A Trial of Antimalarial Drugs Used in Pregnancy in Tanzania
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 3

Summary: 
      Pregnant women are vulnerable to malaria, with significant implications both for their health
      and for the pregnancy. Sulfadoxine-pyrimethamine (SP) is currently the first line drug for
      the treatment of malaria in pregnancy in Tanzania and surrounding countries, but resistance
      is emerging rapidly. Alternative drugs must be found, and new drugs and drug combinations are
      being recommended by many for deployment as first line treatment at the point that SP
      resistance forces a policy change. However, there are few data on the safety and efficacy of
      these combinations in pregnant women. This randomised trial aims to assess efficacy and
      safety, including birth outcome, in pregnant women with malaria in the second or third
      trimesters. A total of 900 pregnant women will be randomised either to standard treatment
      (SP) or to one of three potential drugs, or drug combinations recently recommended by a WHO
      expert panel. These will be SP-amodiaquine, chlorproguanil-dapsone (Lapdap), and
      amodiaquine-artesunate. Primary outcome will be treatment failure. Secondary outcomes will
      include 28 day slide clearance, maternal side effects, foetal viability and birth outcome.
    

Detailed description: 
      The objectives of this study are to assess the therapeutic efficacy and safety of SP as the
      current first line drug, and three other potential alternative combinations in treating
      uncomplicated falciparum malaria during pregnancy, in an area with appreciable levels of SP
      resistance and rising HIV seroprevalence. Specifically the study will compare the clinical
      and parasitological response to and the side effects of the following drug regimes:

        1. SP

        2. SP + amodiaquine (SPAQ)

        3. Chlorproguanil+dapsone (Lapdap)

        4. Amodiaquine + artesunate (AQAS)

      TRIAL DESIGN

      Primary end point

      The primary end-point of the trial will be treatment failure. This will be defined as:-

      Any of:

        1. a need for rescue treatment due to clinical deterioration defined by altered sensorium,
           convulsions, persistent vomiting, renal impairment, respiratory distress, a fall in Hb
           below 75g/dl, or in cases where initial haemoglobin was less than 9 g/dl a drop of 20%
           from the starting Hb if the initial Hb was less than 9g/dl, at any time during
           admission;

        2. persistence of fever with parasitaemia on day 32;

        3. increasing parasite load on day 3;

        4. failure to clear parasites on day 7;

        5. rescue medication for recurrent malaria before day 14;

        6. slide parasite positivity at day 14.

      Secondary endpoints

      Secondary endpoints will include the following:-

        1. Incidence of foetal death during treatment, defined as absence of foetal heartbeat
           assessed by Doppler

        2. Hypoglycaemia requiring treatment

        3. Parasite recrudescence or re-infection on day 28

        4. Parasite clearance on day 3

        5. Level of recovery of haemoglobin on day 14

        6. Fever clearance time

        7. Incidence of perinatal and neonatal mortality, assessed 4-6 weeks after due date of
           delivery

        8. Clinically apparent neonatal abnormality, assessed 4-6 weeks after due date of delivery

        9. Placental malaria

       10. Preterm delivery

       11. Other adverse events during treatment

      The trial

        1. This will be a randomized controlled trial with four arms

        2. The slide reader assessing the primary endpoint will be blind to treatment allocation,
           and analysis will be performed by intention-to-treat

        3. Direct Observed Therapy (DOT) of all doses of study regimens will be employed

        4. Drug doses packed in blister packs, labelled with the patient number will be used where
           possible.

        5. Selection and Withdrawal of Patients

      Pregnant women with mild-moderate, slide proven, falciparum malaria will be recruited from
      the Antenatal wing (ANC) of the Maternal and Child Health (MCH) clinic at Muheza (Teule)
      Hospital. Pregnant women from Muheza Township and surrounding villages attend this clinic.
      Nurses attending the clinic will interview all febrile women and women with a recent (past 24
      hours) history of fever and those with a probable diagnosis of malaria will be referred to
      the study team. Those with signs/symptoms of mild-moderate anaemia will also be referred. All
      referrals will be re-interviewed and examined by the Medical Officer of the study team to
      exclude concomitant infection(s). Duplicate thick and thin blood smears will be made, Giemsa
      stained at pH 7.2, and examined microscopically. The consent form will be administered to
      those meeting the inclusion criteria and they will be enrolled upon consenting.

      Inclusion criteria

      A pregnant woman who has:-

      either a positive blood smear for P.falciparum with at least 1000 asexual parasites/uL in an
      asymptomatic woman or any of the following symptoms within 2 days prior to consultation:
      history of fever; headache, vomiting, chills/rigors, and/or any of the following signs:
      temperature >37.50C and <39.50C, Hb >5 and <9 g/dl) together with P.falciparum parasitaemia
      at any density

      and (in both cases) the following:

        1. has no exclusion criterion (see below)

        2. is 14-34 weeks pregnant on the day of attending the ANC clinic or OPD;

        3. has a viable foetus, defined by presence of foetal heartbeat by sonicaid or pinnard
           (foetal heartbeat is not heard until 14 weeks)

        4. is able to take study drugs by the oral route

        5. is able to attend stipulated days for follow up clinic and provide specimens

        6. gives informed written or witnessed verbal consent to participate by herself, and also
           through her parent/guardian if aged <15 years (in conformity to Tanzania Law)

      Those > 34 weeks are excluded because they are close to term and may deliver during the 28
      day follow up period.

      Exclusion criteria

      Exclusion criteria include:-

        1. severe and complicated forms of malaria (as defined by WHO, 1996);

        2. pregnancy in the first trimester;

        3. a mixed plasmodial infection;

        4. complicated pregnancy e.g. signs/symptoms of toxaemia of pregnancy;

        5. 23 or more abortions or stillbirths;

        6. presence of concomitant disease masking assessment of the response to treatment ;

        7. an intake of drugs contraindicated in pregnancy e.g. tetracycline, cotrimoxazole or a
           macrolide antibiotic;

        8. an intake of drugs with effective antimalarial activity within the last 2 weeks.

        9. significantly abnormal baseline haematology (except anaemia) or clinical chemistry
           parameters e.g. laboratory evidence of renal impairment (serum creatinine >2 mg/dl) or
           of hepatitis (alanine aminotransferase ALT>5 times upper limit of normal);

       10. previous participation in the study: Women having a second episode of malaria after
           completing the 28-day follow up will have details recorded and offered quinine but not
           be re-enrolled.

       11. multiple gestation pregnancies eg twins

       12. Mother aged 38 years or above

      Patients with malaria who do not enter the trial because they fulfil an exclusion criterion
      will be treated in the optimum way decided by the attending physician. In general, those with
      severe disease will receive parenteral quinine whilst those with mild disease will receive
      SP.

      Withdrawal criteria

      Withdrawal criteria will include:-

        1. withdrawal of consent or non-compliance with assigned study regimen;

        2. appearance of other species of Plasmodium;

        3. vomiting within one hour after re-dosing;

        4. protocol violation.

           If it is necessary to withdraw a patient during the treatment phase, administration of
           the study drug will be discontinued. If the patient is still parasitaemic, quinine will
           be given as a rescue therapy unless there are clinical reasons to use another drug. For
           withdrawals outside the treatment phase the team will carry out all the safety and
           efficacy assessment measurements that would have been carried out at the next scheduled
           visit and the same will apply at delivery (unless the patient is lost to follow up).

        5. Patients who fail on treatment will be treated with rescue treatment and counted as
           treatment failures (see above).

      TREATMENT OF PATIENTS

      Study regimens

      Study drugs will be purchased or sourced from reputable sources with Good Manufacturing
      Practice (GMP). Dosages will be based on the body weight (kg) of the patient and the schedule
      will be as below.

        1. SP (sulfadoxine 25mg/kg stat)(SP)

        2. SP (sulfadoxine 25mg/kg stat) + Amodiaquine (10mg/kg x 3 days) (SPAQ)

        3. Chlorproguanil-dapsone (1.2 mg/kg and 2.4 mg/kg respectively 3 days) [Lapdap]

        4. Amodiaquine (10mg/kg x 3 days) + Artesunate (4mg/kg x 3 days) (AQAS)
    

Intervention name(s): SP; SP + amodiaquine; AQ + artesunate; chlorproguanil-dapsone
Intervention type(s): Drug; Drug; Drug; Drug
Intervention MeSH terms: Artesunate; Amodiaquine; Dapsone; Chlorproguanil
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: malaria; pregnancy; treatment; Africa; Tanzania