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

NCT04189744 | Completed Phase 3 DMC

• 1 other identifier: ITDCZO83
• Study Type: interventional
• Target: 5,436
• Locations: 1 country
• Sites: 1

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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.

  8 months

Secondary Outcomes (25)

• Individual components of the primary outcome- adverse pregnancy outcomes

  8 months

• Foetal loss

  8 months

• Neonatal mortality

  8 months

• Low birthweight

  8 months from randomisation

• Preterm birth

  8 months from randomisation

Study Arms (3)

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.

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 .

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.

Drug: IPTp-dihydroartemisinin-piperaquine plus metronidazole

Interventions

IPTp-sulphadoxine-pyrimethamine plus metronidazole DRUG

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.

Also known as: Fansidar, Flagyl

IPTp-SP plus MTZ

IPTp-dihydroartemisinin-piperaquine plus metronidazole DRUG

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.

Also known as: Flagyl, D-ARTEPP®

IPTp-DP plus MTZ

IPTp-sulphadoxine-pyrimethamine DRUG

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.

Also known as: Fansidar

IPTp-SP plus MTZ placebo (control)

Eligibility Criteria

• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• London School of Hygiene and Tropical Medicine: lead

Study Sites (1)

Nchelenge District Health Facilites

Nchelenge, Luapula Province, Zambia

Location

MeSH Terms

Conditions

Vaginosis, Bacterial; Trichomonas Vaginitis

Interventions

Metronidazole; fanasil, pyrimethamine drug combination

Condition Hierarchy (Ancestors)

Bacterial Infections; Bacterial Infections and Mycoses; Infections; Vaginitis; Vaginal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Trichomonas Infections; Protozoan Infections; Parasitic Diseases

Intervention Hierarchy (Ancestors)

Nitroimidazoles; Nitro Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• R. Matthew Chico, MPH, PhD

  London School of Hygiene and Tropical Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Partially placebo controlled
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 28, 2019
• First Posted: December 6, 2019
• Study Start: December 15, 2019
• Primary Completion: October 21, 2022
• Study Completion: March 31, 2023
• Last Updated: May 22, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Five years
• 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.

Locations

ZA (1)