Abstract: Changes in nutrient intake and decreased exercise resulting from cancer therapies as well as their side effects may be contributing factors in the increased body weight and differences in physical fitness observed in survivors of childhood acute lymphoblastic leukemia (ALL). This article will describe the study protocol for an intervention program designed to improve the physical activity and nutrition behaviors of ALL survivors. Twenty-four children aged between 4 years and 12 years with ALL will be randomized to a 6-month technology-based exercise and nutrition program (TLC4ALLKids) or to enhanced usual care (eUC). The participants randomized to the TLC4ALLKids will participate in weekly, 1-hour coaching sessions on nutrition and physical activity and 1-hour physical activity classes delivered by group video conferencing. Participants will be provided with iPad tablets loaded with video conferencing software and the Healthy Lifestyle Tracking calendar to track daily nutrition and physical activity goals and weight. Both groups will be provided with Fitbit™ Zip to monitor physical activity. To assess feasibility, participant recruitment (achievement of proposed sample size), attendance (per weekly online sessions/assessment sessions), and adherence (number of families at 3 and 6 months) will be evaluated. Outcome measures to assess the intervention will include anthropometrics (weight, height, and waist circumference), physical activity (accelerometry), energy and macronutrient intake (food records), sleep habits (Children's Sleep Habits Questionnaire), and quality of life (Pediatric Quality of Life Inventory) will be obtained at baseline, 3 months, and 6 months. Semi-structured interviews will be used to gather information about ways to improve the program and overcome barriers to participation. If successful, the TLC4ALLKids intervention will provide a means to educate and improve the health behaviors of ALL survivors that can be delivered remotely and conveniently to participants. Keywords: acute lymphoblastic leukemia, enhanced usual care, social cognitive theory

Abstract: The concept of noninferiority (NI) trials is based on a belief that the new therapy may potentially offer a benefit for the patient or society in spite of it having a slightly lower efficacy. We introduce advantage deficit assessment (ADA), a simple framework similar to the benefit-risk assessment in superiority trials. ADA balances the advantage gained against the deficit in efficacy on a two-dimensional plane. It requires that NI trials provide quantitative information on both the advantage as well as on efficacy on scales, which can be compared in a meaningful manner. From this perspective, we study the feasibility of ADA among a set of NI trials published in four major medical journals. Among 113 published NI trials, about half assessed and reported at least one claimed advantage. For most other studies, an assessment seems to be feasible if considered in the planning of the study. Many studies claiming noninferiority report a positive gain in advantage. These trials have the potential to demonstrate a significant net benefit in an ADA, substantially changing the final judgment of the study results. ADA seems promising as it overcomes the current limitation of NI trials to demonstrate “only” noninferiority and brings them back to the mainstream of superiority trials by aiming to demonstrate a positive net benefit. ADA seems to be feasible in the majority of NI trials. Keywords: noninferiority, new treatment, potential advantage, advantage deficit assessment, benefit-risk assessment, loss of efficacy

Lessons learnt from implementing an empirically informed recruitment approach for FEM-PrEP, a large HIV prevention clinical trial Caleb Parker,1 Amy Corneli,1 Kawango Agot,2 Jacob Odhiambo,2 Jesse Asewe,2 Khatija Ahmed,3 Joseph Skhosana,3 Malebo Ratlhagana,3 Michele Lanham,1 Christina Wong,1 Jennifer Deese,1 Rachel Manongi,4 Lut Van Damme,1On behalf of the FEM-PrEP recruitment group 1FHI 360, Global Health, Population and Nutrition, Durham, NC, USA; 2Impact Research and Development Organization, Kisumu, Kenya; 3Setshaba Research Centre, Soshanguve, Pretoria, South Africa; 4Kilimanjaro Christian Medical Centre, Moshi, Tanzania Abstract: We implemented an empirically informed, geographically based recruitment approach for FEM-PrEP, a human immunodeficiency virus (HIV) prevention clinical trial of daily oral emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) for HIV prevention. During the formative research phase, we conducted a modification of the Priorities for Local AIDS Control Efforts (PLACE) method and used those data and staff experiences to identify and prioritize for recruitment geographic areas where HIV incidence might be high. During the clinical trial, we implemented a routinely monitored and flexible recruitment plan in the geographical areas identified in the formative research. We describe three lessons learnt from implementing this approach: 1) the PLACE data were critical in identifying places presumed to be high risk; 2) staff experiences, in combination with PLACE data, were needed to inform a practical recruitment strategy; and 3) recruiting in establishments in priority areas identified by the PLACE data led to screening many HIV-positive women at the Bondo site (Kenya), placing additional burden on clinic staff. These lessons learnt highlight the critical importance of having a flexible and monitored recruitment strategy. Although we successfully recruited a study population at higher risk for HIV, FEM-PrEP was unable to determine the effectiveness of FTC/TDF for HIV prevention, due to low adherence to the study product among participants. We must shift the paradigm of recruitment for clinical trials of new products from focusing on identifying populations with high incidence to identifying populations at risk who are motivated and able to adhere to the study product regimen. Keywords: recruitment, PrEP, PLACE, FEM-PrEP, HIV prevention clinical trial, women

Background: The emergence of artemisinin resistance has raised concerns that the most potent antimalarial drug may be under threat. Artesunate + amodiaquine (ASAQ) and artemether-lumefantrine (AL) are respectively the first- and second-line treatments for uncomplicated falciparum malaria in Côte d'Ivoire. A comparison of the efficacy and safety of these two drug combinations was necessary to make evidence-based drug treatment policies. Methods: In an open-label, non inferiority, randomized, controlled clinical trial, children aged 6–59 months were randomized to receive ASAQ or AL. Both drug regimens were given for 3 days, and follow-up was for 28 days. The primary endpoint was the 28-day cure rates and was defined as proportion of patients with polymerase chain reaction (PCR)-corrected cure rate after 28 days of follow-up. Findings : A total of 251 patients who were attending the Ayame and Dabakala hospitals and presenting with symptomatic acute uncomplicated falciparum malaria were randomized to receive ASAQ (128) and AL (123). The intention-to-treat analysis showed effectiveness rates of 94.5% and 93.5% for ASAQ and AL, respectively on day 28. After adjustment for PCR results, these rates were 96.1% and 96.8%, respectively. On day 28, the per-protocol analysis showed effectiveness rates of 98.4% and 96.6% for ASAQ and AL, respectively. After adjustment by PCR for reinfection, these rates were 100% for each drug, and both regimens were well tolerated. Conclusion: ASAQ and AL remain efficacious treatments of uncomplicated falciparum malaria in Ivorian children 5 years after adoption. The efficacy of ASAQ and AL in Côte d'Ivoire requires, therefore, continuous monitoring and evaluation. Keywords: artesunate, amodiaquine, artemether-lumefantrine, ASAQ, AL

Keiichi Yamamoto1 shigemi Matsumoto2 Kazuhiro Yanagihara2 satoshi Teramukai1 Masanori Fukushima1,2,3 1Department of Clinical Trial Design and Management, Translational research Center, Kyoto University hospital, Kyoto, Japan; 2Outpatient Oncology Unit, Kyoto University hospital, Kyoto, Japan; 3Translational research informatics Center, Foundation for Biomedical research and innovation, Kobe, Japan