Pregnancy MalariaPhase 3NCT04189744
The ASPIRE Trial - Aiming for Safe Pregnancies by Reducing Malaria and Infections of the Reproductive Tract
A Phase 3 study testing IPTp-sulphadoxine-pyrimethamine plus metronidazole, IPTp-dihydroartemisinin-piperaquine plus metronidazole and IPTp-sulphadoxine-pyrimethamine in people with Pregnancy Malaria and Bacterial Vaginoses, run by London School of Hygiene and Tropical Medicine at 1 site in Zambia.
Trial summary
Malaria in pregnancy has devastating consequences for mother and foetus. WHO recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) for asymptomatic women, but high-level parasite resistance to SP threatens its efficacy. Read more about this study
- Who is it for?
- Any age, women onlyHealthy volunteers can take part
- Conditions the study is for
- Pregnancy Malaria, Bacterial Vaginoses, Trichomonas Vaginitis
- What is being tested?
- IPTp-sulphadoxine-pyrimethamine plus metronidazole, IPTp-dihydroartemisinin-piperaquine plus metronidazole and IPTp-sulphadoxine-pyrimethamine
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 5,436 participants
- Where
- 1 siteZambia
- Study dates
- 15 Dec 2019to 31 Mar 2023
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- Women only
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- Pregnant women
- HIV-negative
- Gestational age from Week 16 and 0 Days to Week 28 and 0 Days (measured by sonography)
- Carrying a single viable pregnancy
- Resident in the study area
- Express willingness to adhere to scheduled and unscheduled study visit procedures, and deliver at a trial facility
Who cannot join
- HIV-positive
- Carrying multiple pregnancies (twins, etc.),
- Known cardiac ailment
- Severe malformations or nonviable pregnancy observed by ultrasound
- History of receiving IPTp-SP during the current pregnancy
- Known allergy or contraindication to any of the study drugs
- Unable to give consent
- Concurrently participating in any other trial, including prior enrolment in this trial.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Effects of Metronidazole Plus Intermittent Preventive Treatment of Malaria in Pregnancy on Birth Outcomes: a Randomised Controlled Trial in Zambia
Malaria in pregnancy has devastating consequences for mother and foetus. WHO recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) for asymptomatic women, but high-level parasite resistance to SP threatens its efficacy. Dihydroartemisinin-piperaquine (DP) has the potential to replace SP for IPTp. However, the DP strategy has not been found to be superior to SP for reducing the incidence of low birthweight (LBW), small-for-gestational age (SGA), or preterm birth. This may be the result of sulphadoxine having antibacterial properties; it is derived from sulphonamide, which have been used for decades to treat curable STIs/RTIs. However, SP is unlikely to be curative of STIs/RTIs, nor highly effective against malaria parasites. Thus, combination treatment that contains a more efficacious antimalarial and a more efficacious anti-STI/RTI may produce better birth outcomes. The investigators will therefore determine whether combining SP with metronidazole (MTZ) or, separately, DP with MTZ can improve birth outcomes more than SP alone, potentially paving the way for integrated control strategies that will reduce the dual burden of malaria and curable STIs/RTIs.
This is an individually-randomized, 3-arm, partially-placebo controlled superiority trial comparing the efficacy, safety and tolerance of IPTp-SP versus IPTp-SP with MTZ, or IPTp-DP with MTZ to reduce adverse birth outcomes attributable to malaria and curable STIs/RTIs in 5,436 women in the Nchelenge District of Zambia.
Read the detailed description
Title: Effects of metronidazole plus intermittent preventive treatment of malaria in pregnancy on birth outcomes: a randomised controlled trial in Zambia.
Short Title: The ASPIRE Trial - Aiming for Safe Pregnancies by Reducing Malaria and Infections of the Reproductive Tract
Background and rationale: Current interventions in sub-Saharan Africa to reduce the burden of malaria infection and curable STIs/RTIs in pregnancy are inadequate. Malaria infection during pregnancy is responsible for 20% of all stillbirths and 11% of neonatal deaths and is strongly associated with low birthweight (LBW), preterm birth, and small-for-gestational-age (SGA) babies. To protect against adverse pregnancy outcomes in malaria-endemic areas, the WHO recommends providing IPTp-SP to pregnant women at each scheduled ANC visit as directly observed therapy from the second trimester to delivery with at least one month between doses. However, the loss of parasite sensitivity to SP has compromised the efficacy of IPTp.
Apart from syphilis and HIV screening, the WHO recommends the syndromic management of curable STIs/RTIs in low- and middle-income countries involving diagnostic and treatment algorithms based on self-reported symptoms. BV and TV are included in these guidelines. However, syndromic management fails to detect the majority of infections in women for whom STIs/RTIs are most often asymptomatic. This is of genuine consequence in pregnancy. BV is the most common urogenital disorder in the world among women of reproductive age and increases the odds of preterm delivery 1.5-2 times. TV is the most prevalent curable STI in the world and increases the odds of preterm delivery 1.5 times. BV and TV both double the odds of LBW. Although vertical transmission of TV is uncommon, maternal treatment may prevent respiratory or genital infection of the newborn. These adverse pregnancy outcomes could be averted with metronidazole (MTZ); 2g is safe and curative of TV and reduces the recurrence of BV. Importantly, the dose can be provided as directly observed therapy during ANC to ensure compliance.
IPTp-DP is the leading candidate to replace IPTp-SP. A trial in Kenya showed that IPTp-DP was superior to IPTp-SP in preventing clinical malaria episodes and other malaria-related endpoints. Alongside the trial, the investigators will conduct sub-studies that will generate important data about the mechanisms of IPTp-SP action against malaria, BV and TV.
Primary objective: To determine if IPTp with SP or DP, combined with MTZ, for the control of malaria and STIs/RTIs in pregnancy is safe and superior to IPTp with SP alone for reducing adverse pregnancy outcomes.
Hypothesis: IPTp with SP or DP, combined with MTZ, is superior to IPTp with SP alone in preventing adverse pregnancy outcomes.
Overview Study Design: A 3-arm, parallel, partially placebo-controlled, individually randomised, phase-3, superiority trial involving 5,436 (1,812 per arm) pregnant women in ANC facilities of the Nchelenge District of Zambia.
An economic evaluation will be carried out alongside the trial to estimate the cost and cost-effectiveness of interventions. In addition, the acceptability of therapy and the trade-offs between different attributes of the trial arms will be assessed using a discrete choice framework among trial participants and health care providers.
Sub-study 1: Effect of treatment on vaginal and intestinal microbiome and maternal cytokines
Objective: To characterise the effect of treatment across trial arms on the vaginal and intestinal microbiota communities, vaginal and intestinal bacterial loads and soluble markers of inflammation.
Sub-study 2: In vitro testing of sulphadoxine and other antimicrobial agents (Ndola, Zambia)
Objective: To measure the drug sensitivity of several pathogens implicated with WHO syndromes of vaginal discharge, lower abdominal pain, or genital ulcers in the presence of sulphadoxine and other antimicrobial agents.
Sites: The study will be conducted ANC facilities of the Nchelenge District of Zambia where the prior pregnancy cohort was previously carried out, malaria transmission is high, parasite resistance to SP is high, and there is a high prevalence of TV and BV among pregnant women at antenatal care facilities.
Study Population: HIV-negative pregnant women (all gravidae) between 16 and 28 weeks' gestation, as assessed by ultrasound dating who have not yet started IPTp during the current pregnancy.
Study Interventions:
Group 1: IPTp-SP plus MTZ placebo* (control) Group 2: IPTp-SP plus MTZ* Group 3: IPTp-DP plus MTZ*
SP = 3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine (Day 0) MTZ = 4 tablets each containing 500mg as directly observed therapy (Day 0) DP = 3 tablets of 40mg of dihydroartemisinin and 320mg of piperaquine (Days 0, 1, 2)
*MTZ placebo (Group 1) and active MTZ (Groups 2 and 3) will be co-administered with SP or DP during the enrolment visit (gestational week 16-19) and the last ANC visit prior to delivery (gestational week 30-34)
- Being tested
- IPTp-sulphadoxine-pyrimethamine plus metronidazole, IPTp-dihydroartemisinin-piperaquine plus metronidazole, IPTp-sulphadoxine-pyrimethamine
- Keywords
- Pregnancy Malaria, Bacterial Vaginoses, Trichomonas Vaginitis, Zambia, Intermittent Preventive Treatment in Pregnancy (IPTp), Sulfadoxine-Pyrimethamine, Dihydroartemisinin-Piperaquine, Metronidazole, Sub-Saharan Africa
- Medical subject headings
- Vaginosis, Bacterial, Trichomonas Vaginitis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IPTp-sulphadoxine-pyrimethamine plus metronidazoleDrug
Also called Fansidar, Flagyl
Metronidazole (MTZ) is indicated for the treatment of BV and TV and is also safe to administer in the second and third trimesters of pregnancy, and its use with SP or DP may result in better birth outcomes than SP alone. Malaria parasites have developed resistance against SP and the treatment is sub-optimal at clearing malaria infection compared to dihydroartemisinin-piperaquine (DP), therapy that has a suitable profile for use in IPTp. This intervention arm can be compared to the intervention arm IPTp-DP plus MTZ to assess whether DP is superior to SP in preventing adverse birth outcomes. This intervention arm will also be compared to the IPTp-SP plus MTZ placebo arm to assess whether the combination of MTZ with IPTp-SP is superior to IPTp-SP alone in reducing adverse pregnancy outcomes.
IPTp-dihydroartemisinin-piperaquine plus metronidazoleDrug
Also called Flagyl, D-ARTEPP®
Metronidazole (MTZ) is indicated for the treatment of BV and TV and is also safe to administer in the second and third trimesters of pregnancy, and its use with SP or DP may result in better birth outcomes than SP alone. Malaria parasites have developed resistance against SP and the treatment is sub-optimal at clearing malaria infection compared to dihydroartemisinin-piperaquine (DP), therapy that has a suitable profile for use in IPTp. This intervention arm can be compared to the intervention arm IPTp-SP plus MTZ to assess whether DP is superior to SP in in reducing adverse pregnancy outcomes.
IPTp-sulphadoxine-pyrimethamineDrug
Also called Fansidar
The World Health Organization (WHO) recommends providing intermittent preventive treatment (IPTp) using sulphadoxine-pyrimethamine (SP) to pregnant women during the second and third trimesters of pregnancy to clear placental infection.
| Study group | Role | What they receive |
|---|---|---|
| IPTp-SP plus MTZ placebo (control) | Placebo comparator | 3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and metronidazole placebo administered as directly observed therapy. Receives: Drug: IPTp-sulphadoxine-pyrimethamine |
| IPTp-SP plus MTZ | Active comparator | 3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and 4 tablets each containing 500mg metronidazole administered as directly observed therapy . Receives: Drug: IPTp-sulphadoxine-pyrimethamine plus metronidazole |
| IPTp-DP plus MTZ | Active comparator | 3 tablets of 40mg of dihydroartemisinin and 320mg of piperaquine, first dose and will be administered as directly observed therapy with the remaining two doses on the next two consecutive days at home. 4 tablets each containing 500mg metronidazole administered as directly observed therapy. Receives: Drug: IPTp-dihydroartemisinin-piperaquine plus metronidazole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Adverse pregnancy outcome
Composite endpoint of foetal morbidity, defined as any of the following: foetal loss (spontaneous abortion or stillbirth), singleton live births born with low birthweight (LBW), or preterm (PT) (LBW-PT), and subsequent neonatal death by day 28.
Measured: 8 months
Secondary outcomes (25)
Individual components of the primary outcome- adverse pregnancy outcomes
Prevalence of individual components of primary outcome
Measured: 8 months
Foetal loss
Spontaneous abortion or stillbirth (binary)
Measured: 8 months
Neonatal mortality
Death in the first 28 days of life (binary)
Measured: 8 months
Low birthweight
Birthweight <2.5 kg (binary)
Measured: 8 months from randomisation
Preterm birth
Birth at <37 gestational weeks
Measured: 8 months from randomisation
Birth weight (continuous)
Weight at birth (g)
Measured: 8 months from randomisation
Gestational age at delivery (continuous)
Based on gestational age measured by ultrasound at enrolment (days)
Measured: 8 months from randomisation
Z-score for birthweight (continuous)
Z-score for birthweight (g) from regional population reference
Measured: 8 months from randomisation
Small for gestational age (binary)
Estimated as a stand-alone secondary outcome using the 10th percentile of regional reference charts on the corrected birthweight
Measured: 8 months from randomisation
Clinical malaria during pregnancy (binary)
Clinical malaria at any point from enrolment including delivery and 28 day postpartum, both:
- Documented fever (≥37.5°C), or recent history of fever in the past 24 hours, or other symptoms of acute illness that resulted in a woman seeking care with an unscheduled visit
- Maternal malaria patent infection detectable by Rapid Diagnostic Test (RDT) for women with malaria symptoms only
Measured: 8 months from randomisation
Maternal malaria infection (binary)
Malaria infection detected by PCR during pregnancy in the peripheral blood at any point during pregnancy (scheduled and unscheduled visits) from study registration, including delivery.
Measured: 8 months from randomisation
Any malaria at delivery (binary)
Malaria infection at delivery detected in peripheral blood by PCR or placental blood by microscopy, PCR or histology (active infection)
Measured: 8 months from randomisation
Placental malaria infection (binary)
Placental malaria detected by microscopy, PCR , or histology (active and past infection) including any Plasmodium species detected in the placental blood or biopsy tissue by either:
- Placental incision smear microscopy (standard microscopy)
- PCR placental blood (maternal)
- Placental malaria by histology (active and past infection)
Measured: 8 months from randomisation
Congenital malaria infection (binary)
Malaria infection detected in foetal cord blood of the new born at birth by standard microscopy
Measured: 8 months from randomisation
Placental malaria by histology (binary)
- Active Infection:
- Chronic: pigment present and asexual parasites present
- Acute: pigment absent and asexual parasites present
- Past Infection: Pigment in fibrin detected in the absence of asexual parasites.
- Placental histology categories
- Any
- Active
- Active acute
- Active chronic
- Past
Measured: 8 months from randomisation
Placental Inflammation or chorioamnionitis (binary)
Any inflammation in the placenta or chorioamnionitis detected by placental histology
Measured: 8 months from randomisation
Maternal anaemia (binary) and haemoglobin concentration (continuous (g/dL) at enrolment and delivery
Definition:
- No anaemia (Hb >11 g/dL)
- Mild (Hb >10 to <11 g/dL)
- Moderate (Hb >7 to <10 g/dL
- Severe (Hb <7 g/dL)
Measured: 8 months from randomisation
Congenital anaemia in umbilical cord blood at delivery
Hb<12.5 g/dL in umbilical cord blood at birth, which is 2 standard deviations below the mean cord Hb in developed countries
Measured: 8 months from randomisation
Congenital malformations (binary)
Physical abnormality of live born baby detected at delivery or newly noted abnormality during the infant visits (7 days or 2-6 weeks post-natal)
Measured: 8 months from randomisation
Maternal mortality (binary)
Maternal mortality from registration until 28 days after delivery
Measured: 8 months from randomisation
SAEs and AEs defined by MedDRA (listings)
AEs and SAEs will be defined according to the Medical Dictionary for Regulatory Activities (MedDRA) and reported by study arm:
- Overall
- By system organ class and preferred term
Measured: 8 months from randomisation
History of vomiting study drug - Prevalence at each cycle of treatment (binary)
Vomited within 30 minutes of taking study drug at any scheduled administration
Measured: 8 months from randomisation
Dizziness - Prevalence at each cycle of treatment
Dizziness at any point within 30 minutes of first drug administered during a treatment cycle, reported as Mothers adverse event
Measured: 8 months from randomisation
Gastrointestinal complaints - Prevalence at each cycle of treatment (binary)
Nausea or vomiting within 30 minutes of first drug administered during a treatment cycle
Measured: 8 months from randomisation
Presence of any one or more STIs/RTIs - Prevalence at enrolment (binary)
Any or more infection of syphilis, gonorrhoea, chlamydia, trichomoniasis, and bacterial vaginosis
Measured: 8 months from randomisation
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Dec 2019
- Study start15 Dec 2019
- Primary completion21 Oct 2022
- Study completion31 Mar 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Pregnancy MalariaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 5,436 participants (actual)
Sponsor and investigators
- Lead sponsor
- London School of Hygiene and Tropical Medicine
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- R. Matthew Chico, MPH, PhD, Principal investigator, London School of Hygiene and Tropical Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04189744
- Sponsor's protocol ID
- ITDCZO83
- Status last verified
- Mar 2023
- First submitted
- 28 Oct 2019
- Last updated
- 22 May 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data will be shared upon receiving formal request and subject to sharing agreement.
Study at a glance
From the registry record, last updated by the sponsor on 22 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Metronidazole Plus Intermittent Preventive Treatment of Malaria in Pregnancy on Birth Outcomes: a Randomised Controlled Trial in Zambia
- ClinicalTrials.gov ID
- NCT04189744
- Acronym / sponsor ID
- ITDCZO83
- Keywords
- Pregnancy Malaria, Bacterial Vaginoses, Trichomonas Vaginitis, Zambia, Intermittent Preventive Treatment in Pregnancy (IPTp), Sulfadoxine-Pyrimethamine, Dihydroartemisinin-Piperaquine, Metronidazole
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 5,436 participants (actual)
- Lead sponsor
- London School of Hygiene and Tropical MedicineUniversity, hospital or other
- Study start
- 15 Dec 2019 (actual)
- Primary completion
- 21 Oct 2022 (actual)
- Study completion
- 31 Mar 2023 (actual)
- First posted
- 6 Dec 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Malaria in pregnancy has devastating consequences for mother and foetus. WHO recommends intermittent preventive treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) for asymptomatic women, but high-level parasite resistance to SP threatens its efficacy. Dihydroartemisinin-piperaquine (DP) has the potential to replace SP for IPTp. However, the DP strategy has not been found to be superior to SP for reducing the incidence of low birthweight (LBW), small-for-gestational age (SGA), or preterm birth. This may be the result of sulphadoxine having antibacterial properties; it is derived from sulphonamide, which have been used for decades to treat curable STIs/RTIs. However, SP is unlikely to be curative of STIs/RTIs, nor highly effective against malaria parasites. Thus, combination treatment that contains a more efficacious antimalarial and a more efficacious anti-STI/RTI may produce better birth outcomes. The investigators will therefore determine whether combining SP with metronidazole (MTZ) or, separately, DP with MTZ can improve birth outcomes more than SP alone, potentially paving the way for integrated control strategies that will reduce the dual burden of malaria and curable STIs/RTIs.
This is an individually-randomized, 3-arm, partially-placebo controlled superiority trial comparing the efficacy, safety and tolerance of IPTp-SP versus IPTp-SP with MTZ, or IPTp-DP with MTZ to reduce adverse birth outcomes attributable to malaria and curable STIs/RTIs in 5,436 women in the Nchelenge District of Zambia.
Detailed description
Title: Effects of metronidazole plus intermittent preventive treatment of malaria in pregnancy on birth outcomes: a randomised controlled trial in Zambia.
Short Title: The ASPIRE Trial - Aiming for Safe Pregnancies by Reducing Malaria and Infections of the Reproductive Tract
Background and rationale: Current interventions in sub-Saharan Africa to reduce the burden of malaria infection and curable STIs/RTIs in pregnancy are inadequate. Malaria infection during pregnancy is responsible for 20% of all stillbirths and 11% of neonatal deaths and is strongly associated with low birthweight (LBW), preterm birth, and small-for-gestational-age (SGA) babies. To protect against adverse pregnancy outcomes in malaria-endemic areas, the WHO recommends providing IPTp-SP to pregnant women at each scheduled ANC visit as directly observed therapy from the second trimester to delivery with at least one month between doses. However, the loss of parasite sensitivity to SP has compromised the efficacy of IPTp.
Apart from syphilis and HIV screening, the WHO recommends the syndromic management of curable STIs/RTIs in low- and middle-income countries involving diagnostic and treatment algorithms based on self-reported symptoms. BV and TV are included in these guidelines. However, syndromic management fails to detect the majority of infections in women for whom STIs/RTIs are most often asymptomatic. This is of genuine consequence in pregnancy. BV is the most common urogenital disorder in the world among women of reproductive age and increases the odds of preterm delivery 1.5-2 times. TV is the most prevalent curable STI in the world and increases the odds of preterm delivery 1.5 times. BV and TV both double the odds of LBW. Although vertical transmission of TV is uncommon, maternal treatment may prevent respiratory or genital infection of the newborn. These adverse pregnancy outcomes could be averted with metronidazole (MTZ); 2g is safe and curative of TV and reduces the recurrence of BV. Importantly, the dose can be provided as directly observed therapy during ANC to ensure compliance.
IPTp-DP is the leading candidate to replace IPTp-SP. A trial in Kenya showed that IPTp-DP was superior to IPTp-SP in preventing clinical malaria episodes and other malaria-related endpoints. Alongside the trial, the investigators will conduct sub-studies that will generate important data about the mechanisms of IPTp-SP action against malaria, BV and TV.
Primary objective: To determine if IPTp with SP or DP, combined with MTZ, for the control of malaria and STIs/RTIs in pregnancy is safe and superior to IPTp with SP alone for reducing adverse pregnancy outcomes.
Hypothesis: IPTp with SP or DP, combined with MTZ, is superior to IPTp with SP alone in preventing adverse pregnancy outcomes.
Overview Study Design: A 3-arm, parallel, partially placebo-controlled, individually randomised, phase-3, superiority trial involving 5,436 (1,812 per arm) pregnant women in ANC facilities of the Nchelenge District of Zambia.
An economic evaluation will be carried out alongside the trial to estimate the cost and cost-effectiveness of interventions. In addition, the acceptability of therapy and the trade-offs between different attributes of the trial arms will be assessed using a discrete choice framework among trial participants and health care providers.
Sub-study 1: Effect of treatment on vaginal and intestinal microbiome and maternal cytokines
Objective: To characterise the effect of treatment across trial arms on the vaginal and intestinal microbiota communities, vaginal and intestinal bacterial loads and soluble markers of inflammation.
Sub-study 2: In vitro testing of sulphadoxine and other antimicrobial agents (Ndola, Zambia)
Objective: To measure the drug sensitivity of several pathogens implicated with WHO syndromes of vaginal discharge, lower abdominal pain, or genital ulcers in the presence of sulphadoxine and other antimicrobial agents.
Sites: The study will be conducted ANC facilities of the Nchelenge District of Zambia where the prior pregnancy cohort was previously carried out, malaria transmission is high, parasite resistance to SP is high, and there is a high prevalence of TV and BV among pregnant women at antenatal care facilities.
Study Population: HIV-negative pregnant women (all gravidae) between 16 and 28 weeks' gestation, as assessed by ultrasound dating who have not yet started IPTp during the current pregnancy.
Study Interventions:
Group 1: IPTp-SP plus MTZ placebo* (control) Group 2: IPTp-SP plus MTZ* Group 3: IPTp-DP plus MTZ*
SP = 3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine (Day 0) MTZ = 4 tablets each containing 500mg as directly observed therapy (Day 0) DP = 3 tablets of 40mg of dihydroartemisinin and 320mg of piperaquine (Days 0, 1, 2)
*MTZ placebo (Group 1) and active MTZ (Groups 2 and 3) will be co-administered with SP or DP during the enrolment visit (gestational week 16-19) and the last ANC visit prior to delivery (gestational week 30-34)
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| IPTp-SP plus MTZ placebo (control) | Placebo comparator | Drug: IPTp-sulphadoxine-pyrimethamine3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and metronidazole placebo administered as directly observed therapy. |
| IPTp-SP plus MTZ | Active comparator | Drug: IPTp-sulphadoxine-pyrimethamine plus metronidazole3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and 4 tablets each containing 500mg metronidazole administered as directly observed therapy . |
| IPTp-DP plus MTZ | Active comparator | Drug: IPTp-dihydroartemisinin-piperaquine plus metronidazole3 tablets of 40mg of dihydroartemisinin and 320mg of piperaquine, first dose and will be administered as directly observed therapy with the remaining two doses on the next two consecutive days at home. 4 tablets each containing 500mg metronidazole administered as directly observed therapy. |
Who may qualify
- Sex
- Female only
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- Pregnant women
- HIV-negative
- Gestational age from Week 16 and 0 Days to Week 28 and 0 Days (measured by sonography)
- Carrying a single viable pregnancy
- Resident in the study area
Key exclusion criteria (8 listed)
- HIV-positive
- Carrying multiple pregnancies (twins, etc.),
- Known cardiac ailment
- Severe malformations or nonviable pregnancy observed by ultrasound
- History of receiving IPTp-SP during the current pregnancy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IPTp-sulphadoxine-pyrimethamine plus metronidazoleAlso: Fansidar, FlagylMetronidazole (MTZ) is indicated for the treatment of BV and TV and is also safe to administer in the second and third trimesters of pregnancy, and its use with SP or DP may result in better birth outcomes than SP alone. Malaria parasites have developed resistance against SP and the treatment is sub-optimal at clearing malaria infection compared to dihydroartemisinin-piperaquine (DP), therapy that has a suitable profile for use in IPTp. This intervention arm can be compared to the intervention arm IPTp-DP plus MTZ to assess whether DP is superior to SP in preventing adverse birth outcomes. This intervention arm will also be compared to the IPTp-SP plus MTZ placebo arm to assess whether the combination of MTZ with IPTp-SP is superior to IPTp-SP alone in reducing adverse pregnancy outcomes. | Drug | IPTp-SP plus MTZ |
| IPTp-dihydroartemisinin-piperaquine plus metronidazoleAlso: Flagyl, D-ARTEPP®Metronidazole (MTZ) is indicated for the treatment of BV and TV and is also safe to administer in the second and third trimesters of pregnancy, and its use with SP or DP may result in better birth outcomes than SP alone. Malaria parasites have developed resistance against SP and the treatment is sub-optimal at clearing malaria infection compared to dihydroartemisinin-piperaquine (DP), therapy that has a suitable profile for use in IPTp. This intervention arm can be compared to the intervention arm IPTp-SP plus MTZ to assess whether DP is superior to SP in in reducing adverse pregnancy outcomes. | Drug | IPTp-DP plus MTZ |
| IPTp-sulphadoxine-pyrimethamineAlso: FansidarThe World Health Organization (WHO) recommends providing intermittent preventive treatment (IPTp) using sulphadoxine-pyrimethamine (SP) to pregnant women during the second and third trimesters of pregnancy to clear placental infection. | Drug | IPTp-SP plus MTZ placebo (control) |
Primary outcome
Adverse pregnancy outcome
Time frame: 8 months
Composite endpoint of foetal morbidity, defined as any of the following: foetal loss (spontaneous abortion or stillbirth), singleton live births born with low birthweight (LBW), or preterm (PT) (LBW-PT), and subsequent neonatal death by day 28.
25 secondary outcomes
Individual components of the primary outcome- adverse pregnancy outcomes
Time frame: 8 months
Foetal loss
Time frame: 8 months
Neonatal mortality
Time frame: 8 months
Low birthweight
Time frame: 8 months from randomisation
Preterm birth
Time frame: 8 months from randomisation
Birth weight (continuous)
Time frame: 8 months from randomisation
Gestational age at delivery (continuous)
Time frame: 8 months from randomisation
Z-score for birthweight (continuous)
Time frame: 8 months from randomisation
Small for gestational age (binary)
Time frame: 8 months from randomisation
Clinical malaria during pregnancy (binary)
Time frame: 8 months from randomisation
Maternal malaria infection (binary)
Time frame: 8 months from randomisation
Any malaria at delivery (binary)
Time frame: 8 months from randomisation
Placental malaria infection (binary)
Time frame: 8 months from randomisation
Congenital malaria infection (binary)
Time frame: 8 months from randomisation
Placental malaria by histology (binary)
Time frame: 8 months from randomisation
Placental Inflammation or chorioamnionitis (binary)
Time frame: 8 months from randomisation
Maternal anaemia (binary) and haemoglobin concentration (continuous (g/dL) at enrolment and delivery
Time frame: 8 months from randomisation
Congenital anaemia in umbilical cord blood at delivery
Time frame: 8 months from randomisation
Congenital malformations (binary)
Time frame: 8 months from randomisation
Maternal mortality (binary)
Time frame: 8 months from randomisation
SAEs and AEs defined by MedDRA (listings)
Time frame: 8 months from randomisation
History of vomiting study drug - Prevalence at each cycle of treatment (binary)
Time frame: 8 months from randomisation
Dizziness - Prevalence at each cycle of treatment
Time frame: 8 months from randomisation
Gastrointestinal complaints - Prevalence at each cycle of treatment (binary)
Time frame: 8 months from randomisation
Presence of any one or more STIs/RTIs - Prevalence at enrolment (binary)
Time frame: 8 months from randomisation
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 May 2023.
- Individual participant dataSharing planned: Yes. Individual participant data will be shared upon receiving formal request and subject to sharing agreement.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
R. Matthew Chico, MPH, PhD principal investigator
London School of Hygiene and Tropical Medicine
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing IPTp-sulphadoxine-pyrimethamine plus metronidazole, IPTp-dihydroartemisinin-piperaquine plus metronidazole and IPTp-sulphadoxine-pyrimethamine in people with Pregnancy Malaria and Bacterial Vaginoses, run by London School of Hygiene and Tropical Medicine at 1 site in Zambia.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Zambia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Adverse pregnancy outcome (time frame: 8 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 May 2023; AzTrials last refreshed its copy on 6 Nov 2026.