Kilimanjaro IPTi Drug Options Trial
Condition: Malaria
MeSH terms: Malaria
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Malaria and anaemia are major causes of morbidity and mortality in children in sub-Saharan
      Africa. Administration of three courses of sulfadoxine/pyrimethamine (SP) as intermittent
      preventive treatment (IPTi) to infants when they receive EPI vaccines reduced the incidence
      of malaria and anaemia in infants in an area with low SP resistance, low transmission
      pressure and high bednet use. However, it is not clear whether this observation can be
      generalised to areas with high transmission and high SP resistance. The mechanism of the
      protective effect of IPTi is unclear. There is an urgent need to identify other anti-malarial
      drugs that could be used for IPTi instead of SP.

      This study objectives are:

        1. Identification of a drug that could be used safely and effectively for IPTi instead of
           SP in areas, such as north eastern Tanzania, where there is a high level of resistance
           to SP and amodiaquine.

        2. Determination of whether a short acting antimalarial drug (Lapdap) is as effective as a
           long acting drug (mefloquine) when used for IPTi.

        3. Investigation of the effect of the intensity of transmission on the requirements for a
           long or short acting drug for IPTi.

        4. Assessment of the effect of IPTi on the development of clinical immunity in children in
           low and high transmission areas.

      A randomised trial with four treatment regimes is proposed which will be conducted in two
      different transmission settings. The four treatment regimens are as follows: (1) placebo; (2)
      mefloquine; (3) Lapdap; (4) SP. All medications will be given at the time of immunisation
      with DPT/polio 2, DPT/polio 3, and measles vaccines. The study will involve 1280 infants in a
      high endemic area and 2440 infants in a low endemic area, in Tanzania.The primary outcome is
      the incidence of clinical malaria.
    

Detailed description: 
      1. Study design

           The overall study design is a randomised trial of four treatment regimes in two
           different transmission settings. The four treatment regimes are as follows: (1) placebo,
           (2) mefloquine; (3) Lapdap; (4) SP. All medications will be given at the time of
           immunisation with DPT/polio 2, DPT/polio 3, and measles vaccines.

        2. Study procedures

      A list of study infants due for DPT/Polio 2 vaccination in each study EPI clinic on a given
      date will be generated from the enrolment database a week prior to the scheduled date.

      When the study infants return for DPT& Polio 2 (contact 1) the following procedures will be
      carried out: (1) allocation of infants to one the four arms of the study; (2) administration
      of the first dose of the study drug and dispensation of the remaining two doses of drug to be
      given at home in the presence of a study field worker; (3) collection of blood samples for
      Hb, malaria parasite and blood spot for genetic markers of drug resistance parasites and
      haemoglobinopathies; (4) advice given to the caretakers to bring their children to the health
      facility if the child becomes ill before the next scheduled visit.

      In both study areas, the first 200 children will be followed up on day 7 post-administration
      of IPTi first course (contact 1a) and a finger prick blood sample will be collected for
      determination of haemoglobin and preparation of blood film.

      When the study infants return for DPT& Polio 3 (contact 2) the following procedures will be
      carried out: (1) administration of the first dose of the second course of the study drugs and
      dispensation of the remaining two doses of drugs to be given at home in the presence of a
      study field worker; (2) advice given to the caretakers to bring their children to the health
      facility if the child becomes ill before the next scheduled visit.

      When the study infants return for measles (contact 3) the following procedures will be
      carried out: (1) administration of the first dose of the third course of the study drugs and
      dispensation of the remaining two doses of drugs to be given at home in the presence of a
      study field worker; (2) collection of blood samples for measles serology; (3) advice given to
      the caretakers to bring their children to the health facility if the child becomes ill.

      In both study areas, the second 200 children will be followed up on day 7 post-administration
      of IPTi third course (contact 3a) and a finger prick blood sample will be collected for
      determination of haemoglobin and preparation of blood film.

      A list of study infants who are due for blood examination one month after receiving course 3
      of the study drugs will be generated from the contact3 database every month. These infants
      will be visited at home (contact 4) by a study team and a finger prick blood sample (400 μl)
      will be collected for determination of Hb, blood film preparation for malaria parasites and
      measuring anti-VSA antibodies. A random sample of 20% of infants will be visited at home at
      11 months of age or two months after the 3rd course of the study drug (contact 5) and a
      finger prick blood sample will be collected for Hb and blood film preparation. Another random
      sample of 20% of children will be visited at home at 12 months of age or 3 months after the
      3rd course of the drug (contact 6) and a finger prick blood will be collected for Hb and
      blood film preparation. Infant who had a blood sample taken at 11 months of age will be
      excluded from the sample of infants selected for collection of blood samples at 12 months of
      age. . All study children will be visited at home at the age of approximately 18 months
      (contact 7) and a finger prick blood sample (400 μl) will be obtained for determination of
      Hb, blood film preparation for malaria parasites and measuring anti-VSA antibodies.

      All children will be visited at home at the age of approximately 24 months (contact 8) and
      finger prick blood sample will be obtained for screening for malaria using Optimal dipsticks
      and also for preparation of blood slides, filter paper samples and Hb. If a child is positive
      by dipstick test, is currently febrile (Temp >37.5° C) or has a history of fever within the
      past 2 days, and/or has a history of taking SP for a febrile illness during the previous
      week, the child will be treated with quinine.

      If the dipstick test is positive for malaria and there is no history of fever within the past
      2 days and no history of use of SP within the past week, the child will be given a full
      treatment course of any one of the three antimalarial drug used for IPTi ie SP, Lapdap or
      mefloquine, allocated randomly. The randomisation of treatment regime will be done in blocks
      of 6. Within each block of six envelopes, two will contain LapDap, two will contain MQ and
      Lapdap placebo for day 2 and 3, two will contain SP and Lapdap placebo for day 2 and 3. A
      random sample of 10% of children will be visited on day3 to assess whether the drugs were
      given to the children and a urine sample will be taken from approximately 200 children
      (selected randomly through out the year) for testing for mefloquine, dapsone and
      pyrimethamine using high performance liquid chromatography. All children who were treated
      with an antimalarial drug will be followed up on post treatment day 14 (contact 9) and on day
      28 (contact 10). On these two visits a finger prick blood sample will be taken for
      examination of malaria parasite and filter paper sample obtained for subsequent determination
      of resistance markers to SP and Lapdap.

      Randomisation and allocation of study groups

      The unit of randomization will be an individual infant. Infants will be allocated to one of
      the study groups by permuted block randomization. Each study drug, including placebo, will be
      assigned 4 group codes; there will be 16 study groups in total in each study site and these
      will be colour coded. An independent statistician (Dr Tom Smith) will prepare the
      randomization scheme during the preparatory phase of the study. 233 blocks of 16 blister
      packs of study drugs [80 blocks (1280/16 = 80) for the high transmission area, and 153 blocks
      (2448/16 = 153) for the low transmission area] will be prepared and the study drug codes will
      be kept by the independent statistician.

      The tablets will be crushed and mixed with syrup at the time of administration. The first
      dose will be administered at the EPI clinic by a designated member of the study team. The
      drugs for day 2 and 3 will be dispensed in blister packs and the caretakers will be advised
      to administer the drugs at home. The level of compliance and side effects of the drug will be
      monitored by the compliance assessment team during home visits made on day 2 and day 3. If
      drugs had not been given by the caretakers, the project staff will administer the drugs with
      the consent of the caretaker.

      Oral administration of mefloquine can induce vomiting in children suffering from clinical
      malaria. We will observe the incidence of vomiting over an initial period of three months and
      report this information to the Data, Safety and Monitoring Board (DSMB). If the incidence of
      vomiting is significant, the DSMB may recommend that the schedule of mefloquine
      administration should be changed to a split dose (15 mg /kg on day 1 and 10 mg/kg on day 2).

      Monitoring compliance and safety

      Compliance with the three days of medication will be assessed by field staff during their
      visits on days 2 and 3. Urine samples will be collected on a random basis throughout the
      course of the trial at the day 3 visit and tested for mefloquine, dapsone and pyrimethamine
      using high performance liquid chromatography (HPLC).

      Determining the safety and acceptability of mefloquine and Lapdap when used for IPTi will be
      a major objective of the study. This will be accomplished in three main ways:

        1. Changes in haemoglobin during the week following treatment will be measured and related
           to the presence or absence of parasitaemia and or fever at the time of treatment. Data
           for each of the 16 treatment groups will be collated by the investigators and given to
           the DSMB which will be asked to break the code for these subjects and to determine if
           there is are any concerns over a fall in Hb in the approximately 200 infants who have
           received Lapdap. It will be possible to compare findings in these children with those
           children who receive mefloquine, SP or placebo. If necessary, the G-6-P-D status will be
           determined in any children who show a drop in Hb and in matched controls.

        2. . At the time of the day 3 follow-up, a questionnaire will be completed which asks about
           the health of the infant since the time of drug administration.

        3. . An adverse events reporting system will be established in each of the health centres
           participating in the trial. Any severe adverse event will be reported to the chair of
           the DSMB and to GSK within 48 hours.

      Drugs used for IPTi must not have any suppressive on the immune response to EPI vaccines
      given concurrently. An impact on measles vaccination is the issue of most concern. Therefore,
      a serum sample will be collected at the age of 9 months before administering measles
      vaccination and one month after the administration of the vaccine. Antibody concentrations to
      DPT antigens may be measured in these samples.

      Surveillance of clinical malaria

      All study infants will be encouraged to attend the study health facilities for any illness.
      At these visits a health questionnaire will be completed and temperature recorded using an
      electronic thermometer. A finger prick blood sample will be collected for Hb and malaria
      parasite and for detection of molecular markers of resistance from all infants attending the
      study health facilities for any illness that is clinically diagnosed as malaria.

      Children with proven or presumptive malaria will be treated with quinine according to the MoH
      guidelines for managing treatment failures following first line drugs.

      To ensure that IPTi with any of the study drugs does not lead to a rebound in the incidence
      of severe malaria or anaemia during the second year of life all infants enrolled in the study
      will be followed until they reach the age of 24 months. During their second year of life, all
      episodes of possible malaria or anaemia in infants who present to health centre in the study
      area will be documented.

      Monitoring of the trial

      The trial will be conducted under conditions of good clinical practice (GCP), following as
      closely as possible the ICH guidelines. Standard operating procedures (SOPs) will be
      developed for all major operations. A DSMB will be established to look after the trial.
      Discussions will be held with the DSMB prior to the start of the trial to identify their
      requirements for adverse events reporting and these will be met. The DSMB will also be
      consulted about the advisability of an interim analysis, in particular for the SP group as
      this drug may prove to be ineffective.

      At each study site, a local physician will be assigned to be the local safety monitor. In the
      event of a serious adverse event associated with a study drug, the local safety monitor will
      be empowered to break the code for that child and, if it is considered necessary to
      temporarily suspend the trial, prior to discussion with the DSMB.

      It is proposed that a clinical monitor will be appointed by the IPTi consortium to monitor
      all the trials conducted under its auspices and it is anticipated that the monitor will visit
      the study site on at least one occasion during the trial and provide advice that will help to
      ensure that the study is conducted to the highest clinical standard.
    

Intervention name(s): sulphadoxine-pyrimethamine; mefloquine; Chlorproguanil-dapsone; Placebo; Sulphadoxine-pryrimethamine; IPTi mefloquine; Chlorproguanil dapsone
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug
Intervention description(s): Placebo; IPTi doses 1 and 2, at ages 2 and 3 months, sulphadoxine 250mg, pyrimethamine 12.5mg IPTi doses 3, at 9 months of age, sulphadoxine 500mg, pyrimethamine 25mg; IPTi doses 1 & 2 at ages 2 & 3 months, mefloquine 125mg IPTi dose 3 at 9 months, mefloquine 250mg; IPTi doses 1 and 2 at ages 2 and 3 months, doses 15mg chlorproguanil and 18.75mg dapsone IPTi dose 3 at 9 months of age, doses 22.5mg chlorproguanil and 28.13mg dapsone
Other intervention name(s): Fansidar; Larium; Lapdap; Fansidar; Larium; Lapdap
Intervention MeSH terms: Pyrimethamine; Sulfadoxine; Fanasil, pyrimethamine drug combination; Dapsone; Mefloquine; Chlorproguanil; Proguanil
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Diagnostic
Keywords: intermittent preventive treatment; malaria; efficacy; safety; drug options