Project Title

EFFICACY AND SAFETY OF PYRONARIDINE-ARTESUNATE (PYRAMAX) FOR THE TREATMENT OF FALCIPARUM MALARIA IN AFRICAN PREGNANT WOMEN (PYRAPREG)

Halidou TINTO

Maminata TRAORE/ COULIBALY

This is a Phase 3, non-inferiority (95% efficacy and a non-inferiority margin of 5%), multicentre (Burkina Faso, Democratic Republic of Congo, Mali, Mozambique, The Gambia), randomised, open-label clinical trial. A total of 1,875 malaria-infected pregnant women at the second and third trimester will be recruited and randomized 1:1:1 to each study arm, namely pyronaridine-artesunate (PA), artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) and will be actively followed up until day 63 post-treatment, at delivery, and at 4-6 weeks post-delivery. The infants will be visited around the first birthday to check their health status.

The sample size was estimated by assuming an efficacy (PCR-adjusted ACPR at Day 42) of at least 95% and a non-inferiority margin of 5%; Non-inferiority will be tested using a crude pooling of the country data, using a Wilson score interval of proportion difference. The lower limit of the 97.5% Wilson score interval of AL (or DP) proportion of treatment success – PA proportion of treatment success must be greater than -5% to claim non-inferiority. Additionally, an adjusted non-inferiority analysis will allow for the effect of country (Xin Y et al, 2010). Assuming 20% loss to follow up, the total sample size for 90% power would be 3*500/0.8 = 1875, i.e. 375 pregnant women per country and 125 per arm per country. This sample size will maintain the power of the adjusted stratified non-inferiority test. In addition, in case one country fails to recruit the planned number of pregnant women, the sample size would have 80% power to show non-inferiority.

Pregnant women fulfilling the inclusion/exclusion criteria (see section 4) will be recruited during antenatal clinics at study sites and over a period of about 30 months. Scheduled visits will be at day 3, 7 and then every week until day 63 post-treatment. However, women will be encouraged to attend the antenatal clinic if they feel ill between scheduled visits. At each visit, both scheduled and unscheduled, the medical history since the last visit (including any treatment taken), current signs and symptoms (if any) will be collected. A blood sample for thick and thin blood film will be collected and the body temperature checked. Dried blood spots for later genotyping to distinguish between recrudescence and new infection will be collected at Day 0, before treatment, and at every study visit. Information on any adverse event will also be collected. Haematology (Hb, total white blood cell count, differential count and platelets) will be performed at Days 0, 7, 14, 28, 42 and 63; biochemistry (, and creatinine) at Day 0, 1, and 7. In the event of increased liver function tests (LFTs) >3xULN, the result will be verified by taking a further sample for analysis as soon as possible (within 24 hours of the original sample). Subsequent blood samples for LFTs will be taken at 48-hour intervals until the results return to <2xULN. ECG will be taken at day 0, before drug intake, and at day 2 after drug intake. If abnormal at day 2, ECG will be repeated at day 7 and every week until return to normal. At the end of the active follow-up period, after Day 63, women field assistants will visit the study subjects about once a month, to maintain the contact with the study team but without collecting any data or biological samples.

Pregnant women recruited during the third trimester (before 37 weeks) may deliver before the 63-day active follow up is finished. If this occurs, the assessment at delivery will be carried out as usual but the scheduled visits will continue after delivery until the one at day 63 is completed. For example, if a woman delivers between day 28 and day 35, she will be followed up at scheduled visits for the remaining days until day 63, i.e. 42, 49, 56 and 63. Women will be encouraged to deliver at the health facility. Babies born from women who deliver within or 2 weeks after the active follow up will have a blood sample taken to measure LFT and bilirubin within 48 hours of delivery.

The outcome of pregnancy, birth weight and maternal Hb will be collected as soon as possible after delivery. A placenta biopsy will be collected for later histopathological analysis. The new-born will be examined for congenital abnormalities. Both the mother and the new-born will be reassessed twice after delivery for any adverse event: between 4 and 6 weeks and then after one year. Patients will be assessed as summarized in the study visit schedule below.

March 2019