Optimising DTwP-containing vaccine infant immunisation schedules (OptImms) - a protocol for two parallel, open-label, randomised controlled trials.

BACKGROUND: Universal immunisation is the cornerstone of preventive medicine for children, The World Health Organisation (WHO) recommends diphtheria-tetanus-pertussis (DTP) vaccine administered at 6, 10 and 14 weeks of age as part of routine immunisation. However, globally, more than 17 unique DTP-containing vaccine schedules are in use. New vaccines for other diseases continue to be introduced into the infant immunisation schedule, resulting in an increasingly crowded schedule. The OptImms trial will assess whether antibody titres against pertussis and other antigens in childhood can be maintained whilst adjusting the current Expanded Programme on Immunisation (EPI) schedule to provide space for the introduction of new vaccines. METHODS: The OptImms studies are two randomised, five-arm, non-inferiority clinical trials in Nepal and Uganda. Infants aged 6 weeks will be randomised to one of five primary vaccination schedules based on age at first DTwP-vaccination (6 versus 8 weeks of age), number of doses in the DTwP priming series (two versus three), and spacing of priming series vaccinations (4 versus 8 weeks). Additionally, participants will be randomised to receive their DTwP booster at 9 or 12 months of age. A further sub-study will compare the co-administration of typhoid vaccine with other routine vaccines at one year of age. The primary outcome is anti-pertussis toxin IgG antibodies measured at the time of the booster dose. Secondary outcomes include antibodies against other vaccine antigens in the primary schedule and their safety. DISCUSSION: These data will provide key data to inform policy decisions on streamlining vaccination schedules in childhood. TRIAL REGISTRATIONS: ISRCTN12240140 (Nepa1, 7th January 2021) and ISRCTN6036654 (Uganda, 17th February 2021).

Ganaplacide (KAF156) plus lumefantrine solid dispersion formulation combination for uncomplicated Plasmodium falciparum malaria: an open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial.

BACKGROUND: Emergence of drug resistance demands novel antimalarial drugs with new mechanisms of action. We aimed to identify effective and well tolerated doses of ganaplacide plus lumefantrine solid dispersion formulation (SDF) in patients with uncomplicated Plasmodium falciparum malaria. METHODS: This open-label, multicentre, parallel-group, randomised, controlled, phase 2 trial was conducted at 13 research clinics and general hospitals in ten African and Asian countries. Patients had microscopically-confirmed uncomplicated P falciparum malaria (>1000 and <150 000 parasites per µL). Part A identified the optimal dose regimens in adults and adolescents (aged ≥12 years) and in part B, the selected doses were assessed in children (≥2 years and <12 years). In part A, patients were randomly assigned to one of seven groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days; ganaplacide 800 mg plus lumefantrine-SDF 960 mg as a single dose; once a day ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; once a day ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; or twice a day artemether plus lumefantrine for 3 days [control]), with stratification by country (2:2:2:2:2:2:1) using randomisation blocks of 13. In part B, patients were randomly assigned to one of four groups (once a day ganaplacide 400 mg plus lumefantrine-SDF 960 mg for 1, 2, or 3 days, or twice a day artemether plus lumefantrine for 3 days) with stratification by country and age (2 to <6 years and 6 to <12 years; 2:2:2:1) using randomisation blocks of seven. The primary efficacy endpoint was PCR-corrected adequate clinical and parasitological response at day 29, analysed in the per protocol set. The null hypothesis was that the response was 80% or lower, rejected when the lower limit of two-sided 95% CI was higher than 80%. This study is registered with EudraCT (2020-003284-25) and ClinicalTrials.gov (NCT03167242). FINDINGS: Between Aug 2, 2017, and May 17, 2021, 1220 patients were screened and of those, 12 were included in the run-in cohort, 337 in part A, and 175 in part B. In part A, 337 adult or adolescent patients were randomly assigned, 326 completed the study, and 305 were included in the per protocol set. The lower limit of the 95% CI for PCR-corrected adequate clinical and parasitological response on day 29 was more than 80% for all treatment regimens in part A (46 of 50 patients [92%, 95% CI 81-98] with 1 day, 47 of 48 [98%, 89-100] with 2 days, and 42 of 43 [98%, 88-100] with 3 days of ganaplacide 400 mg plus lumefantrine-SDF 960 mg; 45 of 48 [94%, 83-99] with ganaplacide 800 mg plus lumefantrine-SDF 960 mg for 1 day; 47 of 47 [100%, 93-100] with ganaplacide 200 mg plus lumefantrine-SDF 480 mg for 3 days; 44 of 44 [100%, 92-100] with ganaplacide 400 mg plus lumefantrine-SDF 480 mg for 3 days; and 25 of 25 [100%, 86-100] with artemether plus lumefantrine). In part B, 351 children were screened, 175 randomly assigned (ganaplacide 400 mg plus lumefantrine-SDF 960 mg once a day for 1, 2, or 3 days), and 171 completed the study. Only the 3-day regimen met the prespecified primary endpoint in paediatric patients (38 of 40 patients [95%, 95% CI 83-99] vs 21 of 22 [96%, 77-100] with artemether plus lumefantrine). The most common adverse events were headache (in seven [14%] of 51 to 15 [28%] of 54 in the ganaplacide plus lumefantrine-SDF groups and five [19%] of 27 in the artemether plus lumefantrine group) in part A, and malaria (in 12 [27%] of 45 to 23 [44%] of 52 in the ganaplacide plus lumefantrine-SDF groups and 12 [50%] of 24 in the artemether plus lumefantrine group) in part B. No patients died during the study. INTERPRETATION: Ganaplacide plus lumefantrine-SDF was effective and well tolerated in patients, especially adults and adolescents, with uncomplicated P falciparum malaria. Ganaplacide 400 mg plus lumefantrine-SDF 960 mg once daily for 3 days was identified as the optimal treatment regimen for adults, adolescents, and children. This combination is being evaluated further in a phase 2 trial (NCT04546633). FUNDING: Novartis and Medicines for Malaria Venture.

Implementation of accelerated research: strategies for implementation as applied in a phase 1 Ad26.ZEBOV, MVA-BN-Filo two-dose Ebola vaccine clinical trial in Uganda.

BACKGROUND: The 2013-2016 Ebola epidemic in West Africa is the worst ever caused by Ebolaviruses with over 28,000 human cases and 11,325 deaths. The World Health Organisation (WHO) declared the epidemic a public health crisis that required accelerated development of novel interventions including vaccines. The Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit (MRC/UVRI & LSHTM Uganda Research Unit) was among the African research sites that implemented the VAC52150EBL1004 Ebola vaccine trial. OBJECTIVE: We report on the strategies utilised by the Unit and sponsor in ensuring expedited clinical trial approval and accelerated conduct. METHODS: Janssen Vaccines and Prevention B.V. conducted a phase 1 trial to evaluate the safety, tolerability, and immunogenicity of heterologous two-dose vaccination regimens using Ad26.ZEBOV and MVA-BN-Filo, in healthy adults in Africa. Accelerated implementation strategies are hereby presented. RESULTS: Strategies included: holding the African Vaccine Regulatory Forum (AVAREF) joint review meeting; expedited review by institutional ethics and country-specific regulatory bodies; competitive recruitment between sites; electronic data capture (EDC); frequent study monitoring schedule; involvement of a community advisory board (CAB); and utilization of a 'phased' study information-sharing approach in community engagement and participant recruitment. These strategies enabled the site to acquire approvals within 2 months and enrol 47 participants within a spurn of five. The same milestone is usually acquired in at least 1 year without accelerated implementation. CONCLUSION: The use of well-thought strategies by sponsors and research sites can enable the implementation of accelerated research. We recommend the use of similar strategies in other settings.