Primary Chemoablation of Recurrent Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer With UGN-102: A Single-Arm, Open-Label, Phase 3 Trial (ENVISION).

PURPOSE: To evaluate the efficacy and safety of UGN-102 chemoablation for the primary treatment of patients with recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: ENVISION is an ongoing, multinational, single-arm, Phase 3 study in patients with a biopsy-proven recurrence of untreated low-grade intermediate-risk nonmuscle-invasive bladder cancer. Patients received 6 weekly intravesical instillations of UGN-102 (mitomycin; outpatient setting) and were evaluated at 3 months. Patients achieving complete response (CR) (negative cystoscopic examination, cytology, and for-cause biopsy) were surveilled regularly until recurrence, progression, or death. Patients who remain disease-free will be followed up to 5 years, and further results will be reported in the future. RESULTS: Of 240 patients enrolled, 228 (95%) received all 6 planned doses; 191 (79.6%; 95% CI: 73.9, 84.5) achieved CR at 3 months, with an 82.3% (95% CI: 75.9, 87.1) probability of response 12 months later. Median duration of response was not estimable over a median 13.9-month follow-up period. The most common adverse events (≥5.0% of patients) were dysuria, hematuria, urinary tract infection, pollakiuria, fatigue, and urinary retention; generally mild/moderate and resolved/resolving. Serious adverse events were observed in 29/240 (12.1%), 2 were treatment-related (urinary retention/urethral stenosis), both resolved. CONCLUSIONS: Primary chemoablation with UGN-102 in patients with recurrent low-grade-intermediate-risk-nonmuscle-invasive bladder cancer resulted in a 79.6% CR rate. Patients achieving a CR had an 82.3% likelihood of remaining disease-free 1 year later. The benefit-risk profile was favorable, supporting UGN-102 as a non-surgical alternative for transurethral resection of bladder tumors in this patient population. Limitations of this study included lack of tumor sizing after the diagnostic biopsy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05243550.

Treatment of Low-grade Intermediate-risk Nonmuscle-invasive Bladder Cancer With UGN-102 ± Transurethral Resection of Bladder Tumor Compared to Transurethral Resection of Bladder Tumor Monotherapy: A Randomized, Controlled, Phase 3 Trial (ATLAS).

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer is a chronic illness commonly treated by repetitive transurethral resection of bladder tumor. We compared the efficacy and safety of intravesical chemoablation with UGN-102 (a reverse thermal gel containing mitomycin), with or without subsequent transurethral resection of bladder tumor, to transurethral resection of bladder tumor alone in patients with low-grade intermediate-risk nonmuscle-invasive bladder cancer. MATERIALS AND METHODS: This prospective, randomized, phase 3 trial recruited patients with new or recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer to receive initial treatment with either UGN-102 once weekly for 6 weeks or transurethral resection of bladder tumor. Patients were followed quarterly by endoscopy, cytology, and for-cause biopsy. The primary end point was disease-free survival. All patients were followed for adverse events. RESULTS: Trial enrollment was halted by the sponsor to pursue an alternative development strategy after 282 of a planned 632 patients were randomized to UGN-102 ± subsequent transurethral resection of bladder tumor (n=142) or transurethral resection of bladder tumor monotherapy (n=140), rendering the trial underpowered to perform hypothesis testing. Patients were predominantly male and ≥65 years of age. Tumor-free complete response 3 months after initial treatment was achieved by 92 patients (65%) who received UGN-102 and 89 patients (64%) treated by transurethral resection of bladder tumor. The estimated probability of disease-free survival 15 months after randomization was 72% for UGN-102 ± transurethral resection of bladder tumor and 50% for transurethral resection of bladder tumor (hazard ratio 0.45). The most common adverse events (incidence ≥10%) in the UGN-102 group were dysuria, micturition urgency, nocturia, and pollakiuria. CONCLUSIONS: Primary, nonsurgical chemoablation with UGN-102 for the management of low-grade intermediate-risk nonmuscle-invasive bladder cancer offers a potential therapeutic alternative to immediate transurethral resection of bladder tumor monotherapy and warrants further investigation.

Primary Chemoablation of Low-Grade Intermediate-Risk Nonmuscle-Invasive Bladder Cancer Using UGN-102, a Mitomycin-Containing Reverse Thermal Gel (Optima II): A Phase 2b, Open-Label, Single-Arm Trial.

PURPOSE: Low-grade intermediate-risk nonmuscle-invasive bladder cancer (LG IR NMIBC) is a recurrent disease, thus requiring repeated transurethral resection of bladder tumor under general anesthesia. We evaluated the efficacy and safety of UGN-102, a mitomycin-containing reverse thermal gel, as a primary chemoablative therapeutic alternative to transurethral resection of bladder tumor for patients with LG IR NMIBC. MATERIALS AND METHODS: This prospective, phase 2b, open-label, single-arm trial recruited patients with biopsy-proven LG IR NMIBC to receive 6 once-weekly instillations of UGN-102. The primary end point was complete response (CR) rate, defined as the proportion of patients with negative endoscopic examination, negative cytology and negative for-cause biopsy 3 months after treatment initiation. Patients with CR were followed quarterly up to 12 months to assess durability of treatment effect. Safety and adverse events were monitored throughout the trial. RESULTS: A total of 63 patients (38 males and 25 females 33-96 years old) enrolled and received ≥1 instillation of UGN-102. Among the patients 41 (65%) achieved CR at 3 months, of whom 39 (95%), 30 (73%) and 25 (61%) remained disease-free at 6, 9 and 12 months after treatment initiation, respectively. A total of 13 patients had documented recurrences. The probability of durable response 9 months after CR (12 months after treatment initiation) was estimated to be 73% by Kaplan-Meier analysis. Common adverse events (incidence ≥10%) included dysuria, urinary frequency, hematuria, micturition urgency, urinary tract infection and fatigue. CONCLUSIONS: Nonsurgical primary chemoablation of LG IR NMIBC using UGN-102 resulted in significant treatment response with sustained durability. UGN-102 may provide an alternative to repetitive surgery for patients with LG IR NMIBC.

Oral 5-Day Lefamulin for Outpatient Management of Community-Acquired Bacterial Pneumonia: Post-hoc Analysis of the Lefamulin Evaluation Against Pneumonia (LEAP) 2 Trial.

BACKGROUND: Safe and effective oral antibiotics are needed for outpatient management of moderate to severe community-acquired bacterial pneumonia (CABP). OBJECTIVE: We describe a post-hoc analysis of adults with CABP managed as outpatients from the Lefamulin Evaluation Against Pneumonia (LEAP) 2 double-blind, noninferiority, phase 3 clinical trial. METHODS: LEAP 2 compared the efficacy and safety of oral lefamulin 600 mg every 12 h (5 days) vs. oral moxifloxacin 400 mg every 24 h (7 days) in adults (inpatients and outpatients) with Pneumonia Outcomes Research Team (PORT) risk classes II‒IV. RESULTS: Overall, 41% (151 of 368) of patients receiving lefamulin and 43% (159 of 368) of patients receiving moxifloxacin started treatment as outpatients-44% and 40%, respectively, were PORT risk class III/IV, and 21% in both groups had CURB-65 scores of 2‒3. Early clinical response (at 96 ± 24 h) and investigator assessment of clinical response success rates at test of cure (5‒10 days after last study drug dose) were high and similar in both groups among all (lefamulin, 91% vs. moxifloxacin, 89‒90%), PORT risk class III/IV (89‒91% vs. 88‒91%), and CURB-65 score 2‒3 (87‒90% vs. 82‒88%) outpatients. Few outpatients (lefamulin, 2.6%; moxifloxacin, 2.5%) discontinued the study drug because of treatment-emergent adverse events (TEAEs). No outpatient in the lefamulin group was hospitalized for a TEAE, compared with 5 patients (3%), including two deaths, in the moxifloxacin group. CONCLUSIONS: These data suggest that 5 days of oral lefamulin can be given in lieu of fluoroquinolones for outpatient treatment of adults with CABP and PORT risk class III/IV or CURB-65 scores of 2‒3.

End Users Want Alternative Intervention Delivery Models: Usability and Acceptability of the REMOTE-CR Exercise-Based Cardiac Telerehabilitation Program.

OBJECTIVE: Evaluate user experiences of an exercise-based cardiac telerehabilitation intervention (REMOTE-CR) that provided near universal access to real-time remote coaching and behavioral support from exercise specialists. DESIGN: Secondary analysis (12-week follow-up) of a parallel group, single blind, randomized controlled noninferiority trial (ACTRN12614000843651). SETTING: Community-based cardiac rehabilitation. PARTICIPANTS: Adults (N=162) with coronary heart disease who were eligible for outpatient cardiac rehabilitation. Eighty-two of 162 trial participants were randomized to receive REMOTE-CR; 67 completed usability and acceptability assessment at 12-week follow-up. INTERVENTION: REMOTE-CR comprised 12 weeks of individualized exercise prescription, real-time physiological monitoring, coaching, and behavioral support, delivered via a bespoke telerehabilitation platform. OUTCOMES: Ease of use, satisfaction with the technology platform and intervention content, and demand for real-world implementation as an alternative to traditional center-based programs were assessed at 12-week follow-up. RESULTS: Components of usability and acceptability were positively evaluated by most participants (44-66 of 67, 66%-99%). Fifty-eight of 67 (87%) would choose REMOTE-CR if it was available as a usual care service, primarily because it provides convenient and flexible access to real-time individualized support from exercise specialists. Technology challenges were rare and had little effect on user experiences or demand for REMOTE-CR. CONCLUSIONS: REMOTE-CR can extend the reach and impact of existing cardiac rehabilitation services by overcoming traditional participation barriers while preserving expert oversight. Adoption of emerging technologies should be accelerated to support dynamic, engaging, individualized intervention delivery models, but optimizing overall cardiac rehabilitation participation rates will require multiple delivery models that are tailored to satisfy diverse participant preferences.

Skin surface temperature: a possible new outcome measure for skin and soft tissue infection.

BACKGROUND: This study describes the novel use of skin surface temperature to measure the severity and the response to treatment of skin and soft tissue infection (SSTI). METHODS: Patients admitted with SSTI for intravenous antibiotic therapy. Skin temperature was measured daily at the point of maximum heat on the SSTI affected limb and the non-affected limb using a non-contact laser thermometer. FINDINGS: Sixty-three patients were included. Mean length of stay was 4.95 days. The difference between affected and unaffected limb was 3.5° C (95% CI 3.0-3.9) at day one and 2.1° C (95% CI 1.7-2.6) on the last day, a difference of 1.4° C (95% CI 0.7-1.9). Between day one and the last day, there was a significant reduction in affected limb temperature (mean reduction of 2.4° C, 95% CI 1.9-3.0 p<0.001). INTERPRETATION: Skin surface temperature may hold a useful role in the management of SSTI.

Effects and costs of real-time cardiac telerehabilitation: randomised controlled non-inferiority trial.

OBJECTIVE: Compare the effects and costs of remotely monitored exercise-based cardiac telerehabilitation (REMOTE-CR) with centre-based programmes (CBexCR) in adults with coronary heart disease (CHD). METHODS: Participants were randomised to receive 12 weeks of telerehabilitation or centre-based rehabilitation. REMOTE-CR provided individualised exercise prescription, real-time exercise monitoring/coaching and theory-based behavioural strategies via a bespoke telerehabilitation platform; CBexCR provided individualised exercise prescription and coaching via established rehabilitation clinics. Outcomes assessed at baseline, 12 and/or 24 weeks included maximal oxygen uptake (V̇O2max, primary) modifiable cardiovascular risk factors, exercise adherence, motivation, health-related quality of life and programme delivery, hospital service utilisation and medication costs. The primary hypothesis was a non-inferior between-group difference in V̇O2max at 12 weeks (inferiority margin=-1.25 mL/kg/min); inferiority margins were not set for secondary outcomes. RESULTS: 162 participants (mean 61±12.7 years, 86% men) were randomised. V̇O2 max was comparable in both groups at 12 weeks and REMOTE-CR was non-inferior to CBexCR (REMOTE-CR-CBexCR adjusted mean difference (AMD)=0.51 (95% CI -0.97 to 1.98) mL/kg/min, p=0.48). REMOTE-CR participants were less sedentary at 24 weeks (AMD=-61.5 (95% CI -117.8 to -5.3) min/day, p=0.03), while CBexCR participants had smaller waist (AMD=1.71 (95% CI 0.09 to 3.34) cm, p=0.04) and hip circumferences (AMD=1.16 (95% CI 0.06 to 2.27) cm, p=0.04) at 12 weeks. No other between-group differences were detected. Per capita programme delivery (NZD1130/GBP573 vs NZD3466/GBP1758) and medication costs (NZD331/GBP168 vs NZD605/GBP307, p=0.02) were lower for REMOTE-CR. Hospital service utilisation costs were not statistically significantly different (NZD3459/GBP1754 vs NZD5464/GBP2771, p=0.20). CONCLUSION: REMOTE-CR is an effective, cost-efficient alternative delivery model that could-as a complement to existing services-improve overall utilisation rates by increasing reach and satisfying unique participant preferences.

Behavior Change for Youth Drivers: Design and Development of a Smartphone-Based App (BackPocketDriver).

BACKGROUND: The over-representation of youth in road crash injury and fatality rates is a major public health issue globally. In New Zealand, youth drivers are most vulnerable in the restricted license period when they can drive without the requirement for supervision by an experienced adult. Behavioral change interventions delivered using mobile phone technology to young drivers could serve as a useful mechanism to develop safe driving skills, but this potential remains to be fully explored. OBJECTIVE: This study aimed to apply behavioral change principles to design and develop a smartphone-based intervention with the aim of helping youth drivers to develop and hone safe driving skills. METHODS: An iterative process was used to support development of the smartphone intervention. We reviewed behavioral change literature, identifying fundamental principles and exploring use of behavior change techniques (BCTs) in other areas of public health. We engaged with key stakeholders, including young drivers, government agencies, and relevant organizations. We also took into account technology adoption considerations when designing the app. RESULTS: We developed BackPocketDriver (BPD), an Android smartphone app that uses in-built sensors to monitor and infer driver behavior. The app implements features that were identified during the design process and are traceable to BCTs and theory. A key feature is messaging, which is used to instruct, motivate, educate, and relay feedback to participants. In addition, messaging addresses attitudes and beliefs. Other features include journey feedback summaries, goal setting, achievements, and leaderboards. CONCLUSIONS: BPD's design rests on a sound foundation of theory and evidence. With explicit links between theory and features, the app aims to be an effective intervention to change and improve youth driver behavior. The next phase of this study is to run a small pilot study to assess BPD's effectiveness.

Reducing hospital admissions for COPD: perspectives following the Christchurch Earthquake.

The devastating 2011 earthquake in Christchurch destroyed or badly damaged healthcare infrastructure, including Christchurch Hospital. This forced change in management of exacerbations of chronic obstructive pulmonary disease (COPD), which until that point had frequently led to admission to hospital and focused attention on providing safe community options for care. This paper describes the process of understanding factors contributing to high admission frequency with exacerbations of COPD and also describes a process of change, predominantly to healthcare delivery systems and philosophies, and the subsequent outcomes. What became clear in understanding admissions with COPD to Christchurch Hospital was that the behaviour of the patient, in the context of exacerbations, and the subsequent response of the system to the patient, led to admission being the default option, in spite of low severity of the exacerbation itself. By altering systems' responses to exacerbations, with a linked care process between ambulances, community care and hospitals, we were able to safely reduce admissions for COPD, with a sustained overall reduction in bed-day occupancy for COPD of ~48%. We would encourage these discussions and changes to occur without the stimulus of an earthquake in your healthcare environment!

Remotely Delivered Exercise-Based Cardiac Rehabilitation: Design and Content Development of a Novel mHealth Platform.

BACKGROUND: Participation in traditional center-based cardiac rehabilitation exercise programs (exCR) is limited by accessibility barriers. Mobile health (mHealth) technologies can overcome these barriers while preserving critical attributes of center-based exCR monitoring and coaching, but these opportunities have not yet been capitalized on. OBJECTIVE: We aimed to design and develop an evidence- and theory-based mHealth platform for remote delivery of exCR to any geographical location. METHODS: An iterative process was used to design and develop an evidence- and theory-based mHealth platform (REMOTE-CR) that provides real-time remote exercise monitoring and coaching, behavior change education, and social support. RESULTS: The REMOTE-CR platform comprises a commercially available smartphone and wearable sensor, custom smartphone and Web-based applications (apps), and a custom middleware. The platform allows exCR specialists to monitor patients' exercise and provide individualized coaching in real-time, from almost any location, and provide behavior change education and social support. Intervention content incorporates Social Cognitive Theory, Self-determination Theory, and a taxonomy of behavior change techniques. Exercise components are based on guidelines for clinical exercise prescription. CONCLUSIONS: The REMOTE-CR platform extends the capabilities of previous telehealth exCR platforms and narrows the gap between existing center- and home-based exCR services. REMOTE-CR can complement center-based exCR by providing an alternative option for patients whose needs are not being met. Remotely monitored exCR may be more cost-effective than establishing additional center-based programs. The effectiveness and acceptability of REMOTE-CR are now being evaluated in a noninferiority randomized controlled trial.