<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01718054</url>
  </required_header>
  <id_info>
    <org_study_id>VFIT001</org_study_id>
    <secondary_id>WT094780</secondary_id>
    <nct_id>NCT01718054</nct_id>
  </id_info>
  <brief_title>Vascular Function Intervention Trial in Sickle Cell Disease</brief_title>
  <acronym>V-FIT</acronym>
  <official_title>Development of a Ready-to-use Nutraceutical Food for Patients With Sickle Cell Disease (SCD): Testing of Vascular Support Components</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>London School of Hygiene and Tropical Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Wellcome Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>London School of Hygiene and Tropical Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Sickle cell disease (SCD) is the most common inherited disorder worldwide affecting 300,000&#xD;
      births annually, most occuring in sub-Saharan Africa (SSA) where poor detection and care&#xD;
      result in high childhood mortality, malnutrition, illness and disability in survivors. SCD is&#xD;
      caused by abnormal haemoglobin, the compound in red blood cells(RBC) that carries oxygen.&#xD;
      Much of the disability in SCD may be caused by vascular damage from the breakdown of damaged&#xD;
      RBC. Research in high-income countries has led to some effective therapies but these are&#xD;
      currently costly and complex. The investigators will test two different formulations of an&#xD;
      affordable, ready-to-use supplementary food (RUSF) specifically tailored for children with&#xD;
      SCD. As well as containing energy, protein, essential fats, vitamins and minerals, the&#xD;
      vascular RUSF (RUSFv) will be fortified with the amino-acids arginine and citrulline and be&#xD;
      delivered with a daily chloroquine dose to create a novel &quot;nutraceutical&quot; intervention.&#xD;
      Arginine is converted to nitric oxide which is essential for vascular health. Arginine levels&#xD;
      are low in SCD because the arginine-degrading enzyme, arginase, is released from RBCs. The&#xD;
      investigators propose that by supplying additional arginine (and citrulline which converts to&#xD;
      arginine) and suppressing arginase activity (an action of chloroquine) the investigators can&#xD;
      improve vascular function. Our study will test this theory, and if provision of RUSF improves&#xD;
      growth in children with SCD.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Arginine is the substrate of endothelial nitric oxide (NO) synthase. Citrulline converts to&#xD;
      arginine and has a greater bioavailability than arginine. Chloroquine is a competitive&#xD;
      inhibitor of arginase which is released from lysed red cells and possibly through liver&#xD;
      damage. Raised arginase predicts low plasma arginine levels and may predict clinical disease&#xD;
      severity.&#xD;
&#xD;
      The interventions being tested are designed to target:&#xD;
&#xD;
      (i) the moderate to severe growth retardation commonly observed in children with SCD&#xD;
      especially in low income countries; (ii) endothelial dysregulation secondary to low NO&#xD;
      bioavailability, inflammation and oxidant stress, hypothesised to underlie much of the&#xD;
      clinical pathology in SCD.&#xD;
&#xD;
      This study will test the following hypotheses:&#xD;
&#xD;
        1. That the provision of energy, protein and micronutrients within a ready to use&#xD;
           supplementary food will increase linear growth, weight gain and proportion of fat-free&#xD;
           mass in children with SCD.&#xD;
&#xD;
        2. That the provision of supplementary L-arginine and L-citrulline within the matrix of a&#xD;
           twice-daily RUSF plus daily chloroquine (CQ) for 4 months, compared to a standard RUSF&#xD;
           and weekly anti-malarial prophylaxis CQ to children with SCD will:&#xD;
&#xD;
             -  Increase plasma arginine concentrations and the ratio of plasma arginine:&#xD;
                ornithine.&#xD;
&#xD;
             -  Decrease or not alter plasma asymmetric dimethylarginine (ADMA) concentrations&#xD;
&#xD;
             -  Improve NO-dependent vascular function as detected by an increase in maximum flow&#xD;
                mediated dilatation (FMDmax)&#xD;
&#xD;
        3. That the provision of daily CQ at a dosage of 2-3mg base/kg/day for 4 months to children&#xD;
           with SCD will:&#xD;
&#xD;
             -  Decrease the activity of plasma arginase through competitive inhibition&#xD;
&#xD;
             -  Decrease levels of plasma inflammatory markers&#xD;
&#xD;
      If successful then larger studies of efficacy and effectiveness would be needed to assess&#xD;
      long-term endpoints of hospitalization, stroke, and mortality. Existing evidence suggests&#xD;
      that the proposed intervention also has the potential to increase the efficacy of hydroxyurea&#xD;
      (HU) therapy. The successful development of an affordable ready-to-use 'nutraceutical' food&#xD;
      with proven efficacy in growth promotion and vascular health could represent a major step&#xD;
      forward for SCD patients in low-income countries.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>August 2012</start_date>
  <completion_date type="Anticipated">September 2017</completion_date>
  <primary_completion_date type="Anticipated">September 2016</primary_completion_date>
  <phase>Phase 2/Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>ratio of arginine to ornithine concentration &amp; ratio of arginine to ADMA</measure>
    <time_frame>4 or 12 months</time_frame>
    <description>We will compare the effects of the RUSFv compared to the simple RUSF on:&#xD;
The ratio of plasma arginine to ornithine &amp; ratio of arginine to ADMA and adjust for values at baseline&#xD;
Time frame definition:&#xD;
0 months = baseline&#xD;
4 months = after 1st four-month intervention period, before washout 1&#xD;
8 months = after 1st 4 month washout period before 2nd intervention period&#xD;
12 months = after 2nd four-month intervention period, before washout 2&#xD;
16 months = after 2nd 4 month washout period (study end)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Nitric Oxide dependent endothelial function</measure>
    <time_frame>months 4 or 12</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Linear Growth and Weight Gain</measure>
    <time_frame>After 8 months of treatment with RUSFv and RUSF</time_frame>
    <description>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 &amp; 16.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Haemoglobin concentration</measure>
    <time_frame>months 0, 4, 8, 12 &amp; 16</time_frame>
    <description>Full blood counts (FBC) of ethylenediaminetetraacetic acid (EDTA) whole blood will be conducted</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of inflammation and vascular activation</measure>
    <time_frame>months 0, 4 &amp; 12</time_frame>
    <description>Concentrations of soluble adhesion molecules (VCAM-1, vascular endothelial growth factor-1 (VEGF-1), tumor necrosis factor-alpha (TNF-α) &amp; e-selectin, tissue factor and IL-6) will be measured in frozen (-80⁰C) plasma aliquots.&#xD;
C-reactive protein concentrations will be measured in frozen serum samples and leukocyte counts from FBC.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of haemolysis</measure>
    <time_frame>months 0, 4 &amp; 12</time_frame>
    <description>Plasma haemoglobin will be measured in frozen serum aliquots. Unconjugated bilirubin and lactate dehydrogenase in fresh serum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Frequency of vaso-occlusive painful episodes</measure>
    <time_frame>Weekly from month 0-16</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>liver and kidney function clinical chemistry</measure>
    <time_frame>months 0, 4 &amp; 12</time_frame>
    <description>aspartate transaminase, alkaline phosphatase, total and direct bilirubin and creatinine will be measured in fresh serum</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>glomerular filtration rate</measure>
    <time_frame>months 0, 4 and 12</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Sickle Cell Disease</condition>
  <arm_group>
    <arm_group_label>vascular</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In this intervention period children will receive a vascular ready-to-use supplementary food with added L-Arginine &amp; L-Citrulline plus daily chloroquine</description>
  </arm_group>
  <arm_group>
    <arm_group_label>regular</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>In this intervention period children will receive a regular ready-to-use supplementary food plus weekly dose of chloroquine</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Vascular ready-to-use supplementary food</intervention_name>
    <description>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</description>
    <arm_group_label>vascular</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Regular Ready-to-use supplementary food</intervention_name>
    <description>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.</description>
    <arm_group_label>regular</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Chloroquine</intervention_name>
    <arm_group_label>regular</arm_group_label>
    <arm_group_label>vascular</arm_group_label>
    <other_name>Malaviron syrup</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aged 8-11 years old at enrolment and resident within urban Dar-es-Salaam&#xD;
&#xD;
          -  Enrolled in Muhimbili Sickle Cohort and attending routine Muhimbili National Hospital&#xD;
             sickle clinics&#xD;
&#xD;
          -  Homozygous for hemoglobin S (HbSS) phenotype confirmed by electrophoresis and high&#xD;
             performance liquid chromatography (HPLC)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  &gt;95th percentile for body mass index (BMI) for age using British 1990 growth standards&#xD;
&#xD;
          -  Receiving hydroxyurea therapy or significant other long-term drug therapy&#xD;
&#xD;
          -  Diagnosis with clinically significant non-SCD related disease including:&#xD;
&#xD;
               -  Stage III or above HIV - or receiving ART therapy regardless of AIDS stage&#xD;
&#xD;
               -  Tuberculosis infection&#xD;
&#xD;
          -  Blood transfusion within previous 30 days&#xD;
&#xD;
          -  Previously diagnosed clinical pulmonary hypertension or cardiac dysfunction or&#xD;
             clinical signs of pulmonary hypertension (loud pulmonary second heart sound) or heart&#xD;
             failure (displaced apex beat, high jugular venous pressure, enlarged liver, peripheral&#xD;
             oedema)&#xD;
&#xD;
          -  Low visual acuity at baseline (&lt;6/9 using a modified (for Tanzania) Snellen chart or&#xD;
             previously diagnosed chronic eye disorder likely to suggest retinopathy or macular&#xD;
             degeneration&#xD;
&#xD;
          -  Significant hepatic/renal dysfunction assessed by clinical chemistry panel at baseline&#xD;
&#xD;
          -  Epilepsy, psoriasis or currently taking any drugs listed as interacting with&#xD;
             chloroquine&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>8 Years</minimum_age>
    <maximum_age>11 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sharon Cox, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>London School of Hygiene &amp; Tropical Medicine, UK / Muhimbili Wellcome Programme, Tanzania</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Muhimbili University of Heath and Allied Sciences (MUHAS)</name>
      <address>
        <city>Dar es Salaam</city>
        <country>Tanzania</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Tanzania</country>
  </location_countries>
  <verification_date>July 2016</verification_date>
  <study_first_submitted>February 1, 2012</study_first_submitted>
  <study_first_submitted_qc>October 30, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 31, 2012</study_first_posted>
  <last_update_submitted>July 26, 2016</last_update_submitted>
  <last_update_submitted_qc>July 26, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">July 27, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Vascular function</keyword>
  <keyword>Ready to use supplementary foods</keyword>
  <keyword>Chloroquine</keyword>
  <keyword>Children</keyword>
  <keyword>Growth</keyword>
  <keyword>Nitric Oxide</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Sickle Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Chloroquine</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01718054
org study id: VFIT001
secondary id: WT094780
nct id: NCT01718054
lead sponsor: 
collaborator: 
has dmc: Yes
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.
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.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: ratio of arginine to ornithine concentration & ratio of arginine to ADMA
time frame: 4 or 12 months
description: 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)
measure: Nitric Oxide dependent endothelial function
time frame: months 4 or 12
description: 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.
measure: Linear Growth and Weight Gain
time frame: After 8 months of treatment with RUSFv and RUSF
description: 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.
measure: Haemoglobin concentration
time frame: months 0, 4, 8, 12 & 16
description: Full blood counts (FBC) of ethylenediaminetetraacetic acid (EDTA) whole blood will be conducted
measure: Markers of inflammation and vascular activation
time frame: months 0, 4 & 12
description: 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.
measure: Markers of haemolysis
time frame: months 0, 4 & 12
description: Plasma haemoglobin will be measured in frozen serum aliquots. Unconjugated bilirubin and lactate dehydrogenase in fresh serum.
measure: Frequency of vaso-occlusive painful episodes
time frame: Weekly from month 0-16
description: 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.
measure: liver and kidney function clinical chemistry
time frame: months 0, 4 & 12
description: aspartate transaminase, alkaline phosphatase, total and direct bilirubin and creatinine will be measured in fresh serum
measure: glomerular filtration rate
time frame: months 0, 4 and 12
description: 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.
arm group label: vascular
arm group type: Active Comparator
description: In this intervention period children will receive a vascular ready-to-use supplementary food with added L-Arginine & L-Citrulline plus daily chloroquine
arm group label: regular
arm group type: Active Comparator
description: In this intervention period children will receive a regular ready-to-use supplementary food plus weekly dose of chloroquine
intervention type: Dietary Supplement
intervention name: Vascular ready-to-use supplementary food
description: 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
arm group label: vascular
intervention type: Dietary Supplement
intervention name: Regular Ready-to-use supplementary food
description: 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.
arm group label: regular
intervention type: Drug
intervention name: Chloroquine
arm group label: regular
arm group label: vascular
other name: Malaviron syrup
criteria: 
gender: All
minimum age: 8 Years
maximum age: 11 Years
healthy volunteers: No
last name: Sharon Cox, PhD
role: Principal Investigator
affiliation: London School of Hygiene & Tropical Medicine, UK / Muhimbili Wellcome Programme, Tanzania
facility: 
country: Tanzania
responsible party type: Sponsor
mesh term: Anemia, Sickle Cell
mesh term: Chloroquine