Experimental Arm Research Articles

A Phase III Randomized Trial of Integrated Genomics and Avatar Models for Personalized Treatment of Pancreatic Cancer: the AVATAR Trial.

Pancreatic adenocarcinoma (PDAC) has limited treatment options. We compared the efficacy of comprehensive precision medicine against the conventional treatment in PDAC. Phase III trial of advanced PDAC where patients were randomized (1:2) to a conventional treatment treated at physician's discretion (arm A), or to precision medicine (arm B). Subjects randomized to arm B underwent a tumor biopsy for whole exome sequencing (WES) and to generate avatar mouse models and patient derived organoids for phenotypic drug screening, with final treatment recommended by molecular tumor board. The primary objective was median overall survival (OS). 137 patients were enrolled with 125 randomized, 44 to arm A and 81 to Arm B. WES was performed in 80.3% (65/81) patients of arm B, with potentially actionable mutations detected in 21.5% (14/65). Experimental models were generated in 16/81 patients (19.8%). Second-line treatment was administered to 39 patients in the experimental arm, but only 4 (10.2%) received personalized treatment, while 35 could not be receive matched therapy due to rapid clinical deterioration, delays in obtaining study results or absence of actionable targets. Median OS was 8.7 and 8.6 months (p=0.849) and median progression-free survival was 3.8 and 4.3 months (p=0.563) for the conventional and experimental arms, respectively. Notably, the four patients who received personalized treatment had median OS of 19.3 months. Personalized medicine was challenging to implement in most patients with PDAC, limiting the interpretation of intention to treat analysis. Survival was improved in the subset of patients who did receive matched therapy.

RTID-05. STUDY PROTOCOL: A MULTICENTER, INTERNATIONAL RANDOMIZED CONFIRMATORY TRIAL: LOW-ENERGY X-RAY INTRAOPERATIVE RADIATION THERAPY (LEX-IORT) VS. ADJUVANT FRACTIONATED STEREOTACTIC RADIOTHERAPY (FSRT) IN THE MANAGEMENT OF BRAIN METASTASES (LEXIMATE)

Abstract BACKGROUND Fractionated stereotactic radiotherapy to the resection cavity boosts local control of resected brain metastases significantly. However, start of systemic tumor-directed treatment may be protracted and in-hospital times prolonged. Lately, lex-ioRT of BM has been described as a safe and effective one stop-shop treatment modality with a 1-year local control rate of up to 98% while potentially improving patient convenience. Study Design: The LEXIMATE-trial is a multicenter, international, randomized open-label confirmatory trial comparing lex-IORT with FSRT of resected BM. In the experimental arm, INTRABEAM (Carl Zeiss Meditec AG) is used to deliver IORT by application of 50-kV photons at a standard dose of 30 Gy prescribed to the applicator surface. Standard linear accelerator or Gamma Knife based FSRT (3-7 fractions) to the surgical bed is used in the control arm. The primary endpoint is the cumulative incidence of local recurrences (as per RANO-BM) considering death without prior local recurrence as competing event. Inclusion criteria include histologically confirmed BM with indication for resection according to EANO-ESMO/ASCO-SNO-ASTRO guidelines, ≤5 other brain lesions compatible with BM and amenable to radiosurgery and history of solid cancer or CT scan suggestive for localized or metastasized solid cancer (except germ cell tumors, lymphoma, small-cell lung cancer). The resection cavity must be <5cm in size, IORT doses to brainstem or optical tract may not exceed 8 Gy. Study design: Randomized, open-label, non-inferiority. Sample size: 70 patients per group to show a non-inferiority of the experimental therapy compared to the control therapy with a power of approximately 80%. DISCUSSION The best radio-oncologic procedure for resected BM remains under debate. The LEXIMATE-trial offers an opportunity to provide more solid prospective data on effectiveness, safety and patient comfort both for established and new RT techniques.

CTNI-25. TUMOR TREATING FIELDS (TTFIELDS) THERAPY WITH CHEMORADIATION, FOLLOWED BY MAINTENANCE TTFIELDS THERAPY/TEMOZOLOMIDE (TMZ), IN NEWLY DIAGNOSED GLIOBLASTOMA (NDGBM). RESULTS OF PHASE II CLINICAL STUDY

Abstract INTRODUCTION Tumor-Treating Fields (TTFields) are electric fields that exert physical forces to disrupt cancer cell function and tumor progression via a multimodal mechanism of action. Following the phase 3 pivotal EF-14 study, TTFields therapy concomitant with temozolomide (TMZ) maintenance therapy became approved for newly-diagnosed glioblastoma (ndGBM). Pre-clinical data and pilot clinical studies suggests synergistic effect of concomitant TTFields treatment with radiotherapy (RT). OBJECTIVE To assess the efficacy and safety of first line TTFields therapy concomitant with RT/TMZ vs RT/TMZ alone in adult patients with ndGBM. Design: 69 patients with ndGBM and KPS≥70 stratified by MGMT status, extent of resection, and age, were randomized 1:1. The experimental arm received TTFields therapy from the first day of chemoradiation, the control arm started 4 weeks after completion of chemoradiation. Patients continued TTFields therapy until second disease progression or 24months. The primary endpoint was 1-year PFS rate, and secondary endpoints included PFS, OS, and safety. Kaplan-Meier estimates were used to assess whether PFS and OS were improved with first line TTFields therapy/RT/TMZ vs RT/TMZ with delayed TTFields therapy. RESULTS Overall, 46 patients received maintenance chemotherapy and TTFields therapy. Mean age was 62 years (range:27–77). One-year PFS rate was 36% and 19% in the experimental and control arms, respectively (p-value=0.10). Median PFS was 9.9 and 5.6 months (HR 0.53, p-value 0.049). Median OS was 25.9 and 17 months (HR 0.85, p-value=0.6). Two-year OS rates were 52% and 31% (p-value 0.07). Among patients with high TTFields usage (≥75%) 2-year OS rates were 78% and 34% (p=0.01). CONCLUSIONS The addition of concomitant TTFields to standard treatment with temozolomide and RT for patients with ndGBM appears to be another step in improving the outcome of this patients population. This is further investigated in the large-scale TRIDENT study.

A modified intensive, comprehensive aphasia program (mICAP) has better reported outcomes than usual care: a randomized controlled trial

ABSTRACT Background Intensive Comprehensive Aphasia Programs (ICAPs) are a new model of service delivery that show promising pre-post outcomes but have yet to be compared with usual care. Aim To compare the clinical effectiveness of a modified Intensive Comprehensive Aphasia Program (mICAP) to usual care in a parallel two arm study utilizing stratified block randomisation. Methods & Procedures Participants were a referred sample with post stroke aphasia from ten local speech pathology departments. Assessments were completed prior to, immediately after, and follow up at 3 months after the mICAP. While 269 participants with aphasia were approached for the study, only 52 were eligible to be randomised with 113 participants approached not meeting selection criteria and 99 of eligible participants declining to participate. Block randomization was based on matched moderate/mild versus severe aphasia pairs. Three of the 26 mICAP participants withdrew. In the experimental arm of the mICAP (the LIFT program), participants with aphasia and their family attended goal directed tailored therapy three times weekly for 8 weeks. Therapy included 14 hours each of impairment therapy, functional communication therapy, and computer therapy and 7 hours of group therapy and a challenge task. The main outcome measures were the self-reported Assessment for Living with Aphasia (ALA) and Content Information Units (#CIU’s) in connected speech. Outcomes & Results Linear Mixed Modelling was completed on the remaining 42 participants’ data and found a significant benefit for the mICAP on the ALA Total score (p= .014; 95% CI= −21.48- −2.57) ALA Aphasia domain (p = .027; 95% CI= −3.23 - −0.203), ALA Environment domain (p = .017; 95% CI= −4.70 - −0.493) immediately post intervention with maintenance of effects for the ALA Aphasia domain in the follow up period (p = .014; 95% CI= −3.64 - −0.438). Family members in the mICAP reported significant reduction in caregiving burden in the follow up period (p= .017; CI= −14.12 - −1.52.). There were no significant differences on the other main outcome measure of Content Information Units (95% CI= −34.94 – 55.15). Conclusions For those suitable and interested, the mICAP was more beneficial than usual care for participants with aphasia and their family members. However, lack of significant differences in discourse and other language functions, suggests that individual elements of mICAPs and their evaluation require review. Based on these results, the LIFT program has been refined to become the Comprehensive High-dose Aphasia Therapy (CHAT) program.

Using citizen science to explore barriers and facilitators for healthy and sustainable lifestyles in office environments

The socio ecological model states that individual behaviors at work are shaped by the interactions between individual employees and their work environments. This study used citizen science to gain insights into which elements of the built, social, and organizational environment in an office and surrounding neighborhoods in two Swedish cities were perceived as barriers to or facilitators of healthy and sustainable behaviors at work. Participants in the eight-week Sustainable Office Intervention pilot study (SOFIA) (n = 33) were cluster-randomized into an experimental arm (sustainable lifestyle) or a control intervention arm (healthy lifestyle). They used the Our Voice Healthy Neighborhood Discovery Tool mobile app to document contextual elements at their workplaces. In total, 114 photos and text-based narratives were recorded, and four themes emerged: built environment, building design, office ergonomics, and food and beverages. Eighteen percent of the photos were linked to pro-environmental behaviors, all exclusively captured by the experimental arm. Twelve barriers and solutions for improving the workplace environment were identified during discussions with participants in both arms. The findings provide insights for designing or renovating office spaces and urban planning to promote healthier and more sustainable lifestyles for office workers.

Protocol compliance in a multicentric phase III trial investigating scheduled adaptive radiotherapy and dose painting in head and neck cancer

PurposeTo report on quality assurance (QA) and protocol adherence (PA) in a multicentre phase III trial for head and neck cancer, evaluate patterns of protocol deviations and investigate the effect of PA on study outcomes. MethodsAll 221 patients from the ARTFORCE trial (NCT01504815) were included in this study. Pre- and per-treatment QA measures included protocol guidelines, a dummy run, early case reviews and trial meetings. FDG-PET-guided dose painting and scheduled adaptive radiotherapy were reviewed in patients in the experimental arm (eRT). Patient and disease characteristics, as well as institutes’ accrual rate and timing were examined for correlation with PA. Cox regression was used to determine the impact of PA on outcome. ResultsThe dummy run was completed in all nine institutes and early case reviews were completed in five out of nine institutes that contributed 190 out of 221 patients. Among all patients randomized to eRT, 64 % had at least one deviation of the experimental trial components. Protocol deviations were significantly correlated with the institute patients were treated at (Cramer’sV 0.34–0.48). Despite early identification of institute-specific deviations in QA, these continued during the trial. No significant associations were seen between deviations and accrual timing or rate (P ≥ 0.26). Within eRT, no significant relation was observed between experimental PA and locoregional control (LRC), the primary endpoint of the trial (P≥.15). ConclusionsDespite QA, protocol deviations persisted during the trial, which were mostly institute-specific. However, deviations of the experimental treatment strategy did not significantly impact LRC and therefore the trial conclusion.

Evaluating the Value of Eye-Tracking Augmented Debriefing in Medical Simulation-A Pilot Randomized Controlled Trial.

Debriefing after simulation facilitates reflective thinking and learning. Eye-tracking augmented debriefing (ETAD) may provide advantages over traditional debriefing (TD) by leveraging video replay with first-person perspective. This multisite randomized controlled trial compared the impact of ETAD with TD (without eye-tracking and without video) after simulation on 4 outcomes: (1) resident metacognitive awareness (the primary outcome), (2) cognitive load (CL) of residents and debriefers, (3) alignment of resident self-assessment and debriefer assessment scores, and (4) resident and debriefer perceptions of the debriefing experience. Fifty-four emergency medicine residents from 2 institutions were randomized to the experimental (ETAD) or the control (TD) arm. Residents completed 2 simulation stations followed by debriefing. Before station 1 and after station 2, residents completed a Metacognition Awareness Inventory (MAI). After each station, debriefers and residents rated their CL and completed an assessment of performance. After the stations, residents were interviewed and debriefers participated in a focus group. There were no statistically significant differences in mean MAI change, resident CL, or assessment alignment between residents and debriefers. Debriefer CL was lower in the experimental arm. Interviews identified 4 themes: (1) reflections related to debriefing approach, (2) eye-tracking as a metacognitive sensitizer, (3) translation of metacognition to practice, and (4) ETAD as a strategy to manage CL. Residents reported that eye tracking improved the specificity of feedback. Debriefers relied less on notes, leveraged video timestamps, appreciated the structure of the eye-tracking video, and found the video useful when debriefing poor performers. There were no significant quantitative differences in MAI or resident CL scores; qualitative findings suggest that residents appreciated the benefits of the eye-tracking video review. Debriefers expended less CL and reported less perceived mental effort with the new technology. Future research should leverage longitudinal experimental designs to further understand the impact of eye-tracking facilitated debriefing.

Reverse Selection Designs for Accommodating Multiple Control Arms.

Evaluating a novel treatment in a randomized controlled trial requires comparison against existing therapies. If several existing therapies of similar benefit exist, the identification of a single control regimen may be difficult. For this situation, we propose a reverse selection design which, in its simplest form, includes a single experimental treatment arm and two control arms. Rather than carrying both control arms through the entire trial, the control arms are compared at an early interim analysis, ideally while accrual is ongoing. At this time, the worst-performing control arm is dropped and randomization continues to the remaining arms. At the end of the study, we compare the treatment to the remaining control arm. When no head-to-head comparison of the extant therapies is available or feasible, this design requires a smaller sample size than a traditional three-arm design or two sequential trials in which the extant therapies are compared and the better treatment is used in a subsequent trial as the control arm. This is because the final comparison is only between two arms and because the early interim analysis occurs prior to the end of accrual - yet with enough information such that any substantially better control arm will be selected. We evaluate the operating characteristics of a reverse selection design via simulation and show that it reduces the required sample size needed to compare the treatment against the best control, controls type I error, and likely selects the right control arm to use in the final analysis.

OS09.7.A GBM AGILE PLATFORM TRIAL FOR NEWLY DIAGNOSED AND RECURRENT GBM: RESULTS OF FIRST EXPERIMENTAL ARM, REGORAFENIB

Abstract BACKGROUND GBM AGILE (NCT03970447;https://www.gcaresearch.org/research/gbm-agile) is a phase 3 Bayesian adaptive platform trial that efficiently tests multiple arms against common control, with 6 arms included to date. Primary endpoint is overall survival (OS). Stage 1 experimental arms are adaptively randomized against other arms. Demonstrated efficacy in stage 1 leads to fixed randomization stage 2. Stages 1 and 2 are combined for registration. Control randomization is fixed. Regorafenib, a multikinase-inhibitor, entered into GBM AGILE as the first arm and therefore was equally randomized against control. Regorafenib showed OS benefit in recurrent disease (RD) in randomized phase 2 REGOMA trial. MATERIAL AND METHODS Patient subtypes in GBM AGILE are newly diagnosed unmethylated (NDU), RD, and—not considered for regorafenib—ND methylated (NDM). Arm indications (signatures) are combinations of subtypes. Control is temozolomide (ND) and lomustine (RD). Efficacy is assessed by OS hazard ratio(HR), arm/control. Efficacy is demonstrated when Bayesian probability of benefit (HR< 1.00) ≥ 98% (roughly analogous P-value: 0.02). Futility occurs at any monthly analysis when Bayesian predictive power (PP) is < 25% for all signatures. Follow-up continues for 12 months after arm’s accrual stops. RESULTS When PP for all 3 pre-defined signatures was < 25%, regorafenib’s accrual was stopped for futility. Regorafenib/control sample sizes were 49/51, 127/128, 176/179 for signatures NDU, RD, and both. Respective PPs: 0.138, 0.030, 0.025—none close to 0.25. Respective mean HRs: 1.26, 1.25, 1.23. Probabilities of benefit (HR< 1.00): 0.35, 0.18, 0.17. At final analysis, mean HRs were 1.07, 1.08, 1.08 with final probabilities of benefit (HR< 1.00) equal to 0.421, 0.312, 0.296—none close to 0.98. CONCLUSION GBM AGILE efficiently and compellingly addressed regorafenib’s role in GBM, in RD and NDU. These findings are germane as they fail to confirm the REGOMA results in RD. GBM AGILE continues to efficiently assess other therapies, including utilizing concurrent and previously accrued controls. This abstract was accepted and previously presented at the 2023 SNO Annual Meeting and published in Neuro-Oncology, Volume 25, Issue Supplement_5, November 2023, Pages v97-v98.

Nanoparticles use magnetoelectricity to target and eradicate cancer cells.

We investigated the theranostic capabilities of magnetoelectric nanoparticles (MENPs) combined with MRI via a murine model of pancreatic adenocarcinoma. MENPs leverage the magnetoelectric effect to convert an applied magnetic field into local electric fields, which can induce irreversible electroporation of tumor cell membranes when activated by MRI. Additionally, MENPs modulate MRI relaxivity, which can be used to predict the degree of tumor ablation. Through a pilot study (n=21) and a confirmatory study (n=27), we demonstrated that, ≥300 µg of MRI-activated MENPs significantly reduced tumor volumes, averaging a three-fold decrease as compared to controls. Furthermore, there was a direct correlation between the reduction in tumor T 2 relaxation times and tumor volume reduction, highlighting the predictive prognostic value of MENPs. Six of 17 mice in the confirmatory study's experimental arms achieved a durable complete response, showcasing the potential for durable treatment outcomes. Importantly, the administration of MENPs was not associated with any evident toxicities. This study presents the first in vivo evidence of an externally controlled, MRI-based, theranostic agent that effectively targets and treats solid tumors via irreversible electroporation while sparing normal tissues, offering a new and promising approach to cancer therapy.

VI-RADS followed by Photodynamic Transurethral Resection of Non-Muscle-Invasive Bladder Cancer vs White-Light Conventional and Second-resection: the 'CUT-less' Randomised Trial Protocol.

A second transurethral resection of bladder tumour (Re-TURBT) is recommended by European Association of Urology (EAU) Guidelines on non-muscle-invasive bladder cancers (NMIBCs) due to the risk of understaging and/or persistent disease following the primary resection. However, in many cases this may be unnecessary, potentially harmful, and significantly expensive constituting overtreatment. The CUT-less trial aims to combine the preoperative staging accuracy of Vesical Imaging-Reporting and Data System (VI-RADS) and the intraoperative enhanced ability of photodynamic diagnosis (PDD) to overcome the primary TURBT pitfalls thus potentially re-defining criteria for Re-TURBT indications. Single-centre, non-inferiority, phase IV, open-label, randomised controlled trial with 1:1 ratio. The primary endpoint is short-term BC recurrence between the study arms to assess whether patients preoperatively categorised as VI-RADS Score 1 and/or Score 2 (i.e., very-low and low likelihood of MIBC) could safely avoid Re-TURBT by undergoing primary PDD-TURBT. Secondary endpoints include mid- and long-term BC recurrences and progression (i-ii). Also, health-related quality of life (HRQoL) outcomes (iii) and health-economic cost-benefit analysis (iv) will be performed. All patients will undergo preoperative Multiparametric Magnetic Resonance Imaging of the bladder with VI-RADS score determination. A total of 327 patients with intermediate-/high-risk NMIBCs, candidate for Re-TURBT according to EAU Guidelines, will be enrolled over a 3-year period. Participants will be randomised (1:1 ratio) to either standard of care (SoC), comprising primary white-light (WL) TURBT followed by second WL Re-TURBT; or the Experimental arm, comprising primary PDD-TURBT and omitting Re-TURBT. Both groups will receive adjuvant intravesical therapy and surveillance according to risk-adjusted schedules. Measure of the primary outcome will be the relative proportion of BC recurrences between the SoC and Experimental arms within 4.5 months (i.e., any 'early' recurrence detected at first follow-up cystoscopy). Secondary outcomes measures will be the relative proportion of late BC recurrences and/or BC progression detected after 4.5 months follow-up. Additionally, we will compute the HRQoL variation from NMIBC questionnaires modelled over a patient lifetime horizon and the health-economic analyses including a short-term cost-benefit assessment of incremental costs per Re-TURBT avoided and a longer-term cost-utility per quality-adjusted life year gained using 2-year clinical outcomes to drive a lifetime model across the two arms of treatment. ClinicalTrial.gov identifier (ID): NCT05962541; European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) ID: 2023-507307-64-00.

Using the Rehabilitation Treatment Specification System to Describe Experimental and Control Arms of a Clinical Trial for Breast Cancer Survivors

Using the Rehabilitation Treatment Specification System to Describe Experimental and Control Arms of a Clinical Trial for Breast Cancer Survivors

Prospective study on the impact of different antithrombotic therapies on subclinical leaflet thickening and its temporal dynamics in transcatheter aortic valves—The NOTION-4 trial

Transcatheter aortic valve replacement (TAVR) has become the standard-of-care treatment for a majority of patients with severe, symptomatic aortic stenosis. The post-procedural anti-thrombotic therapeutic management is still a topic of debate and could affect the incidence of HALT, a phenomenon which can be assessed by four-dimensional computed tomography (4DCT). The NOTION-4 trial is a randomized controlled trial comprising TAVR patients with no indication for oral anticoagulant (OAC) therapy, comparing lifelong single anti-platelet therapy (standard arm) versus early 3-month direct oral anticoagulant (DOAC) therapy followed by single anti-plateletet therapy (experimental arm). The incidence of HALT and clinical endpoints will be evaluated in both groups at 3 months, 1 year and 5 years after randomization. The primary endpoint is the number of patients with at least one bioprosthetic aortic valve leaflet with HALT as assessed by cardiac 4DCT imaging at 1 year. The trial is powered for superiority testing and started enrollment in 2021. In total, 324 patients will be included. The last patient is expected to be enrolled by the end of 2024 and the primary endpoint is to be presented in 2026. The NOTION-4 trial aims to study whether an early 3-month DOAC therapy after TAVR can result in a sustained lower incidence of HALT in transcatheter aortic valves. This trial holds the potential to give valuable insights into whether early OAC therapy should be integrated in future guidelines for post-TAVR anti-thrombotic therapeutic management. NOTION-4, ClinicalTrials.gov ID NCT06449469, https://clinicaltrials.gov/study/NCT06449469.

Improved Event-Free Survival After Complete or Major Pathologic Response in Patients With Resectable NSCLC Treated With Neoadjuvant Chemoimmunotherapy Regardless of Adjuvant Treatment: A Systematic Review and Individual Patient Data Meta-Analysis

IntroductionNeoadjuvant chemoimmunotherapy has reshaped the treatment landscape for resectable NSCLC, yet the prognostic significance of pathologic response remains unclear. We conducted a systematic review and individual patient data (IPD) meta-analysis to evaluate the impact of achieving pathologic complete response (pCR) or major pathologic response (MPR) on event-free survival (EFS) and assessed the influence of adjuvant immunotherapy. MethodsWe performed an IPD meta-analysis of prospective clinical trials on neoadjuvant or perioperative anti–programmed death-ligand 1 in combination with platinum-based chemotherapy in patients with resectable NSCLC. The IPD was extracted from Kaplan-Meier curves for pCR and/or MPR from the included studies. Survival outcomes were compared between patients achieving pCR or MPR and those who did not, considering both intention-to-treat and resected populations. ResultsAchieving pCR or MPR was associated with improved EFS in the intention-to-treat population (pCR, hazard ratio = 0.13; MPR, hazard ratio = 0.18, respectively) with a 24 months EFS rate of 94% and 88% for patients who achieved pCR and MPR, respectively. Independently from pCR status, patients who were treated in an experimental arm that included adjuvant immunotherapy had similar EFS. ConclusionsOur study reported a strong EFS improvement in patients who achieved either pCR or MPR after neoadjuvant chemoimmunotherapy. The use of adjuvant immunotherapy after tumor resection was not associated with improved EFS.

Effects of abdominal touch, music, and virtual reality video during the non-stress test on maternal anxiety and fetal parameters: A randomized controlled clinical trial

This randomized control trial compared the effects of abdominal touch, music, and virtual reality video on maternal anxiety and fetal parameters. 120 pregnant women were randomly assigned to one of three experimental arms (abdominal touch, music, virtual reality video) or the control group (30 pregnant women in each group). Data were collected through the Participant Information Form, and outcomes were assesssed using the Non-stress test (NST) Findings Registry Form, and the State Anxiety Scale. This trial showed that abdominal touch and virtual reality videos were superior to music in increasing fetal heart rate (p=0.001), and music and virtual reality videos were superior to abdominal touch in decreasing maternal anxiety (p=0.001). Abdominal touch and virtual reality video were effective in increasing fetal heart rate, and music and virtual reality video were effective in decreasing maternal anxiety. It is recommended to provide pregnant women access to abdominal touch, music, and virtual reality videos to reduce maternal stress and anxiety and to increase fetal heart rate.

Most Common Symptomatic Adverse Reactions of Cancer Treatments From US Drug Labels (2015-2021) to Inform Selection of Patient-Reported Outcomes

ObjectivesIncorporating patient-reported outcomes (PROs) to assess symptomatic adverse events (AEs) in cancer clinical trials (CTs) is important to characterize treatment tolerability. Cancer therapies approved over the past decade have expanded the types of expected toxicities. To inform future symptomatic AE PRO item selection, we identified the most common symptomatic adverse reactions from recently approved products. MethodsWe reviewed approvals from 2015 to 2021 for lung, breast, and hematologic cancer indications. Using United States Prescribing Information safety data, we recorded symptomatic adverse reactions reported in ≥20% of patients in the experimental arm of CTs supporting approvals. We calculated the proportion of arms reporting each symptomatic adverse reaction. ResultsIn total, 130 experimental arms were included (lung = 30, breast = 10, hematologic = 90). For all cancer types, fatigue and diarrhea were reported in >50% of the arms. Nausea was reported in ≥50% of the arms for all except lung. Vomiting, decreased appetite, and alopecia, were reported in ≥50% of breast cancer arms. Rash, musculoskeletal pain, and cough were reported in >50% of leukemia/lymphoma arms. Cough was common (50%) in multiple myeloma arms. ConclusionsHeterogeneity in symptomatic adverse reactions across CTs supports the use of item libraries when building a PRO strategy to assess tolerability. Fatigue, diarrhea, and nausea were the most frequent symptomatic adverse reactions reported in contemporary cancer CTs and could provide a starting point when selecting PRO symptomatic AE items. Additional symptomatic AE PRO items should be selected based on the mechanism of action, early clinical data, published literature, and patient and clinician input.

Evidenced-Based Prior for Estimating the Treatment Effect of Phase III Randomized Trials in Oncology.

The primary results of phase III oncology trials may be challenging to interpret, given that results are generally based on P value thresholds. The probability of whether a treatment is beneficial, although more intuitive, is not usually provided. Here, we developed and released a user-friendly tool that calculates the probability of treatment benefit using trial summary statistics. We curated 415 phase III randomized trials enrolling 338,600 patients published between 2004 and 2020. A phase III prior probability distribution for the treatment effect was developed on the basis of a three-component zero-mean mixture distribution of the observed z-scores. Using this prior, we computed the probability of clinically meaningful benefit (hazard ratio [HR] <0.8). The distribution of signal-to-noise ratios and power of phase III oncology trials were compared with that of 23,551 randomized trials from the Cochrane Database. The signal-to-noise ratios of phase III oncology trials tended to be much larger than randomized trials from the Cochrane Database. Still, the median power of phase III oncology trials was only 49% (IQR, 14%-95%), and the power was <80% in 65% of trials. Using the phase III oncology-specific prior, only 53% of trials claiming superiority (114 of 216) had a ≥90% probability of clinically meaningful benefits. Conversely, the probability that the experimental arm was superior to the control arm (HR <1) exceeded 90% in 17% of trials interpreted as having no benefit (34 of 199). By enabling computation of contextual probabilities for the treatment effect from summary statistics, our robust, highly practical tool, now posted on a user-friendly webpage, can aid the wider oncology community in the interpretation of phase III trials.

Patient Engagement in a Mobile App-Based Rehabilitation Program for Total Hip or Knee Arthroplasty: Secondary Data Analysis of a Randomized Controlled Trial.

Health care professionals use mobile apps to support patients' rehabilitation after total hip or knee arthroplasty. Understanding patient engagement in such mobile health interventions can help tailor these interventions to better support patients. This study aimed to investigate patient engagement in a mobile app-based arthroplasty rehabilitation program and to investigate the association between patient engagement and their characteristics. Data were extracted from a pool of 42 participants in the experimental arm of a randomized controlled trial that used a mobile app (WeChat [Tencent Holdings Limited])-based program to support patients' rehabilitation after total hip or knee arthroplasty. The primary outcomes were the number of days the participants accessed the program and completed recommended rehabilitation tasks. Secondary outcomes included data on the participants' posts on a discussion forum, messages sent by the participants, access to the program components, and reading and sharing the program content. Generalized linear models were used to analyze the association between patient engagement and personal characteristics. The participants reported in a rehabilitation diary accessing the program on a mean of 5.2 (SD 2) days per week and completing recommended rehabilitation tasks on a mean of 6.5 (SD 0.8) days per week. The majority (31/42, 74%) posted on the discussion forum, with a mean of 18.1 (SD 21.2) posts. Most participants (37/42, 88%) sent messages to health care professionals, with a mean of 14 (SD 15.9) messages. The program components were visited for a total of 525 times. The program content was read 898 times and shared 82 times in total. Generalized linear models showed that both primary outcomes, the number of days the participants accessed the program (B=6.46, 95% CI 1.98-15.35; χ21=11.1, P=.001) and the number of days they completed rehabilitation tasks (B=2.65, 95% CI 0.45-5.48; χ21=5.7, P=.02), were positively associated with having a high school education or above. In addition, the number of posts on the discussion forum was positively associated with living with family, having a high school education or above, undergoing total knee arthroplasty, having comorbidities, and the score of self-efficacy but was negatively associated with age. The number of messages sent by the participants was positively associated with having a high school education or above, having comorbidities, and the score of self-efficacy. Patient engagement in mobile arthroplasty rehabilitation is associated with their education level, cohabitation status, age, type of surgery, presence of comorbidities, and sense of self-efficacy. Program developers can consider these characteristics and use strategies, such as family involvement, in the design of mobile arthroplasty rehabilitation programs to enhance patient engagement in such interventions. Australian New Zealand Clinical Trials Registry ACTRN12621000867897; https://tinyurl.com/mtdw25fp.

The cost of doing business: Drug costs in federally sponsored cancer clinical trials.

10 Background: Federally sponsored cancer clinical trials (FS-CCTs) address a broad set of clinical cancer research questions that are avoided by industry sponsors, including combining treatment modalities, examining whether approved drugs may work in other cancers, or examining de-escalation therapy. FS-CCTs routinely extend the lives of patients with cancer and inform treatment guidelines. However, FS-CCTs must often be conducted in partnership with industry sponsors since the cost of drugs is high and cannot be paid for by the government. This limits the independence of FS-CCTs. We aimed to examine the drug costs for trials with federal sponsorship. Methods: We included all US-based cancer treatment trials registered in ClinicalTrials.gov that examined pharmaceuticals and/or biological products and started from 2018-2022. Trials with any NIH or other federal sponsorship (as the sole, lead, or other sponsor) were included. Drug names and number of enrollments per arm and drug were extracted from ClinicalTrials.gov and study protocols. The Wholesale Acquisition Cost (WAC) was obtained from IBM Micromedex RED BOOK (2023) by matching the product name, dose strength and administration route. The product acquisition cost (“cost”) per trial was computed by summing the WAC for each drug and multiplying by the number of enrollments. Results: Overall, N=1020 trials were examined (phase I = 343, phase II = 611, phase III = 66). The mean (median) drug costs were $53.9 million (m) ($7.4m) overall, including $73.8m ($19.8m), $47.2m ($8.7m), and $44.7m ($5.8m) for trials solely sponsored, led by, or with secondary/tertiary participation by federal sponsors, respectively. Trial-level drug costs were $19.2m ($3.6m), $51.9m ($9.4m), and $244.9m ($38.8m) for phase I, II, and III trials, respectively. Drug costs were much greater for trials involving immune and/or targeted therapies ($60.1m [$11.4m]) than those with conventional chemotherapies ($30.8m [$1.5m]). In the subset of n=128 phase 2 or 3 comparative trials, drug costs were $97.7m ($21.8m) for experimental arms and $24.1m ($1.4m) for control arms. Conclusions: The costs for drugs in FS-CCTs were very high, especially for the experimental arms, highlighting the necessity for federally sponsored researchers to collaborate with industry partners to conduct trials. Drug costs for immune and/or targeted therapies were higher yet, suggesting that the cost burden to conduct trials for federal sponsors may continue to increase. These findings also suggest that systemwide costs for cancer drugs in clinical practice will continue to increase substantially. These results have implications for how FS-CCTs are designed and conducted, since the necessity of collaboration between federal and industry sponsors likely limits the independence of federal research. Future public policy efforts should focus on mechanisms for independent investigation of new pharmacologic agents.

Contextual-compassion training for borderline personality disorder with long lasting symptoms: a randomized clinical trial

Long-term follow-up studies have shown that the symptoms of borderline personality disorder (BPD) tend to remit over time. However, many patients present long lasting symptoms (LLS), including low mood, emptiness, and persistent impairment in psychosocial adjustment. Given the high rate of LLS in BPD patients, new treatment strategies are needed. We conducted a randomized clinical trial (RCT) to evaluate the efficacy of a novel intervention that combines self-compassion and contextual-based skills for patients with persistent symptoms. Sixty BPD individuals with LLS who had received dialectical behavior therapy skills training (DBT-ST) in the previous six months were recruited and randomized to receive the experimental intervention or treatment as usual (TAU) for 12 weeks. All participants were evaluated pre- and post-intervention and at 3-months follow-up. The primary outcome measure was self-reported well-being. Other clinical variables were also evaluated, including depressive symptoms, BPD symptoms, functionality, self-compassion, and self-criticism. Participants in the experimental arm showed a significant increase in indicators of well-being (e.g., happiness and quality of life) and a significant decrease in depressive symptoms. These results were sustained—and even continued to improve—at the three-month follow-up. No significant changes were observed in BPD severity, self-criticism, or self-compassion. More RCTs are needed to test the efficacy of new interventions targeting this population with persistent symptoms, not only to reduce symptoms but also to promote well-being and personal recovery.