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AzTrials

PregnancyPhase 3IMPROVENCT03208179

Improving PRegnancy Outcomes With Intermittent preVEntive Treatment in Africa

A Phase 3 study testing dihydroartemisinin-piperaquine, sulphadoxine-pyrimethamine and dihydroartemisinin-piperaquine plus azithromycin in people with Pregnancy and Malaria in Pregnancy, run by Liverpool School of Tropical Medicine at 7 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This study evaluates the efficacy and safety of monthly intermittent preventive treatment using dihydroartemisinin piperaquine (DP) alone or in combination with azithromycin (AZ) compared to sulphadoxine-pyrimethamine (SP) for the prevention of malaria in pregnant women in the second and third trimester. Read more about this study

Who is it for?
Ages 16 years and older, women onlyHealthy volunteers can take part
Conditions the study is for
Pregnancy, Malaria in Pregnancy, Malaria
What is being tested?
dihydroartemisinin-piperaquine, sulphadoxine-pyrimethamine and dihydroartemisinin-piperaquine plus azithromycin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
4,680 participants
Where
7 sitesin 3 countries
Study dates
29 Mar 2018to 15 Mar 2020
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 16 years and older
  • Women only
  • Healthy volunteers accepted
  • Child, Adult, Older adult

Who may be able to join

  • Pregnant women between 16-28 weeks' gestation
  • Viable singleton pregnancy
  • Resident of the study area
  • Willing to adhere to scheduled and unscheduled study visit procedures
  • Willing to deliver in a study clinic or hospital
  • Provide written informed consent

Who cannot join

  • Multiple pregnancies (i.e. twin/triplets)
  • HIV-positive
  • Known heart ailment
  • Severe malformations or non-viable pregnancy if observed by ultrasound
  • History of receiving IPTp-SP during this current pregnancy
  • Unable to give consent
  • Known allergy or contraindication to any of the study drugs

Trial locations and contacts

7 sites in 3 countries.

7 sites in 3 countries

Kenya3 sites

  • Ahero Sud-countyHospital

    Ahero, Kisumu County

  • Homa Bay County Hospital

    Homa Bay

  • Rabour Sub-county Hospital

    Kisumu

Other trials in Kenya

Malawi2 sites

  • Chikwawa District Hospital

    Chikwawa

  • Mangochi District Hospital

    Mangochi

Other trials in Malawi

Tanzania2 sites

  • Handeni District Hospital

    Handeni

  • Korogwe District Hospital

    Korogwe

Other trials in Tanzania

About this study

Official title: IPTp With Dihydroartemisinin-piperaquine and Azithromycin for Malaria, Sexually Transmitted and Reproductive Tract Infections in Pregnancy in High Sulphadoxine-pyrimethamine Resistance Areas in Kenya, Malawi and Tanzania

This study evaluates the efficacy and safety of monthly intermittent preventive treatment using dihydroartemisinin piperaquine (DP) alone or in combination with azithromycin (AZ) compared to sulphadoxine-pyrimethamine (SP) for the prevention of malaria in pregnant women in the second and third trimester.

Read the detailed description

Intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) is one of the pillars of malaria prevention in pregnancy in sub-Saharan Africa, in addition to prompt case management and use of long lasting insecticide treated bednets. However, mounting resistance to SP by Plasmodium falciparum increasing renders IPTP-SP ineffective.

Two exploratory trials in Uganda and Kenya demonstrated that IPTp with DP was superior to IPTp-SP for the prevention of malaria infection in pregnancy. However, neither study was adequately powered to look at adverse birth outcomes. This study is a confirmatory efficacy trial in Malawi, Tanzania and Kenya to determine the efficacy and safety of IPTp with DP alone or in combination with AZ.

This will be a 3-arm trial, superiority, partial blinded, placebo controlled, randomized trial comparing IPTp with SP, versus IPTp with DP alone, and IPTp with DP+AZ with the following hypotheses:

  • IPTp with DP is superior to IPTp with SP in preventing adverse pregnancy outcomes.
  • The combination of DP with AZ further reduces adverse pregnancy outcomes compared to IPTp with DP alone.
Being tested
dihydroartemisinin-piperaquine, sulphadoxine-pyrimethamine, dihydroartemisinin-piperaquine plus azithromycin
Keywords
Malaria in Pregnancy, Intermittent Preventive Treatment, IPTp
Medical subject headings
Malaria

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • dihydroartemisinin-piperaquineDrug

    Also called Eurartesim

    Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin placebo

  • sulphadoxine-pyrimethamineDrug

    Also called Fansidar

    Women randomised to this intervention will receive stat dose of 3 tablets of 500 mg sulphadoxine and 25 mg of pyrimethamine each (total dose of 1,500mg sulphadoxine and 75mg pyrimethamine) on a single day of clinic visit

  • dihydroartemisinin-piperaquine plus azithromycinDrug

    Also called Eurartesim plus Zithromax

    Women randomised to this intervention will receive 3 day treatment dose of dihydroartemisinin-piperaquine by body weight plus azithromycin (500mg)

Study groups in NCT03208179
Study groupRoleWhat they receive
IPTp-SPActive comparatorStat course of 3 tablets of quality-assured SP (tablets of 500 mg of sulphadoxine and 25 mg of pyrimethamine) at each scheduled antenatal visit
Receives: Drug: sulphadoxine-pyrimethamine
IPTp-DPExperimentalDihydroartemisinin-piperaquine [3 to 5 tablets of DP (tablets of 40 mg of dihydroartemisinin and 320 mg of piperaquine, based on bodyweight) daily for 3 days] + placebo AZ at each scheduled antenatal visit
Receives: Drug: dihydroartemisinin-piperaquine
IPTp-DPAZExperimentalDihydroartemisinin-piperaquine [3 to 5 tablets of DP (tablets of 40 mg of dihydroartemisinin and 320 mg of piperaquine, based on bodyweight) daily for 3 days] + AZ tablet [1.5g over 3 days as 500mg per day] at each scheduled antenatal visit.
Receives: Drug: dihydroartemisinin-piperaquine plus azithromycin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Adverse pregnancy outcome

    Composite of foetal loss (spontaneous abortion or stillbirth), or singleton live births born small-for-gestational age (SGA), or with low birthweight (LBW), or preterm (PT) (SGA-LBW-PT), or subsequent neonatal death by day 28.

    Measured: 8 months

Secondary outcomes (27)

  1. Composite of foetal loss and neonatal mortality

    Composite of foetal loss (spontaneous abortion or stillbirth) and neonatal mortality

    Measured: 8 months

  2. SGA-LBW-PT composite

    Composite of small for gestational age, low birth weight or preterm birth

    Measured: 6 months

  3. SGA

    Small for gestational age using the new INTERGROWTH population reference's 10th percentile

    Measured: 6 months

  4. LBW

    Low birth weight defined as a corrected birth weight below 2.5 kg

    Measured: 6 months

  5. PT

    Preterm birth defined as birth at a gestational age above 28 weeks but less than 37 completed weeks

    Measured: 6 months

  6. Neonatal length and stunting

    Neonatal length and stunting

    Measured: 8 months

  7. Clinical malaria during pregnancy

    Incidence of clinical malaria during pregnancy

    Measured: 6 months from randomisation

  8. Malaria infection during pregnancy detected by microscopy and PCR

    Prevalence and incidence of peripheral maternal (blood) malaria infection during pregnancy by microscopy and PCR

    Measured: 6 months from randomisation

  9. Composite placental malaria detected by microscopy, by molecular methods or by histology

    Prevalence of placental malaria by microscopy, PCR and placental histology

    Measured: 6 months from randomisation

  10. Placental malaria detected by microscopy

    Prevalence of placental malaria detected in maternal placental blood by microscopy

    Measured: 6 months from randomisation

  11. Placental malaria detected by molecular methods (PCR)

    Prevalence of placental malaria detected in maternal placental blood by PCR

    Measured: 6 months from randomisation

  12. Placental malaria detected by histology

    Prevalence of placental malaria detected in full placental section by histology

    Measured: 6 months from randomisation

  13. Maternal nutritional status

    Changes in maternal nutritional status by MUAC and BMI.

    Measured: 6 months from randomisation

  14. Maternal anaemia during pregnancy and delivery

    Prevalence and incidence of maternal anaemia (Hb < 11g/dl) at enrolment, last antenatal visit and delivery

    Measured: 6 months from randomisation

  15. Congenital anaemia

    Prevalence of anaemia (Hb < 13g/dl) from newborn cord blood

    Measured: 6 months from randomisation

  16. Congenital malaria infection

    Prevalence of malaria infection by microscopy or PCR from newborn cord blood

    Measured: 6 months from randomisation

  17. QTc-prolongation

    QTcF-prolongation of more than 60ms between baseline DTcF prior to first dose of DP (+/- AZ) on day 0 and repeat QTcF 4 - 6 hrs after administration of 3rd dose of DP(+/- AZ) on day 2, or QTcF > 480ms, 4 - 6 hours after on day 2 treatment administration. Only on the DP containing arms.

    Measured: 6 months from randomisation

  18. Congenital malformations

    Any visible external congenital abnormality on surface examination

    Measured: 6 months from randomisation

  19. Maternal mortality

    The death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from accidental or incidental causes.

    Measured: 8 months from randomisation

  20. Other SAEs and AEs

    Incidence of AEs and SAEs

    Measured: 8 months from randomisation

  21. (History of) vomiting study drug

    Prevalence and incidence of vomiting investigational product (IP) twice at the same IP administration visit

    Measured: 6 months from randomisation

  22. Dizziness

    Prevalence of dizziness after a course of IP

    Measured: 6 months from randomisation

  23. Gastrointestinal complaints

    Prevalence of gastrointestinal complaints after a course of IP

    Measured: 6 months from randomisation

  24. Molecular markers of drug resistance in Plasmodium falciparum infections during pregnancy and delivery

    Prevalence and incidence of SP and artemisinin resistance markers from infection isolates after enrollment and at delivery

    Measured: 6 months from randomisation

  25. Presence of STIs/RTIs prior to delivery (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis)

    Prevalence and incidence of STIs/RTIs (syphilis, gonorrhoea, Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis) at randomization and last antenatal visit prior to delivery

    Measured: 6 months from randomisation

  26. Changes in macrolide resistance in Pneumococcus detected in maternal nasopharyngeal samples

    Prevalence and incidence of carriage of macrolide resistant pneumococcus at randomization and delivery

    Measured: 6 months from randomisation

  27. Changes in the colony composition of maternal vaginal microbiota, and intestinal microbiota of mother and infant.

    Changes in maternal reproductive tract and gut microbiota from randomisation to last antenatal visit prior to delivery, and neonatal gut microbiota

    Measured: 6 months from randomisation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Jul 2017
  2. Study start29 Mar 2018
  3. Primary completion15 Mar 2020
  4. Study completion15 Mar 2020

Resources

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
4,680 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03208179
Sponsor's protocol ID
16.049
Acronym
IMPROVE
Status last verified
Jun 2022
First submitted
30 Jun 2017
Last updated
27 Jun 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Individual, de-identified participant data will be made available for meta-analyses as soon as the data analysis is completed, with the understanding that results of the meta-analysis will not be published prior to the results of the individual trial without prior agreement of the investigators. No later than 5 years after the publication of the trial a fully de-identified data set will be available for sharing purposes

Publications

  • Gore-Langton GR, Madanitsa M, Barsosio HC, Minja DTR, Mosha J, Kavishe RA, Mtove G, Gesase S, Msemo OA, Kariuki S, Otieno K, Phiri KS, Lusingu JPA, Mukerebe C, Manjurano A, Ikigo P, Saidi Q, Onyango ED, Schmiegelow C, Dodd J, Hill J, Hansson H, Alifrangis M, Gutman J, Hunter PJ, Klein N, Ashorn U, Khalil A, Cairns M, Ter Kuile FO, Chico RM. Prevalence and risk factors of curable sexually transmitted and reproductive tract infections and malaria co-infection among pregnant women at antenatal care booking in Kenya, Malawi and Tanzania: a cross-sectional study of randomised controlled trial data. BMJ Public Health. 2024 Sep 18;2(2):e000501. doi: 10.1136/bmjph-2023-000501. eCollection 2024 Dec.

    PubMed 40018559

  • Madanitsa M, Barsosio HC, Minja DTR, Mtove G, Kavishe RA, Dodd J, Saidi Q, Onyango ED, Otieno K, Wang D, Ashorn U, Hill J, Mukerebe C, Gesase S, Msemo OA, Mwapasa V, Phiri KS, Maleta K, Klein N, Magnussen P, Lusingu JPA, Kariuki S, Mosha JF, Alifrangis M, Hansson H, Schmiegelow C, Gutman JR, Chico RM, Ter Kuile FO. Effect of monthly intermittent preventive treatment with dihydroartemisinin-piperaquine with and without azithromycin versus monthly sulfadoxine-pyrimethamine on adverse pregnancy outcomes in Africa: a double-blind randomised, partly placebo-controlled trial. Lancet. 2023 Mar 25;401(10381):1020-1036. doi: 10.1016/S0140-6736(22)02535-1. Epub 2023 Mar 10.

    PubMed 36913959

  • Mtove G, Abdul O, Kullberg F, Gesase S, Scheike T, Andersen FM, Madanitsa M, Ter Kuile FO, Alifrangis M, Lusingu JPA, Minja DTR, Schmiegelow C. Weight change during the first week of life and a new method for retrospective prediction of birthweight among exclusively breastfed newborns. Acta Obstet Gynecol Scand. 2022 Mar;101(3):293-302. doi: 10.1111/aogs.14323. Epub 2022 Feb 13.

    PubMed 35156190

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing dihydroartemisinin-piperaquine, sulphadoxine-pyrimethamine and dihydroartemisinin-piperaquine plus azithromycin in people with Pregnancy and Malaria in Pregnancy, run by Liverpool School of Tropical Medicine at 7 sites in 3 countries.

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 7 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 27 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Kenya, Malawi, Tanzania. 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. 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?

On the ClinicalTrials.gov record for NCT03208179, which also lists 3 linked publications.

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 27 Jun 2022.

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