover trial. Lancet Haematol. 2018 Apr;5(4):e147-e160. doi: 10.1016/S2352-3026(18)30020-6. Epub 2018 Mar 13.
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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.
Sharon Cox, PhD principal investigator
London School of Hygiene & Tropical Medicine, UK / Muhimbili Wellcome Programme, Tanzania
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Vascular ready-to-use supplementary food, Regular Ready-to-use supplementary food and Chloroquine in people with Sickle Cell Disease, run by London School of Hygiene and Tropical Medicine at 1 site in Tanzania.
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 3 inclusion and 10 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: status not confirmed, as of the sponsor's last update on 27 Jul 2016. 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 Tanzania. 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.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
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?
ratio of arginine to ornithine concentration & ratio of arginine to ADMA (time frame: 4 or 12 months). The study lists 3 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 NCT01718054, which also lists 1 linked publication.
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 27 Jul 2016.