Navrongo Drug Options for IPT in Pregnancy Trial
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      In areas of stable transmission, pregnant women, especially during the first and second
      pregnancies, have an increased susceptibility to Plasmodium falciparum malaria,
      malaria-related anaemia and an increased risk of having low birthweight babies. Intermittent
      Preventive Treatment in pregnancy(IPTp) with sulphadoxine-pyrimethamine has been shown to be
      effective in reducing the effects of malaria in pregnancy. This has mainly been in areas of
      perennial transmission and there is a need to study this effect in intense seasonal
      transmission settings. The emergence and spread of resistance to SP is likely to undermine
      its useful lifespan and it is important that other antimalarials that are safe and effective
      are identified for use in IPTp. The options are however limited. Amodiaquine has been shown
      to be effective in treatment of clinical cases of malaria, even in areas where chloroquine
      resistance is prevalent, and its combination with SP has been associated with favourable
      results. Both are affordable. However, there is limited data on their use in pregnancy. This
      study aims to assess the efficacy of SP in an area of intense seasonal transmission, and
      evaluate the safety and efficacy of amodiaquine and a combination of
      sulphadoxine-pyrimethamine and amodiaquine as possible alternatives to SP for use as IPTp.
    

Detailed description: 
      Background Pregnant women, particularly during the first and second pregnancy, have a high
      risk of Plasmodium falciparum infection and these infections are often asymptomatic but lead
      to maternal anaemia and low birth-weight. One approach to preventing malaria in pregnancy is
      prompt effective management of clinical malaria. In areas of moderate and high transmission
      however, peripheral parasitaemia is not a sensitive indicator as many women with placental
      parasitaemia may not have peripheral parasitaemia. Another option is to administer full
      curative doses of an effective antimalarial drug at predefined intervals during pregnancy
      (IPTp) without screening for parasitaemia. The efficacy of IPTp has been studied mostly in
      areas of high perennial transmission in Kenya and Malawi. IPTp has however been little
      investigated in West Africa where transmission is often intense and highly seasonal. It may
      not be appropriate to translate results between areas with different ranges of transmission
      intensities across the sub-Saharan African region and there is a need to study the effect of
      IPTp in highly seasonal intense transmission areas in West Africa.

      IPTp with SP has been shown to be effective in reducing maternal anaemia, prevalence of
      placental parasitaemia and the incidence of low birth weight. SP offers a reasonable
      combination of ease of use and associated increased compliance, low cost, and relatively good
      tolerance and safety. However, the useful therapeutic life (UTL) predicted for SP is likely
      to be short, in part due to its prolonged half-life, causing a higher probability of
      selecting resistant strains and consequent rapid development of resistance. The emergence and
      spread of SP resistance will increasingly undermine this strategy, depleting the currently
      available and affordable drugs usable for intervention during pregnancy. It is therefore
      important that alternative antimalarials that are safe and effective in pregnancy are
      identified.

      Specific primary objective To assess and compare the efficacy of a combination of
      sulphadoxine-pyrimethamine and amodiaquine, sulphadoxine-pyrimethamine or amodiaquine used as
      IPTp, in reducing the incidence of anaemia(Hb<11g/dl) at weeks 34-36 among primigravidae and
      secundigravidae.

      Specific secondary objectives

      To evaluate the effect of SP/AQ, SP or AQ on:

        1. The mean birthweight of infants among primigravidae and secundigravidae

        2. The incidence of clinical malaria during pregnancy among primigravidae and
           secundigravidae

        3. The prevalence of anaemia (Hb <11g/dl) at delivery among primigravidae and
           secundigravidae

        4. The prevalence of placental parasitaemia among women in their first or second
           pregnancies delivering at health facilities or by trained TBAs

        5. The prevalence of peripheral parasitaemia at weeks 34-36 among primigravidae and
           secundigravidae

        6. The prevalence of maternal peripheral parasitaemia at delivery among primigravidae and
           secundigravidae

        7. To determine the safety and tolerability of AQ, SP used alone and in combination, among
           pregnant women of all parities

        8. To determine the prevalence of molecular markers of resistance to AQ and SP among
           pregnant women who have malaria parasitaemia at enrolment

        9. To document the factors that influence women's attitude towards ANC attendance, use of
           chemoprophylaxis and ITNs, and to determine what informs their choice to deliver at a
           particular facility

      STUDY SITE The study will be carried out in the Kassena-Nankana district of northern Ghana.
      The residents are mainly subsistence farmers. There are two main seasons, a short wet season
      from June to September, during which the transmission of Plasmodium species peaks and a long
      dry season. The primary resource of the Navrongo Health Research Centre is a district-wide
      surveillance system, the Navrongo Demographic Surveillance System (NDSS), a longitudinal
      population registration system that is updated every 90 days. The district has 4 health
      centres, 3 clinics and a 140-bed hospital that serves as a referral centre. Information
      collated for the year 2002 in the Kassena-Nankana district indicated that out of an expected
      6050 pregnancies, 95% registered for ANC, the average number of visits being 2.7. There were
      2173(36%) supervised deliveries, 1279 of these at health facilities and 894 by trained TBAs.
      794 out of 2405(33%) pregnant women had haemoglobin levels less than 10g/dl at registration.

      STUDY POPULATION Pregnant women between 16 -32 weeks gestation attending antenatal care
      clinics at the district hospital or any of the four main health centres in the district will
      be eligible to join the study. The main endpoints will be assessed in primigravidae and
      secundigravidae however safety data will be collected for all women.

      STUDY DESIGN The study will be carried out in two phases, a pre-intervention phase which will
      document women's knowledge, attitudes and practices on antenatal care, chemoprophylaxis and
      use of insecticide treated bednets and factors that influence their choice of where to
      deliver. The second phase, which is the intervention, will be a three-arm randomized blinded
      controlled trial.

      Intervention study - Enrolment procedure The study will be explained to women as a group
      before each day's ANC activities begin. In order not to interfere with the routine ANC
      activities women who may want to be recruited will then proceed to the study team after their
      routine ANC care. After obtaining informed consent, socio-demographic information, an
      obstetric history including previous ANC attendances during current pregnancy, a history of
      any illness in the past week, and information on bed net use will be collected. Gestational
      age will be obtained from the ANC card as assessed by the midwife. Anthropometric indices
      measured will be weight, height and mid-upperarm circumference. The blood pressure and
      axillary temperature will also be measured. Fingerstick blood sample will be drawn for
      haemoglobin testing, malaria thick blood smear and filter paper samples, after which each
      woman will be assessed for eligibility. Subjects will be randomized individually to receive
      the study drugs. The code on the envelope will be written on all the study forms and samples.
      The subject's name, address and date of first dosing will be noted on the envelope, to ensure
      that each woman receives the right regimen over the three-day period and also during
      subsequent doses of IPTp. To ensure compliance, all doses will be supervised either at the
      health facility, or through home visits (on Days 1 and 2). Women will receive between one and
      three doses of the drugs, depending on gestational age at recruitment, thus women recruited
      at 16 - 19 weeks will receive three doses, those recruited at 20 -26 weeks, two doses and
      those recruited from 27 -32weeks, one dose. The interval between dosing schedules will be 8
      weeks, however the minimum interval allowed will be 4 weeks.

      All women will be encouraged to deliver at a health facility or by a trained traditional
      birth attendant, and they will be given an identification card to take to the health facility
      so that the necessary samples can be taken and labelled adequately during delivery. These
      identification cards will also bear a note that the woman may have received AQ, SP or a
      combination as IPTp and should therefore not be given those drugs for clinical malaria, to
      avoid women being given repetitive doses within short intervals of time. Such women will be
      given Quinine 10mg/kg 8 hourly for 7days as recommended by the national treatment guidelines.

      Assessment of drug tolerance and adverse drug reactions All women will be visited at home
      between Days 7 and 10 to look for any adverse events due to the study drugs. They will be
      advised to report to a health facility if they should experience any untoward effect of the
      drugs prior to, or after this home visit. The frequency and severity of spontaneous and
      elicited adverse events will be recorded. In the light of the information obtained, the
      association between the event and any of the study drugs will be judged as per the WHO
      guidelines52. All serious and adverse events will be reported to the DSMB immediately, and
      followed up with a written report which will fully document the event, and any available
      laboratory information or clinical data, will be included in the report.

      Follow-up At subsequent visits for IPTp and at weeks 34 -36, a simple questionnaire will be
      administered to assess the presence of malaria symptoms, potential side effects of the study
      drugs since the last assessment, and bednet use. To ensure that women complete subsequent
      doses of IPTp, lists of women due for second or third doses will be computer-generated, and
      they will be reminded at least a week before the next dose is due to attend the ANC. At 34
      -36 weeks blood samples will be taken to assess for haemoglobin levels (Hb) and peripheral
      parasitaemia. Women with severe anaemia (Hb levels <7g/dl) will be referred to the hospital
      for further investigations and management. Women who do not turn up at the ANC will be
      followed up at home to collect the blood sample. Blood slides from symptomatic women will be
      read immediately and women found to have parasitaemia will be given Quinine 10mg/kg 8 hourly
      for 7 days as per national treatment guidelines.

      Delivery Women delivering at the hospital will have bloodsmears made from a fingerprick, and
      maternal side of the placenta, and have Hb level assessed. Women delivering at the health
      centre will have placental blood smears, and a peripheral blood smear taken. Those delivered
      by TBAs will have the placental smear taken.

      Blood samples for haemoglobin estimation for women delivering at the health centre or by TBAs
      will be taken at home within 7 days of delivery. Assessment of Hb will be carried out on
      women who delivered spontaneously without any complications such as post-partum haemorrhage
      at the hospital on day of delivery to 7days post delivery, to construct a nomogram which
      would be used to estimate the haemoglobin levels at delivery for women who delivered at the
      health centre or by TBA who could not have an Hb done on day of delivery for logistic
      reasons.

      All infants delivered at the hospital or health centre will be weighed and gestational age
      assessed by a modification of Dubowitz's examination within 24 hours of delivery53. To ensure
      that birthweights of infants delivered at home are taken within seven days of delivery, a
      list of women with gestation of 34 weeks or more will be generated according to area of
      residence. This would be given to Community Key Informants (CKI) who would be contacted
      weekly by field staff for information on those who were delivered by TBAs or at home. A
      follow-up will then be made to take the weight of the babies. Mothers will be encouraged to
      inform CKIs soon after delivery. The TBAs will be asked to inform CKIs whenever they
      delivered a study subject, so that the samples can be collected.

      Infants for whom the Dubowitz score is obtained will be classified as follows:

      Premature -LBW : gestational age is <37weeks and birthweight is <2500g IUGR-LBW: gestational
      age is ≥ 37weeks and birthweight is <2500g Normal birthweight : birthweight is ≥ 2500g

      Withdrawal from study A withdrawal shall be any enrolled subject who does not complete the
      study as planned. This may be due to (a) withdrawal of consent, (b) reaction attributable to
      any of the study drugs or (c) termination of pregnancy (abortions or miscarriages). A
      withdrawal form shall be filled for such persons, indicating reasons for withdrawal, and they
      will be followed up for outcome measures, unless they decline to give consent.
    

Intervention name(s): Sulphadoxine-pyrimethamine; Sulphadoxine-pyrimethamine, amodiaquine
Intervention type(s): Drug; Drug
Intervention MeSH terms: Pyrimethamine; Sulfadoxine; Fanasil, pyrimethamine drug combination; Amodiaquine
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double
Primary purpose: Prevention
Keywords: intermittent preventive treatment; malaria; pregnancy; efficacy; safety