Ignite Creation Date:
2024-05-05 @ 11:50 AM
Last Modification Date:
2024-10-26 @ 9:14 AM
Study NCT ID:
NCT00146731
Status:
COMPLETED
Last Update Posted:
2017-01-12
First Post:
2005-09-05
Brief Title:
A Trial of Antimalarial Drugs Used in Pregnancy in Tanzania
Sponsor:
London School of Hygiene and Tropical Medicine
Organization:
London School of Hygiene and Tropical Medicine
Study Overview
Official Title:
Treating Malaria During Pregnancy A Randomized Trial of Potential Options for Treatment in an Area of High Drug Resistance in Tanzania
Status:
COMPLETED
Status Verified Date:
2017-01
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 Chlorproguanildapsone 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 75gdl or in cases where initial haemoglobin was less than 9 gdl a drop of 20 from the starting Hb if the initial Hb was less than 9gdl 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 signssymptoms 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 infections Duplicate thick and thin blood smears will be made Giemsa stained at pH 72 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 Pfalciparum with at least 1000 asexual parasitesuL in an asymptomatic woman or any of the following symptoms within 2 days prior to consultation history of fever headache vomiting chillsrigors andor any of the following signs temperature 3750C and 3950C Hb 5 and 9 gdl together with Pfalciparum 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 parentguardian 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 eg signssymptoms 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 eg 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 eg laboratory evidence of renal impairment serum creatinine 2 mgdl or of hepatitis alanine aminotransferase ALT5 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 25mgkg statSP
2 SP sulfadoxine 25mgkg stat Amodiaquine 10mgkg x 3 days SPAQ
3 Chlorproguanil-dapsone 12 mgkg and 24 mgkg respectively 3 days Lapdap
4 Amodiaquine 10mgkg x 3 days Artesunate 4mgkg x 3 days AQAS
1 SP
2 SP amodiaquine SPAQ
3 Chlorproguanildapsone 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 75gdl or in cases where initial haemoglobin was less than 9 gdl a drop of 20 from the starting Hb if the initial Hb was less than 9gdl 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 signssymptoms 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 infections Duplicate thick and thin blood smears will be made Giemsa stained at pH 72 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 Pfalciparum with at least 1000 asexual parasitesuL in an asymptomatic woman or any of the following symptoms within 2 days prior to consultation history of fever headache vomiting chillsrigors andor any of the following signs temperature 3750C and 3950C Hb 5 and 9 gdl together with Pfalciparum 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 parentguardian 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 eg signssymptoms 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 eg 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 eg laboratory evidence of renal impairment serum creatinine 2 mgdl or of hepatitis alanine aminotransferase ALT5 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 25mgkg statSP
2 SP sulfadoxine 25mgkg stat Amodiaquine 10mgkg x 3 days SPAQ
3 Chlorproguanil-dapsone 12 mgkg and 24 mgkg respectively 3 days Lapdap
4 Amodiaquine 10mgkg x 3 days Artesunate 4mgkg x 3 days AQAS
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None