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The ASPIRE Trial - Aiming for Safe Pregnancies by Reducing Malaria and Infections of the Reproductive Tract

Primary Purpose

Pregnancy Malaria, Bacterial Vaginoses, Trichomonas Vaginitis

Status
Completed
Phase
Phase 3
Locations
Zambia
Study Type
Interventional
Intervention
IPTp-sulphadoxine-pyrimethamine plus metronidazole
IPTp-dihydroartemisinin-piperaquine plus metronidazole
IPTp-sulphadoxine-pyrimethamine
Sponsored by
London School of Hygiene and Tropical Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Pregnancy Malaria focused on measuring Pregnancy Malaria, Bacterial Vaginoses, Trichomonas Vaginitis, Zambia, Intermittent Preventive Treatment in Pregnancy (IPTp), Sulfadoxine-Pyrimethamine, Dihydroartemisinin-Piperaquine, Metronidazole, Sub-Saharan Africa

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)FemaleAccepts Healthy Volunteers

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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.

Sites / Locations

  • Nchelenge District Health Facilites

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Placebo Comparator

Active Comparator

Active Comparator

Arm Label

IPTp-SP plus MTZ placebo (control)

IPTp-SP plus MTZ

IPTp-DP plus MTZ

Arm Description

3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and metronidazole placebo administered as directly observed therapy.

3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and 4 tablets each containing 500mg metronidazole administered as directly observed therapy .

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Individual components of the primary outcome- adverse pregnancy outcomes
Prevalence of individual components of primary outcome
Foetal loss
Spontaneous abortion or stillbirth (binary)
Neonatal mortality
Death in the first 28 days of life (binary)
Low birthweight
Birthweight <2.5 kg (binary)
Preterm birth
Birth at <37 gestational weeks
Birth weight (continuous)
Weight at birth (g)
Gestational age at delivery (continuous)
Based on gestational age measured by ultrasound at enrolment (days)
Z-score for birthweight (continuous)
Z-score for birthweight (g) from regional population reference
Small for gestational age (binary)
Estimated as a stand-alone secondary outcome using the 10th percentile of regional reference charts on the corrected birthweight
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
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.
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)
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)
Congenital malaria infection (binary)
Malaria infection detected in foetal cord blood of the new born at birth by standard microscopy
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
Placental Inflammation or chorioamnionitis (binary)
Any inflammation in the placenta or chorioamnionitis detected by placental histology
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)
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
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)
Maternal mortality (binary)
Maternal mortality from registration until 28 days after delivery
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
History of vomiting study drug - Prevalence at each cycle of treatment (binary)
Vomited within 30 minutes of taking study drug at any scheduled administration
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
Gastrointestinal complaints - Prevalence at each cycle of treatment (binary)
Nausea or vomiting within 30 minutes of first drug administered during a treatment cycle
Presence of any one or more STIs/RTIs - Prevalence at enrolment (binary)
Any or more infection of syphilis, gonorrhoea, chlamydia, trichomoniasis, and bacterial vaginosis

Full Information

First Posted
October 28, 2019
Last Updated
May 19, 2023
Sponsor
London School of Hygiene and Tropical Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT04189744
Brief Title
The ASPIRE Trial - Aiming for Safe Pregnancies by Reducing Malaria and Infections of the Reproductive Tract
Official Title
Effects of Metronidazole Plus Intermittent Preventive Treatment of Malaria in Pregnancy on Birth Outcomes: a Randomised Controlled Trial in Zambia
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Completed
Study Start Date
December 15, 2019 (Actual)
Primary Completion Date
October 21, 2022 (Actual)
Study Completion Date
March 31, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
London School of Hygiene and Tropical Medicine

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. 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.
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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pregnancy Malaria, Bacterial Vaginoses, Trichomonas Vaginitis
Keywords
Pregnancy Malaria, Bacterial Vaginoses, Trichomonas Vaginitis, Zambia, Intermittent Preventive Treatment in Pregnancy (IPTp), Sulfadoxine-Pyrimethamine, Dihydroartemisinin-Piperaquine, Metronidazole, Sub-Saharan Africa

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Partially placebo controlled
Allocation
Randomized
Enrollment
5436 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IPTp-SP plus MTZ placebo (control)
Arm Type
Placebo Comparator
Arm Description
3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and metronidazole placebo administered as directly observed therapy.
Arm Title
IPTp-SP plus MTZ
Arm Type
Active Comparator
Arm Description
3 tablets each containing 500mg sulphadoxine and 25mg pyrimethamine and 4 tablets each containing 500mg metronidazole administered as directly observed therapy .
Arm Title
IPTp-DP plus MTZ
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
IPTp-sulphadoxine-pyrimethamine plus metronidazole
Other Intervention Name(s)
Fansidar, Flagyl
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
IPTp-dihydroartemisinin-piperaquine plus metronidazole
Other Intervention Name(s)
Flagyl, D-ARTEPP®
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
IPTp-sulphadoxine-pyrimethamine
Other Intervention Name(s)
Fansidar
Intervention Description
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.
Primary Outcome Measure Information:
Title
Adverse pregnancy outcome
Description
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.
Time Frame
8 months
Secondary Outcome Measure Information:
Title
Individual components of the primary outcome- adverse pregnancy outcomes
Description
Prevalence of individual components of primary outcome
Time Frame
8 months
Title
Foetal loss
Description
Spontaneous abortion or stillbirth (binary)
Time Frame
8 months
Title
Neonatal mortality
Description
Death in the first 28 days of life (binary)
Time Frame
8 months
Title
Low birthweight
Description
Birthweight <2.5 kg (binary)
Time Frame
8 months from randomisation
Title
Preterm birth
Description
Birth at <37 gestational weeks
Time Frame
8 months from randomisation
Title
Birth weight (continuous)
Description
Weight at birth (g)
Time Frame
8 months from randomisation
Title
Gestational age at delivery (continuous)
Description
Based on gestational age measured by ultrasound at enrolment (days)
Time Frame
8 months from randomisation
Title
Z-score for birthweight (continuous)
Description
Z-score for birthweight (g) from regional population reference
Time Frame
8 months from randomisation
Title
Small for gestational age (binary)
Description
Estimated as a stand-alone secondary outcome using the 10th percentile of regional reference charts on the corrected birthweight
Time Frame
8 months from randomisation
Title
Clinical malaria during pregnancy (binary)
Description
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
Time Frame
8 months from randomisation
Title
Maternal malaria infection (binary)
Description
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.
Time Frame
8 months from randomisation
Title
Any malaria at delivery (binary)
Description
Malaria infection at delivery detected in peripheral blood by PCR or placental blood by microscopy, PCR or histology (active infection)
Time Frame
8 months from randomisation
Title
Placental malaria infection (binary)
Description
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)
Time Frame
8 months from randomisation
Title
Congenital malaria infection (binary)
Description
Malaria infection detected in foetal cord blood of the new born at birth by standard microscopy
Time Frame
8 months from randomisation
Title
Placental malaria by histology (binary)
Description
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
Time Frame
8 months from randomisation
Title
Placental Inflammation or chorioamnionitis (binary)
Description
Any inflammation in the placenta or chorioamnionitis detected by placental histology
Time Frame
8 months from randomisation
Title
Maternal anaemia (binary) and haemoglobin concentration (continuous (g/dL) at enrolment and delivery
Description
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)
Time Frame
8 months from randomisation
Title
Congenital anaemia in umbilical cord blood at delivery
Description
Hb<12.5 g/dL in umbilical cord blood at birth, which is 2 standard deviations below the mean cord Hb in developed countries
Time Frame
8 months from randomisation
Title
Congenital malformations (binary)
Description
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)
Time Frame
8 months from randomisation
Title
Maternal mortality (binary)
Description
Maternal mortality from registration until 28 days after delivery
Time Frame
8 months from randomisation
Title
SAEs and AEs defined by MedDRA (listings)
Description
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
Time Frame
8 months from randomisation
Title
History of vomiting study drug - Prevalence at each cycle of treatment (binary)
Description
Vomited within 30 minutes of taking study drug at any scheduled administration
Time Frame
8 months from randomisation
Title
Dizziness - Prevalence at each cycle of treatment
Description
Dizziness at any point within 30 minutes of first drug administered during a treatment cycle, reported as Mothers adverse event
Time Frame
8 months from randomisation
Title
Gastrointestinal complaints - Prevalence at each cycle of treatment (binary)
Description
Nausea or vomiting within 30 minutes of first drug administered during a treatment cycle
Time Frame
8 months from randomisation
Title
Presence of any one or more STIs/RTIs - Prevalence at enrolment (binary)
Description
Any or more infection of syphilis, gonorrhoea, chlamydia, trichomoniasis, and bacterial vaginosis
Time Frame
8 months from randomisation

10. Eligibility

Sex
Female
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: 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 Exclusion Criteria: 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
R. Matthew Chico, MPH, PhD
Organizational Affiliation
London School of Hygiene and Tropical Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Nchelenge District Health Facilites
City
Nchelenge
State/Province
Luapula Province
Country
Zambia

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data will be shared upon receiving formal request and subject to sharing agreement.
IPD Sharing Time Frame
Five years
IPD Sharing Access Criteria
The full protocol will be available on request to any interested professional. All requests for data for secondary analysis will be considered by a Data Access Committee to ensure that use of data is within the terms of consent and ethics approval.

Learn more about this trial

The ASPIRE Trial - Aiming for Safe Pregnancies by Reducing Malaria and Infections of the Reproductive Tract

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