Vascular Function Intervention Trial in Sickle Cell Disease (V-FIT)
|Sickle Cell Disease||Dietary Supplement: Vascular ready-to-use supplementary food Dietary Supplement: Regular Ready-to-use supplementary food Drug: Chloroquine||Phase 2 Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Development of a Ready-to-use Nutraceutical Food for Patients With Sickle Cell Disease (SCD): Testing of Vascular Support Components|
- 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.
- Haemoglobin concentration [ Time Frame: months 0, 4, 8, 12 & 16 ]Full blood counts (FBC) of ethylenediaminetetraacetic acid (EDTA) whole blood will be conducted
- Markers of inflammation and vascular activation [ Time Frame: months 0, 4 & 12 ]
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.
- Markers of haemolysis [ Time Frame: months 0, 4 & 12 ]Plasma haemoglobin will be measured in frozen serum aliquots. Unconjugated bilirubin and lactate dehydrogenase in fresh serum.
- Frequency of vaso-occlusive painful episodes [ Time Frame: Weekly from month 0-16 ]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.
- liver and kidney function clinical chemistry [ Time Frame: months 0, 4 & 12 ]aspartate transaminase, alkaline phosphatase, total and direct bilirubin and creatinine will be measured in fresh serum
- glomerular filtration rate [ Time Frame: months 0, 4 and 12 ]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.
|Study Start Date:||August 2012|
|Estimated Study Completion Date:||September 2017|
|Estimated Primary Completion Date:||September 2016 (Final data collection date for primary outcome measure)|
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
Dietary Supplement: Vascular ready-to-use supplementary food
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 acidsDrug: Chloroquine
Other Name: Malaviron syrup
Active Comparator: regular
In this intervention period children will receive a regular ready-to-use supplementary food plus weekly dose of chloroquine
Dietary Supplement: Regular Ready-to-use supplementary food
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.Drug: Chloroquine
Other Name: Malaviron syrup
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01718054
|Muhimbili University of Heath and Allied Sciences (MUHAS)|
|Dar es Salaam, Tanzania|
|Principal Investigator:||Sharon Cox, PhD||London School of Hygiene & Tropical Medicine, UK / Muhimbili Wellcome Programme, Tanzania|