Development of a Ready-to-use Nutraceutical Food for Patients With Sickle Cell Disease (SCD): Testing of Vascular Support Components
试验速览
- 阶段
- 2 期
- 入组人数
- 120
- 试验地点
- 1
- 主要终点
- Linear Growth and Weight Gain
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 8 Years 至 11 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •>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
研究组 & 干预措施
vascular
In this intervention period children will receive a vascular ready-to-use supplementary food with added L-Arginine & L-Citrulline plus daily chloroquine
干预措施: Vascular ready-to-use supplementary food (Dietary Supplement)
vascular
In this intervention period children will receive a vascular ready-to-use supplementary food with added L-Arginine & L-Citrulline plus daily chloroquine
干预措施: Chloroquine (Drug)
regular
In this intervention period children will receive a regular ready-to-use supplementary food plus weekly dose of chloroquine
干预措施: Regular Ready-to-use supplementary food (Dietary Supplement)
regular
In this intervention period children will receive a regular ready-to-use supplementary food plus weekly dose of chloroquine
干预措施: Chloroquine (Drug)
结局指标
主要结局
Linear Growth and Weight Gain
时间窗: 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.
Nitric Oxide dependent endothelial function
时间窗: 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.
ratio of arginine to ornithine concentration & ratio of arginine to ADMA
时间窗: 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)
次要结局
- Haemoglobin concentration(months 0, 4, 8, 12 & 16)
- Markers of haemolysis(months 0, 4 & 12)
- Frequency of vaso-occlusive painful episodes(Weekly from month 0-16)
- liver and kidney function clinical chemistry(months 0, 4 & 12)
- glomerular filtration rate(months 0, 4 and 12)
- Markers of inflammation and vascular activation(months 0, 4 & 12)