- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01718054
Vascular Function Intervention Trial in Sickle Cell Disease (V-FIT)
Development of a Ready-to-use Nutraceutical Food for Patients With Sickle Cell Disease (SCD): Testing of Vascular Support Components
Study Overview
Status
Conditions
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 Type
Enrollment (Anticipated)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
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Dar es Salaam, Tanzania
- Muhimbili University of Heath and Allied Sciences (MUHAS)
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- 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)
Exclusion Criteria:
- >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
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Crossover Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Active Comparator: vascular
In this intervention period children will receive a vascular ready-to-use supplementary food with added L-Arginine & L-Citrulline plus daily chloroquine
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Other Names:
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
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Active Comparator: regular
In this intervention period children will receive a regular ready-to-use supplementary food plus weekly dose of chloroquine
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Other Names:
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.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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) |
4 or 12 months
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Nitric Oxide dependent endothelial function
Time Frame: months 4 or 12
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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.
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months 4 or 12
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Linear Growth and Weight Gain
Time Frame: After 8 months of treatment with RUSFv and RUSF
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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.
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After 8 months of treatment with RUSFv and RUSF
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Haemoglobin concentration
Time Frame: months 0, 4, 8, 12 & 16
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Full blood counts (FBC) of ethylenediaminetetraacetic acid (EDTA) whole blood will be conducted
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months 0, 4, 8, 12 & 16
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Markers of inflammation and vascular activation
Time Frame: months 0, 4 & 12
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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. |
months 0, 4 & 12
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Markers of haemolysis
Time Frame: months 0, 4 & 12
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Plasma haemoglobin will be measured in frozen serum aliquots.
Unconjugated bilirubin and lactate dehydrogenase in fresh serum.
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months 0, 4 & 12
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Frequency of vaso-occlusive painful episodes
Time Frame: Weekly from month 0-16
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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.
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Weekly from month 0-16
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liver and kidney function clinical chemistry
Time Frame: months 0, 4 & 12
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aspartate transaminase, alkaline phosphatase, total and direct bilirubin and creatinine will be measured in fresh serum
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months 0, 4 & 12
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glomerular filtration rate
Time Frame: months 0, 4 and 12
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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.
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months 0, 4 and 12
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Sharon Cox, PhD, London School of Hygiene & Tropical Medicine, UK / Muhimbili Wellcome Programme, Tanzania
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- VFIT001
- WT094780 (Other Grant/Funding Number: The Wellcome Trust, UK)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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