A Study on Immunological Effect of Vitamin A and Zinc in a Placebo Controlled 4 Cell Trial
Condition: Immunity; Diarrhea; Respiratory Tract Infections
MeSH terms: Respiratory Tract Infections; Diarrhea
Study type: Interventional

Summary: 
      Vitamin A deficiency in children is associated with increased mortality and morbidity due to
      respiratory tract and diarrhoeal infections. Vitamin A supplementation has been shown in some
      studies to reduce morbidity due to respiratory diseases. However, other studies to reduce
      could not document such benefit from vitamin A supplementation. The role of vitamin A on
      immunity in humans is not yet clear due to inconclusive results. To evaluate immune changes
      and compare those with of a known immunopotent agent like zinc, a randomised double blind
      study will be carried out in 1-3 year aged children without acute illness and wt/age between
      61% and 70% of NCHS standard. Baseline anthropometry and vitamin A status will be determined
      using MRDR test and immune status will be estimated. Each group consisting of 50 children
      will either receive vitamin A 200,000 IU over 7 days or 40 m elemental zinc daily for 7 days
      or both or placebo. After 8 weeks immunity test will be repeated. Immunity tests will include
      serum 1gA, 1gM, 1gG an lymphocyte simulation and 8 antigen multiple skin test. Undiminished
      children will be given measles vaccine and serum titre will be measured before and after
      supplementation. Vitamin A status will be estimated by MRDR test. Vitamin A2 will be given
      and 1ml blood sample will be collected after 5 hours to see the ratio of vitamin A1 and A2
      (<0.06 as cut off) as the modified relative dose response (MRDR test). Doses of vitamin A or
      zinc will be repeated at the completion of 2 month. The results will be compared between
      groups and within groups at baseline and after 6 weeks. The study will generate information
      which will help to examine the immune response of vitamin A therapy in children as an
      underlying factor for reduction in mortality or morbidity. The study will be completed within
      a year.
    

Detailed description: 
      Immunological indicators will be monitored at the beginning and after 8 weeks of giving
      vitamin A or zinc in a double blind randomized trial. A clinical based study will be done to
      see the effect of zinc or vitamin A supplementation in malnourished subjects. Vitamin A
      status will be estimated using the newer indicator, modified relatively dose response.
      (MRDR).Procedure:Study population:Children aged 1 to 3 years will be included. Forty children
      in each group will be assigned to either group A group B and group C and group D. children
      will be selected from families within Dhaka city who come to the diarrhoea treatment centre
      of ICDDR,B.Inclusion criteria:1. Children aged between 1 and 3 years having weight for age
      between 70% and 61% of NCHS standard.2. Who come to the out patient department of ICDDR,B for
      treatment of acute water diarrhoea with3. No signs of vitamin A deficiency (non invasive
      diarrhoea and without systematic infection) and has not received vitamin A during last 4
      months.4. Who has not received measles vaccine and did not have measles primarily identified
      for the study.5. Children who has not reside in and around Dhaka city After one week recovery
      from diarrhoea:1. Baseline immunological profile will be studied.2. Intervention for one week
      at the schedule doses and immunological profile will be repeated after 8 weeks.Study groups
      are:A. Zinc B. Vitamin A C. Zinc and vitamin A D. PlaceboExclusion criteria:1. Children who
      needs immediate vitamin A supplementation (clear sign of vitamin deficiency)2. Children who
      received vitamin A within the last 4 months3. Children with other systematic infection4.
      Subjects who develop any kind of sign and symptoms of vitamin A deficiency will be given
      vitamin A and will be analysed separately.Randomisation procedure: Parents who give their
      consent for the study will be selected. Children will be randomised into four groups to
      receive either of the treatments. A master randomisation chart will be prepared using table
      in permuted block design by dividing serial number into four equal groups. There will be no
      need for stratification but according to the selection criteria, better nourished (70%
      wt/age) or severely malnourished (60%) children will be excluded. Severely malnourished
      patients with diarrhoea may immediately need vitamin A or well nourished will not show effect
      of supplements. Steps will be kept to compensate dropouts.The intervention and
      non-intervention groups will receive identical bottles and syrups with some flavour and only
      single unique serial number will be written outside the bottles. The number will indicate an
      exact subject of study and will be kept out of the reach of the investigators. The children
      will receive the 2nd dose at 8 weeks with vitamin A or zinc who has not received that in the
      first dose without breaking the randomization code. The code will be broken only after
      completion of study and analysis according to groups.Base line survey will be done to take
      socio-economic information, dietary habits, previous illness, immunization, washing of hands
      and water use, frequency of cooking of food containing vit A, cooking method, and frequency
      of use of green leafy vegetables.In the beginning of the study, baseline vitamin A status
      will be determined using MRDR test. Anthropometry will be done to select children at the
      baseline, at the end of 8 weeks, and subsequent months for 6 months. Duration, frequency,
      dose:One teaspoonful, (5 ml) syrup will be given in a twice-daily schedule for 7
      days.Composition of syrup:For all groups, the main vehicle and bulk of the base syrup will
      consist of the same chemicals; in addition to this, each group will have either of the
      treatment substance (i.e. zinc or vitamin A or both or none).Syrup A : Quantity per 5 ml Zinc
      acetate 20 mg elemental

      Syrup B :

      Vitamin A palmitate 15,000IU

      Syrup C :

      Zinc : 20 mg elemental + vitamin A : 15,000 IU Syrup D : Y base substance Base substance:
      Ascorbic acid 30 mg Glycerine USP 1.2 ml Propylene glycol USP 0.75 ml Sorbitol 70 % BP 2.0 ml
      Methyl Paraban USFN 3.5 mg Polysorbate-80 50 mg (Tween-80) BPC Lemon oil pH grade 0.0125 ml
      Caramel Brown colour 1 mg Powder water 0.75 ml Organization of the study:The study will be
      conducted among the children who will attend the out patient department of the clinical
      research centre of ICDDR,B. Children will be selected at the acute diarrhoea phase who will
      attend only with non invasive simple or mild diarrhoea within the nutritional status defined
      earlier of NCHS standard. The children will be taken for study 1 week after the recovery of
      diarrhoea and the first immunological test at base line will be done at this time. Mothers
      will be instructed on the dose. A twice-daily dose of syrup for one week will be schedule for
      better compliance of the children. After completion of doses at 8 weeks, the immunity test
      will be repeated a 8 weeks. Tears will be collected in a small piece of sponge and will be
      used for secretary 1 gA estimation. Skin test for Cell Medicated Immunity will be performed
      in each child regardless of treatment group with multitest kit developed by Institute
      Merieux. These children will be followed up every alternate day for the 1st week and then
      weekly for development of any illness for 2 months. Necessary treatment measures will be
      undertaken.Clinical care: Patient care will be provided on clinical problems identified
      during treatment of diarrhoea or follow up. A team of medical officers and paramedics will
      examine and record the vitamin A deficiency symptoms and other medical problems on a
      predesigned questionnaire and provide the necessary care. Any children develop an acute
      symptom of night blindness or Bitot's spot will be given a vitamin A capsule (200,000 in)
      which will be recorded.Baseline test on immunity will be performed by the following
      tests:Components of immunity and other variables:1. Eight antigens multiple skin tests
      measured by 48 hours.2. Eight 1gA, 1gM3. MRDR, plasma 1gA, 1gM, 1gG.(This will require 2 ml
      blood)4. Lymphocyte proliferation assays.For T lymphocytes- PHA, Con A antigen will be used
      For T and B lymphocytes - PWM (Poke weed Mitogen)(This will require 3 ml blood in heparinized
      tube) 5. Lymphocyte Phenotype using monoclonal antibodies to CD3, CD4, CD8, CD20.Schedules:
      for immunity test, skin test before dose and after 8 weeks. MRDR will be done at base line
      and at 8 weeks.6. Base line titre of measles antibody 1gG will be measured and will be
      followed by a dose of measles vaccine and titre be measure at 8 weeks of supplementation.7.
      'Serum zinc, RBP, albumin & alkaline phosphatase at baseline after 8 week.Anthropometry will
      be done with weight, height, MUAC, at base line, at 8 weeks.Body weight- will be measured
      (nude) with an electronic scale with a 1gLength:- will be measured in knee-heel vernier with
      1mm sensitivity. Data collection on morbidityA predesigned questionnaire will be used to
      record incidence and duration of illness during the follow up period
    

Intervention name(s): Zinc, or Vitamin A or both
Intervention type(s): Drug
Intervention MeSH terms: Vitamin A
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Prevention
Keywords: Zinc; vitamin A; immunity; morbidity; height gain; weight gain; Children aged between 1 and 3 years; Weight for age between 70% and 61% of NCHS standard; Acute diarrhoeal Patients; No signs of vitamin A deficiency; Who has not received measles vaccine