Exertion2 Trial: THE Weight Gain Prevention in Renal Transplant Online Study—a Randomized Controlled Feasibility Trial

BACKGROUND AND AIMS Adverse weight gain within the first year of receiving a kidney transplant is associated with adverse health outcomes. Kidney transplant recipients (KTRs) have asked for support with physical activity and following healthy lifestyles. There is no recognised intervention to address weight gain prevention for new KTRs. Usability of an online intervention to prevent weight gain in new KTRs has recently been reported. The aim of this study was to examine the feasibility of undertaking a randomised controlled trial of an online intervention group (IG) compared with usual care UC) to address weight gain prevention in new KTRs. METHOD Participants were recruited from two south-London transplant sites, had a kidney transplant within 3 months, and had access to an internet compatible device. Exclusion criteria included history of an unstable medical condition, non-English speaking or <18 years. At baseline assessment participants were randomized to either UC or IG. The UC group received standard dietary and physical activity education. The IG received access to a 12-week password-protected website, weekly email reminders, and could contact the research physiotherapist via a secure message function. Primary feasibility outcomes included screening rates, consent rates, adherence to study visits, acceptability of outcomes, engagement with the intervention, retention, willingness to be randomized, adverse events, hospitalizations, experience using the online intervention and experience taking part in the trial. Secondary outcomes were recorded at baseline, 3- and 12-months. These included body weight, body mass index (BMI), bioimpedance (BIA), pulse wave velocity (PWV), augmentation index (AI) and six-minute walk distance (6MWD). RESULTS Seventeen new KTRs (median age 49 years, 10 males, median 62 days post-transplant) were randomized to the IG (n = 9) or UC (n = 8). Screening rate was 84.2% (95% CI: 68.8–94.0), recruitment 62.5% (95% CI: 43.7–79.0) and intervention adherence at 12 months was 76.4% (95% CI: 50.0–93.2). All pre-set progression criteria for feasibility were achieved. There were no associated adverse events. Qualitative analysis revealed four themes;optimizing participation and recruitment, impact of Coronavirus disease 2019 (COVID-19), engagement is a choice (technical and personal factors) and mechanisms of action (assessment and intervention factors). The IG appeared to stabilize median body weight across the study;94.5 kg, (IQR: 63.0, 102.0), 95.0 kg, (IQR: 66.7, 105.3) and 94.7 kg (IQR: 77.2, 117.3). Whereas UC participants increased [81.3 kg, (IQR: 73.6,94.6), 86.2 kg (75.4, 96.5) and 93.3 kg (70.3, 101.9)]. IG increased 6MWD [450 m, (IQR: 450, 540), 525 m (IQR: 472.5, 615) and 495 m (IQR: 465, 615)] and UC decreased 6MWD [517.5 m (IQR: 436, 570), 507.5 m (IQR: 442.5, 605) and 435 m (IQR 435, 555)]. All other outcomes were comparable across the sample. CONCLUSION Limitations include inadequate power and small sample size, and it was a single-centre study. Integrated mixed methods analysis demonstrate congruency of both qualitative and quantitative data. Participant attitudes, experiences and engagement with the study and intervention provide insight for future trial design. A future definitive trial is warranted and welcomed by KTRs.

The Feasibility and User-Experience of a Digital Health Intervention Designed to Prevent Weight Gain in New Kidney Transplant Recipients-The ExeRTiOn2 Trial.

Half of kidney transplant recipients (KTRs) gain more than 5% of their body weight in the first year following transplantation. KTRs have requested support with physical activity (PA) and weight gain prevention, but there is no routine care offered. There are few high-quality studies investigating the clinical value of diet, PA or combined interventions to prevent weight gain. The development and evaluation of theoretically informed complex-interventions to mitigate weight gain are warranted. The aims of this mixed-methods randomized controlled trial (RCT) were to explore the feasibility, acceptability and user-experience of a digital healthcare intervention (DHI) designed to prevent post-transplant weight gain, in preparation for a large multi-center trial. New KTRs (<3 months) with access to an internet compatible device were recruited from a London transplant center. The usual care (UC) group received standard dietary and PA advice. The intervention group (IG) received access to a 12-week DHI designed to prevent post-transplant weight gain. Primary feasibility outcomes included screening, recruitment, retention, adherence, safety and hospitalizations and engagement and experience with the DHI. Secondary outcomes (anthropometrics, bioimpedance, arterial stiffness, 6-minute walk distance and questionnaires) were measured at baseline, 3- and 12-months. 38 KTRs were screened, of which 32 (84.2%) were eligible, and of those 20 (62.5%) consented, with 17 participants (85%) completing baseline assessment (Median 49 years, 58.8% male, Median 62 days post-transplant). Participants were randomized using a computer-generated list (n = 9 IG, n = 8 UC). Retention at 12-months was 13 (76.4%) (n = 6 IG, n = 7 UC). All a priori progression criteria were achieved. There were no associated adverse events. Reflexive thematic analysis revealed four themes regarding trial participation and experience whilst using the DHI. Halting recruitment due to COVID-19 resulted in the recruitment of 40% of the target sample size. Mixed-methods data provided important insights for future trial design. A definitive RCT is warranted and welcomed by KTRs. Clinical Trial Registration: www.clinicalTrials.gov, identifier: NCT03996551.

The Feasibility and User-Experience of a Digital Health Intervention Designed to Prevent Weight Gain in New Kidney Transplant Recipients—The ExeRTiOn2 Trial

Half of kidney transplant recipients (KTRs) gain more than 5% of their body weight in the first year following transplantation. KTRs have requested support with physical activity (PA) and weight gain prevention, but there is no routine care offered. There are few high-quality studies investigating the clinical value of diet, PA or combined interventions to prevent weight gain. The development and evaluation of theoretically informed complex-interventions to mitigate weight gain are warranted. The aims of this mixed-methods randomized controlled trial (RCT) were to explore the feasibility, acceptability and user-experience of a digital healthcare intervention (DHI) designed to prevent post-transplant weight gain, in preparation for a large multi-center trial. New KTRs (<3 months) with access to an internet compatible device were recruited from a London transplant center. The usual care (UC) group received standard dietary and PA advice. The intervention group (IG) received access to a 12-week DHI designed to prevent post-transplant weight gain. Primary feasibility outcomes included screening, recruitment, retention, adherence, safety and hospitalizations and engagement and experience with the DHI. Secondary outcomes (anthropometrics, bioimpedance, arterial stiffness, 6-minute walk distance and questionnaires) were measured at baseline, 3- and 12-months. 38 KTRs were screened, of which 32 (84.2%) were eligible, and of those 20 (62.5%) consented, with 17 participants (85%) completing baseline assessment (Median 49 years, 58.8% male, Median 62 days post-transplant). Participants were randomized using a computer-generated list (n = 9 IG, n = 8 UC). Retention at 12-months was 13 (76.4%) (n = 6 IG, n = 7 UC). All a priori progression criteria were achieved. There were no associated adverse events. Reflexive thematic analysis revealed four themes regarding trial participation and experience whilst using the DHI. Halting recruitment due to COVID-19 resulted in the recruitment of 40% of the target sample size. Mixed-methods data provided important insights for future trial design. A definitive RCT is warranted and welcomed by KTRs. Clinical Trial Registration www.clinicalTrials.gov, identifier: NCT03996551.

Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia. TRIAL DESIGN: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care. PARTICIPANTS: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust. INCLUSION: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease CRP ≥ 30mg/L at any time point Informed consent from patient or personal or professional representative Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all participants of childbearing potential for 42 days after the last dose of study drug. For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study drug. EXCLUSION: Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point after hospital admission but before baseline, not related to a pre-existing condition (e.g., obstructive sleep apnoea) Grade ≥ 5 severity on the modified WHO COVID-19 Ordinal Scale, i.e. SpO2 < 90% on ≥ 60% inspired oxygen by facemask at baseline; non-invasive ventilation; or invasive mechanical ventilation In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective of the provision of therapy Known severe allergic reactions to the investigational agents Child-Pugh B or C grade hepatic dysfunction Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or RUX), as listed in the Summary of Product Characteristics Pregnant or breastfeeding Any medical condition or concomitant medication that in the opinion of the investigator would compromise subjects' safety or compliance with study procedures. Any medical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study Non-English speakers will be able to join the study. If participants are unable to understand verbal or written information in English, then hospital translation services will be requested at the participating site for the participant where possible. INTERVENTION AND COMPARATOR: RUXOLITINIB (RUX) (14 days): An oral selective and potent inhibitor of Janus Associated Kinases (JAK1 and JAK2) and cell proliferation (Verstovek, 2010). It is approved for the treatment of disease-related splenomegaly or constitutional symptoms in myelofibrosis, polycythaemia vera and graft-versus-host-disease. RUX will be administered orally 10mg bd Day 1-7 and 5mg bd Day 8-14. FOSTAMATINIB (FOS) (14 days): An oral spleen tyrosine kinase inhibitor approved for the treatment of thrombocytopenia in adult participants with chronic immune thrombocytopenia. FOS will be administered orally 150mg bd Day 1-7 and 100mg bd Day 8-14. Please see protocol for recommended dose modifications where required. COMPARATOR (Standard of Care, SOC): experimental arms will be compared to participants receiving standard of care. It is accepted that SOC may change during a rapidly evolving pandemic. Co-enrolment to other trials and rescue therapy, either pre- or post-randomisation, is permitted and will be accounted for in the statistical analysis. MAIN OUTCOMES: Pairwise comparison (RUX vs SOC and FOS vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a score ≥ 5 on a modified WHO COVID-19 Ordinal Scale, comprising the following indicators of disease severity: Death OR Requirement for invasive ventilation OR Requirement for non-invasive ventilation including CPAP or high flow oxygen OR O2 saturation < 90% on ≥60% inspired oxygen RANDOMISATION: Participants will be allocated to interventions using a central web-based randomisation service that generates random sequences using random permuted blocks (1:1:1), with stratification by age (<65 and ≥65 years) and site. BLINDING (MASKING): No participants or caregivers are blinded to group assignment. Clinical outcomes will be compared blind to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): For an early informal dose examination by the Data Monitoring Committee a minimum of 30 participants will be recruited. For Stage 1 of this multi-arm multi-stage study, 171 participants will be randomised, with 57 participants in each arm. If at least one experimental intervention shows promise, then Stage 2 will recruit a further 95 participants per arm. Sample size calculations are given in the protocol. TRIAL STATUS: Recruitment is ongoing and started 2nd October 2020. We anticipate completion of Stage 1 by July 2021 and Stage 2 by April 2022. The current protocol version 2.0 of 11th February 2021 is appended. TRIAL REGISTRATION: EudraCT: 2020-001750-22 , 9th July 2020 ClinicalTrials.gov: NCT04581954 , 9th October 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Advantages of visualisations to evaluate and communicate adverse event information in randomised controlled trials.

BACKGROUND: Randomised controlled trials (RCTs) provide valuable information and inform the development of harm profiles of new treatments. Harms are typically assessed through the collection of adverse events (AEs). Despite AEs being routine outcomes collected in trials, analysis and reporting of AEs in journal articles are continually shown to be suboptimal. One key challenge is the large volume of AEs, which can make evaluation and communication problematic. Prominent practice is to report frequency tables of AEs by arm. Visual displays offer an effective solution to assess and communicate complex information; however, they are rarely used and there is a lack of practical guidance on what and how to visually display complex AE data. METHODS: In this article, we demonstrate the use of two plots identified to be beneficial for wide use in RCTs, since both can display multiple AEs and are suitable to display point estimates for binary, count, or time-to-event AE data: the volcano and dot plots. We compare and contrast the use of data visualisations against traditional frequency table reporting, using published AE information in two placebo-controlled trials, of remdesivir for COVID-19 and GDNF for Parkinson disease. We introduce statistical programmes for implementation in Stata. RESULTS/CASE STUDY: Visualisations of AEs in the COVID-19 trial communicated a risk profile for remdesivir which differed from the main message in the published authors' conclusion. In the Parkinson's disease trial of GDNF, the visualisation provided immediate communication of harm signals, which had otherwise been contained within lengthy descriptive text and tables. Asymmetry in the volcano plot helped flag extreme events that were less obvious from review of the frequency table and dot plot. The dot plot allowed a more comprehensive representation by means of a more detailed summary. CONCLUSIONS: Visualisations can better support investigators to assimilate large volumes of data and enable improved informal between-arm comparisons compared to tables. We endorse increased uptake for use in trial publications. Care in construction of visual displays needs to be taken as there can be potential to overemphasise treatment effects in some circumstances.

Me Not You: The trouble with mainstream feminism

There has rightly been wide-spread criticism regarding social media 'black-outs' and 'anti-racist reading lists' representing the be-all and end-all of anti-racist action, or as Phipps puts it in a recent blog2, 'a pre-made panacea'. Despite this it is true that for many the process of deconstructing racism must begin with an awareness and critical understanding of individual racialised privilege. [...]though Phipps could not have known at the time, her book #Me, Not You is a lens through which to understand the current activism protesting systems of racial capitalism. [...]she examines the implications of the term 'sexual misconduct', noting that it does not reflect systemic abuses of power, but rather individual sexual behaviour. Phipps notes that the propensity towards 'call out culture' and 'naming and shaming' leads to short-term institutional reputational damage, but often little by the way of concrete action to tackle and dismantle systems of sexual oppression.