The RIO Trial: Rationale, Design, And The Role of Community Involvement In A Randomised Placebo-Controlled Trial of Antiretroviral Therapy Plus Dual Long-Acting HIV-Specific Broadly Neutralising Antibodies (bNAbs) In Participants Diagnosed With Recent HIV Infection - Study Protocol For A Two-Stage Randomised Phase II Trial

• Background:Antiretroviral therapy (ART) has led to dramatic improvements in survival for people living with HIV, but is unable to cure infection, or induce viral control off therapy. Designing intervention trials with novel agents with the potential to confer a period of HIV remission without ART, remains a key scientific and community goal. We detail the rationale, design, and outcomes of a randomised, placebo-controlled trial of two HIV-specific long-acting broadly neutralising antibodies (bNAbs); 3BNC117-LS and 10-1074-LS, which target CD4 binding site and V3 loop respectively, on post-treatment viral control.• Methods:RIO is a randomised, placebo-controlled, double-blinded prospective phase II study. Eligible individuals will have started ART within 3 months of primary HIV infection and have viral sequences that appear to be sensitive to both bNAbs. It will randomise 72 eligible participants 1:1 to the following arms via a two-stage design. In stage 1, arm A participants are given dual long-acting (LS-variants) bNAbs infusions, followed by intensively monitored Analytical Treatment Interruption (ATI) (n=36); in arm B, participants receive placebo infusions followed by ATI. The primary endpoint will be time to viral rebound within 36 weeks after ATI. Upon viral rebound, the participant and researcher are unblinded. Participants in arm A recommence ART and complete the study. Participants in arm B are invited to restart ART and enroll into stage 2 where they will receive open-label LS bNAbs, followed by a second ATI 24 weeks after. Secondary and exploratory endpoints include adverse events, time to undetectable viraemia after re-starting ART, immunological markers, HIV proviral DNA, serum bNAb concentrations in blood, bNAb resistance at viral rebound, and quality of life measures.• Discussion:The two-stage design was determined in collaboration with community involvement. This design allows all participants the option to receive bNAbs. It also tests the hypothesis that bNAbs may drive sustained HIV-control beyond the duration of detectable bNAb concentrations. Community representatives were involved at all stages. This included the two-stage design, discussion on the criteria to restart ART, frequency of monitoring visits off ART and reducing the risk of onward transmission to HIV-negative partners. It also included responding to the challenges of COVID-19.Trial registration: The protocol is registered on Clinical.trials.gov and EudraCT and has approval from UK Ethics and MHRA.

Trial Design for a Diagnostic Accuracy Study of a Point-of-Care Test for the Detection of Taenia solium Taeniosis and (Neuro)Cysticercosis in Community Settings of Highly Endemic, Resource-Poor Areas in Zambia: Challenges and Rationale

Field-applicable, high-quality, and low-cost diagnostic tools are urgently needed for Taenia solium. The aim of this paper is to describe the design, challenges, and rationale for the design of a diagnostic accuracy study in low-resource community settings in Zambia. The trial was designed as a prospective study with a two-stage design to evaluate a new point-of-care test (TS POC) for the detection of taeniosis and (neuro)cysticercosis. Participants within randomly selected households were tested with the TS POC test (index test). Participants who tested TS POC positive for taeniosis and/or cysticercosis and a subset of the negatives were requested to give blood and stool samples for reference testing, and to undergo clinical examination and a cerebral CT scan. The difficulties of conducting a clinical trial in settings with limited research and neuroimaging infrastructure as well as peculiarities specifically related to the disease (low prevalence of taeniosis and the lack of a gold standard) were taken into consideration for the design of this study. The two-stage design increased the efficiency of the study by reducing the number of samples, clinical examinations, and CT scans. Simplified flows and sampling processes were preferred over complex follow-up and randomization systems, aiming to reduce bias and increase the generalizability of the study.

Optimal two-stage design of single arm Phase II clinical trials based on median event time test

The Phase II clinical trials aim to assess the therapeutic efficacy of a new drug. The therapeutic efficacy has been often quantified by response rate such as overall response rate or survival probability in the Phase II setting. However, there is a strong desire to use survival time, which is the gold standard endpoint for the confirmatory Phase III study, when investigators set the primary objective of the Phase II study and test hypotheses based on the median survivals. We propose a method for median event time test to provide the sample size calculation and decision rule of testing. The decision rule is simple and straightforward in that it compares the observed median event time to the identified threshold. Moreover, it is extended to optimal two-stage design for practice, which extends the idea of Simon’s optimal two-stage design for survival endpoint. We investigate the performance of the proposed methods through simulation studies. The proposed methods are applied to redesign a trial based on median event time for trial illustration, and practical strategies are given for application of proposed methods.

Phase II trial of the CDK4/6 inhibitor abemaciclib in patients (pts) with advanced and refractory well‐differentiated gastroenteropancreatic neuroendocrine tumors (GEP NETs).

TPS376 Background: Despite advances in the treatment of advanced GEP NETs, long‐term disease control remains a challenge. Overexpression and altered regulation of cyclin-dependent kinases (CDK) 4 and 6 have been observed in multiple subtypes of GEP NETs. Preclinical studies have demonstrated that the CDK 4/6 inhibitor palbociclib reduces growth of pancreatic NET cell lines and levels of phosphorylated retinoblastoma protein in vitro. Moreover, the drug significantly inhibited tumor growth in vivo in pancreatic NET xenograft models. Abemaciclib is a selective small molecule CDK 4/6 inhibitor, approved for the treatment of HR+ HER2– metastatic breast cancer. Clinical activity and central nervous system penetration of the drug have been observed in several tumor types in clinical trials, including partial response in one pt with metastatic small intestinal NET. We have developed a Phase 2 trial of abemaciclib in GEP NETs to evaluate its efficacy and safety in these rare cancers. Methods: This is an investigator-initiated non-randomized phase 2 trial using a two-stage design. Eligible pts have metastatic or locally advanced unresectable well-differentiated grade 1-2 GEP NETs, ECOG PS 0-2, and must have progressed on at least one line of systemic therapy. Prior or concurrent treatment with somatostatin analogs is allowed,. Abemaciclib is administered at a dose of 200 mg orally every 12 hours continuously in 28-day cycles. Dose reductions for toxicities are allowed to level -1 (150 mg) and -2 (100 mg). Primary endpoint is objective response rate (ORR) by RECIST v1.1. Secondary endpoints include progression free survival (PFS), overall survival (OS), and toxicity. A two‐stage design with 88% power to detect an increase in ORR to 20% with abemaciclib at the 1‐sided 0.05 level would require a total of 37 patients. Stage 1 will include 20 patients, and if one response is seen among these patients, the study will continue to enroll another 17 patients. The trial was activated in January 2020, and 3 patients have been enrolled to date. Available archival tumor tissue and molecular profiling data are collected for future correlative studies including assessment of response biomarkers.

Technological support of fixed split joint impermeability in two-stage circuit of production organization

The oretical equations are shown for the calculation of fixed split joint impermeability taking into account contact-ing surface quality. There are given theoretical and empirical dependences for the definition of quality parameters in parts surfaces for different methods of their processing. A two-stage design-technological support of fixed split metal joint impermeability is presented.