Vascular Function Intervention Trial in Sickle Cell Disease (V-FIT)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Wellcome Trust
Information provided by (Responsible Party):
London School of Hygiene and Tropical Medicine
ClinicalTrials.gov Identifier:
NCT01718054
First received: February 1, 2012
Last updated: March 25, 2013
Last verified: March 2013
  Purpose

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.


Condition Intervention Phase
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 Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, 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

Resource links provided by NLM:


Further study details as provided by London School of Hygiene and Tropical Medicine:

Primary Outcome Measures:
  • ratio of arginine to ornithine concentration & ratio of arginine to ADMA [ Time Frame: 4 or 12 months ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Haemoglobin concentration [ Time Frame: months 0, 4, 8, 12 & 16 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 120
Study Start Date: August 2012
Estimated Study Completion Date: April 2014
Estimated Primary Completion Date: April 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 acids
Drug: 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

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:

  1. 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.
  2. 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)
  3. 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.

  Eligibility

Ages Eligible for Study:   8 Years to 11 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01718054

Locations
Tanzania
Muhimbili University of Heath and Allied Sciences (MUHAS)
Dar es Salaam, Tanzania
Sponsors and Collaborators
London School of Hygiene and Tropical Medicine
Wellcome Trust
Investigators
Principal Investigator: Sharon Cox, PhD London School of Hygiene & Tropical Medicine, UK / Muhimbili Wellcome Programme, Tanzania
  More Information

No publications provided

Responsible Party: London School of Hygiene and Tropical Medicine
ClinicalTrials.gov Identifier: NCT01718054     History of Changes
Other Study ID Numbers: VFIT001, WT094780
Study First Received: February 1, 2012
Last Updated: March 25, 2013
Health Authority: Tanzania: Food & Drug Administration

Keywords provided by London School of Hygiene and Tropical Medicine:
Vascular function
Ready to use supplementary foods
Chloroquine
Children
Growth
Nitric Oxide

Additional relevant MeSH terms:
Anemia, Sickle Cell
Anemia
Anemia, Hemolytic
Anemia, Hemolytic, Congenital
Genetic Diseases, Inborn
Hematologic Diseases
Hemoglobinopathies
Chloroquine
Chloroquine diphosphate
Amebicides
Analgesics
Analgesics, Non-Narcotic
Anthelmintics
Anti-Infective Agents
Anti-Inflammatory Agents
Anti-Inflammatory Agents, Non-Steroidal
Antimalarials
Antinematodal Agents
Antiparasitic Agents
Antiprotozoal Agents
Antirheumatic Agents
Central Nervous System Agents
Filaricides
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sensory System Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014