Prevention of Severe Anaemia in Gambian Children
Condition: Anemia
MeSH terms: Anemia
Study type: Interventional
Phase: Phase 3

Summary: 
      Severe anaemia is a frequent cause of admission to hospitals in tropical Africa and about 10%
      of such children die. In endemic countries, anaemia has multiple causes such as nutritional
      deficiencies, infections and haemoglobinopathies. However, Plasmodium falciparum infection is
      believed to be the major contributory factor to the aetiology of severe anaemia. Severe
      anaemia is usually treated by blood transfusion although transfusion carries the attendant
      risk of transmission of HIV and other blood-borne infections. Thus, there is a need to
      explore novel strategies to reduce the incidence of severe anaemia in high-risk groups such
      as children with suboptimal haemoglobin levels because these children are at increased risk
      of developing severe anaemia if they develop a malaria infection before their haemoglobin
      level has normalized. Therefore, it is proposed to study whether monthly chemoprophylaxis
      with sulphadoxine/pyrimethamine (S/P) given during malaria transmission season can protect
      Gambian children from developing severe anaemia. After receiving treatment from the hospital,
      1200 children admitted to the hospital with a haematocrit of less than 21% were randomised to
      receive either monthly S/P or placebo during the rest of the malaria transmission season.
      Morbidity was monitored throughout the rainy season. Study subjects were seen at the end of
      the dry season to document morbidity and mortality.
    

Detailed description: 
      Objectives

        1. To assess the effectiveness of monthly prophylaxis with S/P on haematological recovery
           in children who have been treated for severe anaemia.

        2. To measure compliance with the intervention

        3. To investigate whether or not infection with chloroquine and S/P resistant strains
           contributes to the pathogenesis of severe anaemia

      Study design and methods

      Study site:

      The study was based at the 75-bed paediatric unit of The Royal Victoria Hospital (RVH), which
      is located in the capital, Banjul. This is the main referral hospital for the country. The
      paediatric unit admits about 7000 children a year, of whom about 800 are anaemic (PCV < 33%).

      Enrolment of children:

      Study subjects were recruited fom paediatric unit of RVH, MRC Hospital, and Brikama, Essau
      and Sibanor Health Centres. Study subjects were enrolled by non-coercive methods if they
      fulfil the inclusion criteria and had none of the exclusion criteria.

      Screening process and enrolment:

      Patients were recruited on presentation to the ward. All children in the right age group who
      presented to the ward had their haematocrit and blood film done by a project field worker.
      Children with a PCV of less than 21% were offered assessment by a project doctor. If
      assessment was permitted, and the patient fulfilled the entry criteria, then written consent
      was sought from the parent/guardian. The study was explained in the parent's/ guardian's
      preferred language, and written informed consent was obtained on approved forms.

      On entry into the trial a detailed clinical history, drug history, family history and
      information on bednet usage and impregnation was obtained. The study physician examined the
      child, documented nutritional status and recorded the findings in a case report form. In
      addition, a detailed address was obtained. Each study child was provided with a photo ID card
      to facilitate identification at each contact.

      A 5-ml baseline blood sample was obtained for determination of the following:

        -  Hb, red cell indices, white cell and platelet count (Coulter counter)

        -  Reticulocyte count

        -  Markers of iron status (serum iron and ferritin) (first 100 children)

        -  Sickling test and, if positive, haemoglobin electrophoresis

        -  Stool examination for hookworm and other parasites (first 100 children)

      Other investigations such as chest x-ray and urine examinations were carried out as
      clinically indicated.

      Inpatient management:

      During admission, children with malaria were treated with IM quinine or chloroquine plus S/P
      as clinically indicated. Children with a PCV < 15% and those with signs of respiratory
      distress and/or a 'gallop' rhythm were transfused. In addition, all patients received iron
      for 28 days, treatment starting at the time of their discharge from hospital. Patients were
      treated for other conditions as clinically indicated.

      Treatment regimens

      Treatment was given as follows:

      S/P (tablets containing 500 mg sulfadoxine/ 25 mg pyrimethamine) at an approximate dose of
      1.25 mg pyrimethamine/25 mg sulphadoxine per kg stat dose.

      Oral chloroquine: 10mg daily for 3 days.

      S/c chloroquine: 5mg/kg 6 hourly x 7 doses.

      IM Quinine: 20 mg/kg loading dose, then 10 mg/kg 12 hourly for 5 days.

      Iron was given as syrup at a target dose of 2 mg/kg elemental iron.

      Assessment of resistance to chloroquine and antifolates :

      To investigate whether or not infection with chloroquine or S/P resistant parasites
      contributes to the pathogenesis of severe anaemia in Gambian children, filter paper blood
      samples were collected from the first 100 children entered into the study who have
      P.falciparum parasitaemia and an equal number of aged matched children who attended the OPD
      clinic with uncomplicated symptomatic malaria. Nested PCR on extracted DNA was used to tested
      for mutation in genes associated with resistance; Pfcrt and Pfmdr for chloroquine and DHRF /
      DHPS genes for S/P using standard techniques.

      Study subjects were individually randomised into either the S/P or the placebo group in a 1:1
      fashion at the time of discharge from hospital, although chemoprophylaxis was not be started
      for another week as the children are likely to have received antimalarials whilst in
      hospital. Randomisation was in blocks. Block size were selected to enhance blinding and
      maintain balance in the treatment allocation ratio as recruitment progresses

      Home visit:

      As soon as possible after discharge from hospital, patients were visited at home by a project
      field worker to collect information on social economic and environmental risk factors that
      may predisposes an individual child to develop severe anaemia. A housing survey was conducted
      during this visit to determine possible risk factors for malaria which might act as
      confounders in determination of the primary trial end-point. Field workers interviewed the
      parents/guardians of study subject to record characteristics about the house that might
      influence mosquito biting behaviour. These items included building material, an evaluation of
      the presence of eaves, impregnation and condition of bed nets. During the visit, parents were
      encouraged to protect the study child with a bed net.

      First OPD visit after discharge from hospital One week after discharge, study subjects
      enrolled in the study were asked to return to the OPD clinic for routine assessment. At this
      visit a fingerprick blood sample was collected for PCV measurement and thick blood film for
      malaria parasite. The first dose of trial medication was given during this visit.

      Randomisation:

      S/P and matching placebo (identical shape and size) were stored in 8 boxes labelled 1 to 8 (4
      for S/P tablets and 4 for placebo). The randomisation code were kept in sealed opaque
      envelopes by the local safety monitor who alone will knew the code, which associated each
      treatment group with either S/P or placebo.

      Continuation of chemoprophylaxis in the health centre:

      Study subjects received their monthly chemoprophylaxis at their local health centre under
      direct supervision by staff of the health centre identified by the health centre and trained
      to take this important role in the study. Health centre staff were provided with a list
      containing the study number, photographs and randomisation group of each study subject. Study
      subjects were observed for 30 minutes after dosing and if vomiting occurs within 30 minutes,
      the dose was repeated. S/P (tablets containing 500 mg sulfadoxine/ 25 mg pyrimethamine) will
      be given at an approximate dose of 1.25 mg pyrimethamine/25 mg sulphadoxine per kg. Enrolment
      of patients started in July and surveillance continued until end of malaria transmission
      season.

      Morbidity surveillance during the rainy season:

      Study subjects were followed throughout the rainy season. Mothers/guardians were encouraged
      to take their child to the RVH OPD clinic or the health centre identified as being closest to
      their home at any time after discharge if the child became unwell. Project staff were based
      at each of these health centres, initially to identify children in the trial and to ensure
      that they were seen, properly investigated and treated promptly by health centre staff. At
      each visit axillary temperature was recorded using a digital thermometer. A dipstick for
      diagnosis of malaria was used to guide treatment if fever (axillary temperature of > 37.5°C)
      or history of fever within the previous 48 hours is present. In addition, a thick blood smear
      for malaria parasites was collected for subsequent confirmation of the diagnosis. Filter
      paper sample to test for S/P resistance were collected from all malaria cases detected during
      morbidity surveillance. Study subjects with documented fever (axillary temperature of >
      37.5°C) or history of recent fever and malaria parasitaemia were treated with S/P and
      chloroquine. The treatment of study subjects seen at the health centres was the carried out
      by health centre staff in accordance with national guidelines. Study patients who needed
      admission were referred to RVH paediatric unit or the MRC ward.

      End of malaria transmission season cross-sectional survey:

      Children enrolled in the study were seen at the OPD clinic at the end of malaria transmission
      season for examination by a study physician and a finger-prick blood sample was obtained for
      preparation of thick blood smear and determination of haematocrit. A standardized
      questionnaire was administered to the parents/guardians of the study subject, to collect
      information regarding illness that had occurred since the last visit, symptoms experienced,
      use of healthcare facilities and use of medicines. Information on the use of bednets was
      collected again at this visit.

      Dry season follow-up:

      At the end of the dry season study subjects visited once. During this visit, a questionnaire
      was administered to document morbidity and mortality.

      Sample size calculations:

      Assuming an attack rate of 0.1 episodes of clinical malaria (as defined for the primary
      end-point) per month in children in the control group (a figure based on previous surveys
      from The Gambia) and a drop out rate during follow up of 15%, 131 episodes was expected in
      children in the control group followed until the end of one malaria transmission season.
      Thus, with a total of 1200 children recruited to the trial, the study will have an 80% power
      to detect at 5% level of significance a 32% reduction in incidence of clinical attacks of
      malaria in children who receive chemoprophylaxis.

      Previous studies in The Gambia indicate that about 20% of children under 5 years of age have
      a PCV of < 20% at the end of the malaria transmission season. With 1200 children enrolled,
      this trial will have a 80% power to detect a 34% reduction in the prevalence of anaemia of
      this degree of severity.
    

Intervention name(s): sulfadoxine-pyrimethamine
Intervention type(s): Drug
Intervention MeSH terms: Pyrimethamine; Sulfadoxine; Fanasil, pyrimethamine drug combination
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: prevention; recurrence; severe; anaemia