Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria

A multicentre randomized control trial

Michael Nambozi, Modest Mulenga, Tinto Halidou, Harry Tagbor, Victor Mwapasa, Linda Kalilani Phiri, Gertrude Kalanda, Innocent Valea, Maminata Traore, David Mwakazanga, Yves Claeys, Céline Schurmans, Maaike De Crop, Joris Menten, Raffaella Ravinetto, Kamala Ley-Thriemer, Jean-Pierre Van geertruyden, Theonest Mutabingwa, Umberto D'Alessandro

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    Abstract

    Background: Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided.

    Design: A Phase 3, non-inferiority, multicentre, randomized, open-label clinical trial on safety and efficacy of 4 ACT when administered during pregnancy was carried out in 4 African countries: Burkina Faso, Ghana, Malawi and Zambia. This is a four arm trial using a balanced incomplete block design. Pregnant women diagnosed with malaria are randomised to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin-piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4–6 weeks post-delivery. The offspring is visited at the time of the first birthday. The primary endpoint is treatment failure (PCR adjusted) at day 63 and safety profiles. Secondary endpoints included PCR unadjusted treatment failure up to day 63, gametocyte carriage, Hb changes, placenta malaria, mean birth weight and low birth weight. The primary statistical analysis will use the combined data from all 4 centres, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all 6 possible pair-wise treatment comparisons using all available data.

    Discussion: 
    The strength of this trial is the involvement of several African countries, increasing the generalisability of the results. In addition, it assesses most ACTs currently available, determining their relative ‘-value-’ compared to others. The balanced incomplete block design was chosen because using all 4-arms in each site would have increased complexity in terms of implementation. Excluding HIV-positive pregnant women on antiretroviral drugs may be seen as a limitation because of the possible interactions between antiretroviral and antimalarial treatments. Nevertheless, the results of this trial will provide the evidence base for the formulation of malaria treatment policy for pregnant women in sub-Saharan Africa.

    Original languageEnglish
    Article number5
    Pages (from-to)1-10
    Number of pages10
    JournalReproductive Health
    Volume12
    Issue number1
    DOIs
    Publication statusPublished - 1 Jan 2015

    Fingerprint

    Malaria
    Pregnant Women
    Antimalarials
    Pregnancy
    dihydroartemisinin
    Africa South of the Sahara
    Treatment Failure
    Safety
    Clinical Trials
    Mefloquine
    Burkina Faso
    Zambia
    Therapeutics
    Malawi
    Polymerase Chain Reaction
    Ghana
    Far East
    Low Birth Weight Infant
    Birth Weight
    Placenta

    Cite this

    Nambozi, Michael ; Mulenga, Modest ; Halidou, Tinto ; Tagbor, Harry ; Mwapasa, Victor ; Phiri, Linda Kalilani ; Kalanda, Gertrude ; Valea, Innocent ; Traore, Maminata ; Mwakazanga, David ; Claeys, Yves ; Schurmans, Céline ; Crop, Maaike De ; Menten, Joris ; Ravinetto, Raffaella ; Ley-Thriemer, Kamala ; geertruyden, Jean-Pierre Van ; Mutabingwa, Theonest ; D'Alessandro, Umberto. / Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria : A multicentre randomized control trial. In: Reproductive Health. 2015 ; Vol. 12, No. 1. pp. 1-10.
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    abstract = "Background: Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided.Design: A Phase 3, non-inferiority, multicentre, randomized, open-label clinical trial on safety and efficacy of 4 ACT when administered during pregnancy was carried out in 4 African countries: Burkina Faso, Ghana, Malawi and Zambia. This is a four arm trial using a balanced incomplete block design. Pregnant women diagnosed with malaria are randomised to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin-piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4–6 weeks post-delivery. The offspring is visited at the time of the first birthday. The primary endpoint is treatment failure (PCR adjusted) at day 63 and safety profiles. Secondary endpoints included PCR unadjusted treatment failure up to day 63, gametocyte carriage, Hb changes, placenta malaria, mean birth weight and low birth weight. The primary statistical analysis will use the combined data from all 4 centres, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all 6 possible pair-wise treatment comparisons using all available data.Discussion: The strength of this trial is the involvement of several African countries, increasing the generalisability of the results. In addition, it assesses most ACTs currently available, determining their relative ‘-value-’ compared to others. The balanced incomplete block design was chosen because using all 4-arms in each site would have increased complexity in terms of implementation. Excluding HIV-positive pregnant women on antiretroviral drugs may be seen as a limitation because of the possible interactions between antiretroviral and antimalarial treatments. Nevertheless, the results of this trial will provide the evidence base for the formulation of malaria treatment policy for pregnant women in sub-Saharan Africa.",
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    author = "Michael Nambozi and Modest Mulenga and Tinto Halidou and Harry Tagbor and Victor Mwapasa and Phiri, {Linda Kalilani} and Gertrude Kalanda and Innocent Valea and Maminata Traore and David Mwakazanga and Yves Claeys and C{\'e}line Schurmans and Crop, {Maaike De} and Joris Menten and Raffaella Ravinetto and Kamala Ley-Thriemer and geertruyden, {Jean-Pierre Van} and Theonest Mutabingwa and Umberto D'Alessandro",
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    Nambozi, M, Mulenga, M, Halidou, T, Tagbor, H, Mwapasa, V, Phiri, LK, Kalanda, G, Valea, I, Traore, M, Mwakazanga, D, Claeys, Y, Schurmans, C, Crop, MD, Menten, J, Ravinetto, R, Ley-Thriemer, K, geertruyden, J-PV, Mutabingwa, T & D'Alessandro, U 2015, 'Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria: A multicentre randomized control trial', Reproductive Health, vol. 12, no. 1, 5, pp. 1-10. https://doi.org/10.1186/1742-4755-12-5

    Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria : A multicentre randomized control trial. / Nambozi, Michael; Mulenga, Modest; Halidou, Tinto; Tagbor, Harry; Mwapasa, Victor; Phiri, Linda Kalilani; Kalanda, Gertrude; Valea, Innocent; Traore, Maminata; Mwakazanga, David; Claeys, Yves; Schurmans, Céline; Crop, Maaike De; Menten, Joris; Ravinetto, Raffaella; Ley-Thriemer, Kamala; geertruyden, Jean-Pierre Van; Mutabingwa, Theonest; D'Alessandro, Umberto.

    In: Reproductive Health, Vol. 12, No. 1, 5, 01.01.2015, p. 1-10.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Safe and efficacious artemisinin-based combination treatments for African pregnant women with malaria

    T2 - A multicentre randomized control trial

    AU - Nambozi, Michael

    AU - Mulenga, Modest

    AU - Halidou, Tinto

    AU - Tagbor, Harry

    AU - Mwapasa, Victor

    AU - Phiri, Linda Kalilani

    AU - Kalanda, Gertrude

    AU - Valea, Innocent

    AU - Traore, Maminata

    AU - Mwakazanga, David

    AU - Claeys, Yves

    AU - Schurmans, Céline

    AU - Crop, Maaike De

    AU - Menten, Joris

    AU - Ravinetto, Raffaella

    AU - Ley-Thriemer, Kamala

    AU - geertruyden, Jean-Pierre Van

    AU - Mutabingwa, Theonest

    AU - D'Alessandro, Umberto

    PY - 2015/1/1

    Y1 - 2015/1/1

    N2 - Background: Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided.Design: A Phase 3, non-inferiority, multicentre, randomized, open-label clinical trial on safety and efficacy of 4 ACT when administered during pregnancy was carried out in 4 African countries: Burkina Faso, Ghana, Malawi and Zambia. This is a four arm trial using a balanced incomplete block design. Pregnant women diagnosed with malaria are randomised to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin-piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4–6 weeks post-delivery. The offspring is visited at the time of the first birthday. The primary endpoint is treatment failure (PCR adjusted) at day 63 and safety profiles. Secondary endpoints included PCR unadjusted treatment failure up to day 63, gametocyte carriage, Hb changes, placenta malaria, mean birth weight and low birth weight. The primary statistical analysis will use the combined data from all 4 centres, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all 6 possible pair-wise treatment comparisons using all available data.Discussion: The strength of this trial is the involvement of several African countries, increasing the generalisability of the results. In addition, it assesses most ACTs currently available, determining their relative ‘-value-’ compared to others. The balanced incomplete block design was chosen because using all 4-arms in each site would have increased complexity in terms of implementation. Excluding HIV-positive pregnant women on antiretroviral drugs may be seen as a limitation because of the possible interactions between antiretroviral and antimalarial treatments. Nevertheless, the results of this trial will provide the evidence base for the formulation of malaria treatment policy for pregnant women in sub-Saharan Africa.

    AB - Background: Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided.Design: A Phase 3, non-inferiority, multicentre, randomized, open-label clinical trial on safety and efficacy of 4 ACT when administered during pregnancy was carried out in 4 African countries: Burkina Faso, Ghana, Malawi and Zambia. This is a four arm trial using a balanced incomplete block design. Pregnant women diagnosed with malaria are randomised to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin-piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4–6 weeks post-delivery. The offspring is visited at the time of the first birthday. The primary endpoint is treatment failure (PCR adjusted) at day 63 and safety profiles. Secondary endpoints included PCR unadjusted treatment failure up to day 63, gametocyte carriage, Hb changes, placenta malaria, mean birth weight and low birth weight. The primary statistical analysis will use the combined data from all 4 centres, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all 6 possible pair-wise treatment comparisons using all available data.Discussion: The strength of this trial is the involvement of several African countries, increasing the generalisability of the results. In addition, it assesses most ACTs currently available, determining their relative ‘-value-’ compared to others. The balanced incomplete block design was chosen because using all 4-arms in each site would have increased complexity in terms of implementation. Excluding HIV-positive pregnant women on antiretroviral drugs may be seen as a limitation because of the possible interactions between antiretroviral and antimalarial treatments. Nevertheless, the results of this trial will provide the evidence base for the formulation of malaria treatment policy for pregnant women in sub-Saharan Africa.

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    KW - comparative study

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    KW - gametocyte

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    KW - human

    KW - in vitro study

    KW - low birth weight

    KW - major clinical study

    KW - malaria

    KW - Malawi

    KW - mean birth weight

    KW - multicenter study (topic)

    KW - open study

    KW - parameters concerning the fetus, newborn and pregnancy

    KW - patient monitoring

    KW - phase 3 clinical trial (topic)

    KW - placenta malaria

    KW - pregnancy

    KW - pregnant woman

    KW - randomized controlled trial (topic)

    KW - time to treatment

    KW - Zambia

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    JO - Reproductive Health

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