The ASPIRE Trial - Aiming for Safe Pregnancies by Reducing Malaria and Infections of the Reproductive Tract
Study Details
Study Description
Brief 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. 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 3 |
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
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: IPTp-SP plus MTZ placebo (control) 3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and metronidazole placebo administered as directly observed therapy. |
Drug: IPTp-sulphadoxine-pyrimethamine
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.
Other Names:
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| Active Comparator: IPTp-SP plus MTZ 3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and 4 tablets each containing 500mg metronidazole administered as directly observed therapy . |
Drug: IPTp-sulphadoxine-pyrimethamine plus metronidazole
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.
Other Names:
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| Active Comparator: IPTp-DP plus MTZ 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. |
Drug: IPTp-dihydroartemisinin-piperaquine plus metronidazole
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.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Adverse pregnancy outcome [8 months]
Composite endpoint of foetal morbidity, defined as any of the following: foetal loss (spontaneous abortion or stillbirth), singleton live births born small-for-gestational age (SGA), or with low birthweight (LBW), preterm (PT) (SGA-LBW-PT), subsequent neonatal death by day 28. Small for gestational age will be defined using the new INTERGROWTH population reference's 10th percentile.
Secondary Outcome Measures
- Individual components of the primary outcome- adverse pregnancy outcomes [8 months]
Prevalence of individual components of primary outcome
- Neonatal length and stunting [8 months]
Neonatal length and stunting (height-for-age Z-score<-2)
- Clinical malaria during pregnancy [6 months from randomisation]
Incidence of clinical malaria during pregnancy
- Malaria infection during pregnancy detected by microscopy [6 months from randomisation]
Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy
- Composite placental malaria detected by microscopy, by molecular methods or by histology (past and active infection) [6 months from randomisation]
Prevalence of placental malaria by microscopy, PCR and placental histology
- Maternal anaemia concentration during pregnancy and delivery [6 months from randomisation]
Prevalence and incidence of maternal anaemia (Hb < 11g/dl) at enrolment, last antenatal visit and delivery
- Maternal haemoglobin concentration during pregnancy and delivery [6 months from randomisation]
Maternal haemoglobin concentration (g/dL) during pregnancy and delivery
- Congenital anaemia [6 months from randomisation]
Prevalence of anaemia (Hb < 13g/dL) from newborn cord blood
- Congenital malaria infection [6 months from randomisation]
Prevalence of malaria infection by microscopy or PCR from newborn cord blood
- TV treatment efficacy by participant group [approximately 28 days]
TV clearance from visit 1 to visit 2 among women found retrospectively to have had TV
- BV treatment efficacy by participant group [approximately 28 days]
BV clearance from visit 1 to visit 2 among women found retrospectively to have had BV
- Vomiting of investigational product [6 months from randomisation]
Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit
- Dizziness following ingestion of investigational product [6 months from randomisation]
Prevalence of dizziness after a course of IP
- Gastrointestinal complaints following ingestion of investigational product [6 months from randomisation]
Prevalence of gastrointestinal complaints after a course of IP
- Presence of STIs/RTIs prior to delivery (syphilis, gonorrhoea, chlamydia trichomoniasis, and bacterial vaginosis) [6 months from randomisation]
Prevalence of STIs/RTIs prior to delivery (syphilis, gonorrhoea, chlamydia trichomoniasis, and bacterial vaginosis)
- Changes in the colony composition of maternal vaginal microbiota [6 months from randomisation]
Changes in maternal reproductive tract and gut microbiota from randomisation to last antenatal visit prior to delivery, and neonatal gut microbiota
- Changes in intestinal microbiota of mother [6 months from randomisation]
Changes in intestinal microbiota of mothers will be characterised across treatment groups via analysis of vaginal swabs and stool samples.
- Changes in intestinal bacterial loads [6 months from randomisation]
Changes in intestinal bacterial loads of mothers will be characterised across treatment groups via analysis of vaginal swabs and stool samples.
- Changes in soluble markers of inflammation [6 months from randomisation]
Prevalence of markers of inflammation across treatment groups as assessed via analysis of vaginal swabs.
- In vitro sensitivity of pathogens implicated with WHO syndromes of vaginal discharge, lower abdominal pain, or genital ulcers to sulphadoxine and other antimicrobial agents [6 months from randomisation]
Sensitivity of pathogens to sulphadoxine and other antimicrobial agents will be assessed across treatment groups by sensitivity testing of cultured bacterial isolates from vaginal swabs.
- Cost of providing the intervention and alternatives, and economic outcomes related to the primary endpoint [6 months from randomisation]
A full economic evaluation of the cost of providing trials interventions and alternatives, and economic outcomes related to the primary endpoint
- Mothers' and health care providers' preferences for treatment-arm attributes and masking flavours at dosing to increase acceptability [6 months from randomisation]
Qualitative metrics of mothers' and health care providers' preferences for treatment-arm attributes and masking flavours at dosing to increase acceptability, assessed by a piloted questionnaire.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Pregnant women
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HIV-negative
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Gestational age from Week 16 and 0 Days to Week 28 and 0 Days (measured by sonography)
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Carrying a single viable pregnancy
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Resident in the study area
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Express willingness to adhere to scheduled and unscheduled study visit procedures, and deliver at a trial facility
Exclusion Criteria:
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HIV-positive
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Carrying multiple pregnancies (twins, etc.),
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Known cardiac ailment
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Severe malformations or nonviable pregnancy observed by ultrasound
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History of receiving IPTp-SP during the current pregnancy
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Known allergy or contraindication to any of the study drugs
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Unable to give consent
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Concurrently participating in any other trial, including prior enrolment in this trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Nchelenge District Health Facilites | Nchelenge | Luapula Province | Zambia |
Sponsors and Collaborators
- London School of Hygiene and Tropical Medicine
Investigators
- Principal Investigator: R. Matthew Chico, MPH, PhD, London School of Hygiene and Tropical Medicine
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ITDCZO83