Vascular Function Intervention Trial in Sickle Cell Disease

NCT01718054 | Unknown Phase 2 DMC

• 2 other identifiers: VFIT001WT094780
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Sickle Cell Disease

Keywords

Vascular function; Ready to use supplementary foods; Chloroquine; Children; Growth; Nitric Oxide

Outcome Measures

Primary Outcomes (3)

• 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)

  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.

  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.

  After 8 months of treatment with RUSFv and RUSF

Secondary Outcomes (6)

• Haemoglobin concentration

  months 0, 4, 8, 12 & 16

• Markers of inflammation and vascular activation

  months 0, 4 & 12

• 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

Study Arms (2)

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

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

Dietary Supplement: Regular Ready-to-use supplementary food; Drug: Chloroquine

Interventions

Vascular ready-to-use supplementary food DIETARY_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

vascular

Regular Ready-to-use supplementary food DIETARY_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.

regular

Chloroquine DRUG

Also known as: Malaviron syrup

regular; vascular

Eligibility Criteria

• Age: 8 Years - 11 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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)

You may not qualify if:

• \>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

Sponsors & Collaborators

• London School of Hygiene and Tropical Medicine: lead
• Wellcome Trust: collaborator

Study Sites (1)

Muhimbili University of Heath and Allied Sciences (MUHAS)

Dar es Salaam, Tanzania

Location

Related Publications (1)

• 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.

  PMID: 29548623 DERIVED

MeSH Terms

Conditions

Anemia, Sickle Cell

Interventions

Chloroquine

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Sharon Cox, PhD

  London School of Hygiene & Tropical Medicine, UK / Muhimbili Wellcome Programme, Tanzania

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 1, 2012
• First Posted: October 31, 2012
• Study Start: August 1, 2012
• Primary Completion: September 1, 2016
• Study Completion: September 1, 2017
• Last Updated: July 27, 2016

Record last verified: 2016-07

Locations

TA (1)