SPIRIT 2013 checklist: Recommended items to address in a clinical trial protocol and related documents*.

SPIRIT 2013 checklist: Recommended items to address in a clinical trial protocol and related documents*.</p

List of inclusion and exclusion criteria.

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13–24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]. https://clin.larvol.com/trial-detail/ACTRN12622000129785.</div

Assessment methods and tools used in this study.

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13–24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]. https://clin.larvol.com/trial-detail/ACTRN12622000129785.</div

S1 File -

Anorexia is experienced by most people with lung cancer during the course of their disease and treatment. Anorexia reduces response to chemotherapy and the ability of patients to cope with, and complete their treatment leading to greater morbidity, poorer prognosis and outcomes. Despite the significant importance of cancer-related anorexia, current therapies are limited, have marginal benefits and unwarranted side effects. In this multi-site, randomised, double blind, placebo controlled, phase II trial, participants will be randomly assigned (1:1) to receive once-daily oral dosing of 100mg of anamorelin HCl or matched placebo for 12 weeks. Participants can then opt into an extension phase to receive blinded intervention for another 12 weeks (weeks 13–24) at the same dose and frequency. Adults (≥18 years) with small cell lung cancer (SCLC); newly diagnosed with planned systemic therapy OR with first recurrence of disease following a documented disease-free interval ≥6 months, AND with anorexia (i.e., ≤ 37 points on the 12-item Functional Assessment of Anorexia Cachexia Treatment (FAACT A/CS) scale) will be invited to participate. Primary outcomes are safety, desirability and feasibility outcomes related to participant recruitment, adherence to interventions, and completion of study tools to inform the design of a robust Phase III effectiveness trial. Secondary outcomes are the effects of study interventions on body weight and composition, functional status, nutritional intake, biochemistry, fatigue, harms, survival and quality of life. Primary and secondary efficacy analysis will be conducted at 12 weeks. Additional exploratory efficacy and safety analyses will also be conducted at 24 weeks to collect data over longer treatment duration. The feasibility of economic evaluations in Phase III trial will be assessed, including the indicative costs and benefits of anamorelin for SCLC to the healthcare system and society, the choice of methods for data collection and the future evaluation design. Trial registration. The trial has been registered with the Australian New Zealand Clinical Trials Registry [ACTRN12622000129785] and approved by the South Western Sydney Local Health District Human Research Ethics Committee [2021/ETH11339]. https://clin.larvol.com/trial-detail/ACTRN12622000129785.</div

Study diagram.

*The optional extension is entirely based on participants’ preference for blinded continuation for weeks 13–24.</p

Schedule of enrollment, intervention and assessment.

PE, Physical examination; AKPS, Australia-modified Karnofsky Performance Status; SBT, Short Blessed Test; ECG, Electrocardiogram; FAACT, Functional Assessment of Anorexia Cachexia Treatment; CPR, C-reactive protein; IL-6, Interleukin 6; SCLC, small cell lung cancer; BMI, Body Mass Index; BIA, Bio-electrical impedance); DEXA, dual x-ray absorptiometry; CT, computed tomography; FACIT-F, Functional Assessment of Chronic Illness Therapy-Fatigue; SQUASH, Short Questionnaire to Assess Health Enhancing Physical Activity; CGI-S, Clinical Global Impression of Severity; EQ-5D-5L, EuroQol 5-level 5-Dimensions; ICECAP-A, ICEpop CAPability Measure for Adults; TUG–Timed Up and Go test; CGI-I, Clinical Global Impression of Improvement; GIC, Global Impression of Change. a First telephone follow-up visit will occur 7 days after the Week 12 or Week 24 (if did not elect to enter extension) visit or the early termination visit due to withdrawal if treatment was ceased early. Subsequent telephone follow-up visits will occur every 7 days thereafter for a period of 4 weeks. There will be 4 follow-up visits in total. 1 Standard physical activity and dietary advice leaflets will be provided to both arms at baseline. 2 ICECAP-A will be administered after the EQ-5D-5L questionnaire.^ All electronically stored data from chest CT scans whenever they are done clinically will be used for evaluation of change in muscle mass at the thoracic (T4) level. *Only if people elect NOT to enter the extension. § Or withdrawal.</p

Still in Search for an EAAT Activator: GT949 Does Not Activate EAAT2, nor EAAT3 in Impedance and Radioligand Uptake Assays

Excitatory amino acid transporters (EAATs) are important regulators of amino acid transport and in particular glutamate. Recently, more interest has arisen in these transporters in the context of neurodegenerative diseases. This calls for ways to modulate these targets to drive glutamate transport, EAAT2 and EAAT3 in particular. Several inhibitors (competitive and noncompetitive) exist to block glutamate transport; however, activators remain scarce. Recently, GT949 was proposed as a selective activator of EAAT2, as tested in a radioligand uptake assay. In the presented research, we aimed to validate the use of GT949 to activate EAAT2-driven glutamate transport by applying an innovative, impedance-based, whole-cell assay (xCELLigence). A broad range of GT949 concentrations in a variety of cellular environments were tested in this assay. As expected, no activation of EAAT3 could be detected. Yet, surprisingly, no biological activation of GT949 on EAAT2 could be observed in this assay either. To validate whether the impedance-based assay was not suited to pick up increased glutamate uptake or if the compound might not induce activation in this setup, we performed radioligand uptake assays. Two setups were utilized; a novel method compared to previously published research, and in a reproducible fashion copying the methods used in the existing literature. Nonetheless, activation of neither EAAT2 nor EAAT3 could be observed in these assays. Furthermore, no evidence of GT949 binding or stabilization of purified EAAT2 could be observed in a thermal shift assay. To conclude, based on experimental evidence in the present study GT949 requires specific assay conditions, which are difficult to reproduce, and the compound cannot simply be classified as an activator of EAAT2 based on the presented evidence. Hence, further research is required to develop the tools needed to identify new EAAT modulators and use their potential as a therapeutic target