Discontinuation Trial Research Articles

Completion and reporting of COVID-19 clinical trials registered on ClinicalTrials.gov during the first 6 months of the pandemic: cohort study

BackgroundEarly in the COVID-19 pandemic, numerous clinical trials were initiated. Although concerns were raised regarding the quality of the trials, the eventual research output yielded from the trials remains unknown....

Qualitative understanding of experiences of people with cystic fibrosis in a treatment discontinuation trial: The QUEST study

Qualitative understanding of experiences of people with cystic fibrosis in a treatment discontinuation trial: The QUEST study

Analyzing determinants of premature trial discontinuation in leukemia clinical trials

Clinical trials are crucial for improving patient outcomes. Although a significant number of trials are discontinued prematurely, our understanding of factors influencing early termination is limited. We conducted a comprehensive search of ClinicalTrials.gov to identify leukemia trials from 2000 to 2020, followed by data abstraction performed by two independent reviewers. Among 3522 leukemia clinical trials identified, 28.4% were terminated prematurely. Slow accrual was the leading cause of termination 38.2%. The termination rate increased significantly from 17.0% between 2000 and 2005 to 30.9% between 2010 and 2015 (p < .001). Large trials had a lower termination rate than small trials (p < .001). Academic-sponsored trials had the highest termination rates compared to other sponsors’ trials (p < .001). Early-phase trials showed higher termination rates compared to late-phase (p < .001). Other significant factors included a sequential assignment, single-center, and non-randomized trials (p < .001). Much of leukemia trials are terminated prematurely, with slow accrual being the most common reason for early termination.

Efficacy and Safety of TransCon PTH in Adults with Hypoparathyroidism: 52-Week Results From the Phase 3 PaTHway Trial.

Conventional therapy for hypoparathyroidism aims to alleviate symptoms of hypocalcemia but does not address insufficient parathyroid hormone (PTH) levels. Assess the long-term efficacy and safety of TransCon PTH (palopegteriparatide) for hypoparathyroidism. Phase 3 trial with a 26-week double-blind, placebo-controlled period followed by a 156-week open-label extension (OLE). 21 sites across North America and Europe. 82 adults with hypoparathyroidism were randomized and received study drug and 78 completed week 52. All OLE participants received TransCon PTH administered once daily. Multi-component efficacy endpoint: proportion of participants at week 52 who achieved normal serum calcium (8.3-10.6 mg/dL) and independence from conventional therapy (≤600 mg/day of elemental calcium and no active vitamin D). Other efficacy endpoints included patient-reported outcomes (PROs) and bone mineral density (BMD). Safety was assessed by 24-hour urine calcium and treatment-emergent adverse events (TEAEs). At week 52, 81% (63/78) met the multi-component efficacy endpoint, 95% (74/78) achieved independence from conventional therapy, and none required active vitamin D. PROs showed sustained improvements in quality of life, physical functioning, and well-being. Mean BMD Z-scores decreased toward age- and sex-matched norms from baseline to week 52. Mean (SD) 24-hour urine calcium excretion decreased from 376 (168) mg/day at baseline to 195 (114) mg/day at week 52. Most TEAEs were mild or moderate and none led to trial discontinuation during the OLE. At week 52 of the PaTHway trial, TransCon PTH showed sustained efficacy, safety, and tolerability in adults with hypoparathyroidism.

Self-reported chronic therapy use after 24-weeks of follow-up by participants who completed the simplify randomized, controlled trial

BackgroundHighly effective CFTR modulator therapy (HEMT) has improved the health of many people with cystic fibrosis (pwCF), offering opportunities to discontinue burdensome therapies. SIMPLIFY included randomized, controlled trials that confirmed non-inferiority of discontinuing versus continuing dornase alfa (DA) or hypertonic saline (HS) for 6 weeks in pwCF on HEMT. In this study of post-trial treatment use by SIMPLIFY participants, we hypothesized that randomization to discontinue DA or HS during the trial would be associated with a higher likelihood of non-use of each medication during follow-up. MethodsWe electronically surveyed SIMPLIFY participants every 4 weeks for 24 weeks after trial completion but before the main trial results were publicly disclosed. We asked them how often they used medications during the previous week. We estimated covariate-adjusted odds ratios (ORs) of DA or HS non-use by logistic regression with generalized estimating equations. ResultsAfter exclusions mostly due to lack of any surveys, 472 participants were included in the analysis population, 181 from the HS trial and 291 from the DA trial. Approximately half of the analysis population completed all six surveys. At every month of follow-up in both trials, the percentage of individuals reporting non-use of DA or HS during the previous week was greater among those randomized to discontinue therapy. Among participants with responses at 24 weeks, 30/122 (24.6 %) in the HS trial and 79/222 (35.6 %) in the DA trial reported non-use of the respective study medication. After adjusting for covariates, participants randomized to discontinue DA were 8.7-times (95 % CI: 4.3–17.7) more likely to not use DA during follow-up than those randomized to continue DA, and participants randomized to discontinue HS were 5.2-times (95 % CI: 2.1–12.8) more likely to not use HS during follow-up compared to those randomized to continue. ConclusionsIn healthy pwCF on ETI, randomization to discontinue DA or HS during SIMPLIFY was associated with greater odds of not using each medication after the trial compared to randomization to continue. These findings suggest that participation in a treatment discontinuation trial can influence participants’ post-trial treatment decisions. This possibility may be relevant during discussions about research participation and clinical care.

Physician-Reported Facilitators and Barriers for Side Effect Management of Heart Failure Medications.

Physician underprescribing and patient nonadherence are major barriers to the benefits of guideline-directed medical therapy. An important contributor to both underprescribing and patient nonadherence is concern about medication-related side effects. Yet, there are few to no data on approaches used by physicians to: (1) elicit medication-related side effects, (2) attribute these side effects to specific medications, and (3) take appropriate action. The authors conducted semistructured interviews with physicians to identify facilitators and barriers to each critical step of heart failure medication management: elicitation of side effects, attribution of side effects to a medication, and action in response to attributed side effects. Interviews were transcribed and coded using directed content analysis. For elicitation of potential side effects, limited patient communication and family discordance in reporting were key barriers, whereas guiding questions, measurement, and open channels of communication were key facilitators. For attribution of side effects, confounding from other medications, limited time for clinical encounters, and nonspecific symptoms were key barriers, whereas time-limited medication discontinuation trials and medication rechallenges were key facilitators. For taking action, challenges with weighing risks and benefits and physician fear about causing harm or interfering with other clinicians were barriers, whereas patient-physician communication and the results of a medication discontinuation trials and medication rechallenge were facilitators. This study generated key facilitators and barriers to 3 key aspects of heart failure medication management related to side effects that should drive future work to improve heart failure medication management.

Analysis of the discontinuation and nonpublication of neurooncological randomized clinical trials.

Premature discontinuation and nonpublication of clinical trials contribute to research waste and compromise our ability to improve patient outcomes. However, the extent to which these problems exist in neurooncological randomized clinical trials (RCTs) is not known. This study aimed to evaluate the prevalence of discontinuation and nonpublication of neurooncological RCTs, identify contributing factors, and assess trial characteristics associated with each. We performed a retrospective, cross-sectional study of neurooncological RCTs registered in Clinicaltrials.gov before March 7, 2023. Data were collected from Clinicaltrials.gov and associated publications were located. We attempted to contact authors for all trials without associated publications or an identified reason for discontinuation. Of 139 included RCTs, 57 (41%) were discontinued. The most common reason for discontinuation identified was slow enrollment or accrual (23%), though 30 trials (53%) were discontinued for unknown reasons. Trials funded by sources other than industry or the National Institutes of Health were more likely to be discontinued (odds ratio 4.2, 95% confidence interval 1.3-13.8). In total, 67 of the 139 (48%) RCTs were unpublished, including 50 of the 57 (88%) discontinued studies and 17 of the 82 (21%) completed studies. In our study, discontinuation of neurooncological clinical trials was common and often occurred for unknown reasons. Trials were also frequently unpublished, particularly those that were discontinued. Addressing these findings may provide an opportunity to reduce research waste and improve outcomes for patients with neurological cancers.

Discontinuation and non-publication of randomized controlled trials on cervical cancer or precancer.

Research waste is a considerable problem in clinical trials, with nonpublication being a significant contributor. We aimed to determine the prevalence of discontinuation and nonpublication of randomized controlled trials (RCTs) on cervical cancer or precancer. We searched ClinicalTrials.gov for registered RCTs investigating cervical cancer or precancer that started between January 2000 and December 2020. The primary and secondary outcomes were trial nonpublication and premature discontinuation, respectively. Publication status was determined by systematic searches of peer-reviewed journals using the PubMed and Scopus databases. A total of 113 RCTs met the inclusion criteria. Among the 85 trials completed before December 2020, 44 (51.8%) were prematurely discontinued and 40 (47.1%) were unpublished. A single-center design (61.4% vs. 34.1%, P=.012) and lack of external funding (59.1% vs. 36.6%, P=.038) were significantly associated with trial discontinuation. Large-scale (target sample size >400; 46.7% vs. 17.5%, P=.004) and externally funded trials (66.7% vs. 35.0%, P=.004) were more likely to be published. Multivariate logistic analysis revealed that a large sample size [odd ratio (OR): 4.125, 95% confidence interval (CI): 1.511-11.259, P=.006] and presence of external funding (OR: 3.714, 95% CI: 1.513-9.117, P=.004) were independent positive factors for trial publication. A significant proportion of RCTs related to cervical cancer or precancer were discontinued early or remain unpublished, resulting in a waste of research resources.

Factor XI inhibition in cardiovascular disease.

Cardiovascular disease remains the leading global cause of mortality, requiring effective antithrombotic strategies to prevent thromboembolic events. Currently available therapies are effective but have inherent bleeding risks which may limit or preclude their use, particularly in patients at the highest risk of bleeding. Factor XI (FXI) inhibitors are a promising new class of anticoagulants which may mitigate the risk of bleeding while maintaining efficacy. Further, they have the potential to provide effective anticoagulation in indications where direct oral anticoagulants (DOACs) are proven less effective than vitamin K antagonists (VKAs) or when DOACs are contraindicated. The development of FXI inhibitors was based on mechanistic considerations suggesting FXI's role in thrombus formation without significantly affecting hemostasis, supported by epidemiological data and animal experiments. FXI inhibitors, including antisense oligonucleotides, monoclonal antibodies, and small‑molecule inhibitors, target different stages of FXI production or activation, offering a diversity of therapeutic options with differing onset and offset of action, drug interaction potential, and renal elimination. FXI inhibitors have shown potential benefits in phase II trials, demonstrating similar or reduced bleeding rates to existing agents, including DOACs. The early termination of AZALEA‑TIMI 71 (Safety and Tolerability of Abelacimab [MAA868] vs Rivaroxaban in Patients With Atrial Fibrillation) and OCEANIC‑AF (A Study to Learn How Well the Study Treatment Asundexian Works and How Safe it is Compared to Apixaban to Prevent Stroke or Systemic Embolism in People With Irregular and Often Rapid Heartbeat [Atrial Fibrillation], and at Risk for Stroke) trials underscores challenges in the selection of appropriate patient populations and anticoagulant class, agent, and dose. Ongoing phase III trials including OCEANIC‑STROKE (A Study to Test Asundexian for Preventing a Stroke Caused by a Clot in Participants After an Acute Ischemic Stroke or After a High‑risk Transient Ischemic Attack, a So‑called Mini Stroke) and LIBREXIA trials aim to further explore the efficacy of FXI inhibitors in stroke, acute coronary syndrome, and atrial fibrillation. In conclusion, FXI inhibitors hold promise as next‑generation anticoagulants, potentially addressing limitations of current therapies. Ongoing research is required to establish their place in clinical practice and address unresolved questions.

Decline in Smartphone-Assessed Physical Activity Level is Associated With Clinical Outcomes in Phase I/II Clinical Cancer Trials.

A decline in physical function may be an early predictor for complications of cancer treatment. This study examined whether repeated objective smartphone measurements of physical activity and exercise capacity in patients with cancer are feasible during early-phase clinical trials (EPCTs) and whether a decline in physical function is associated with clinical outcomes. Physical activity (steps/day) and exercise capacity (6-minute walk test [6MWT]) were measured with a smartphone before EPCT start (T0) and after 4 weeks (T1) and 8 weeks (T2). Univariable logistic regression analyzed associations between a decline in step count (≥20%), 6MWT distance (≥10%), or deterioration of ECOG performance status (PS) and trial discontinuation at 8 weeks and 90 days. Cox proportional hazards models were used to examine associations with progression-free survival (PFS) and overall survival (OS), adjusting for trial phase (I vs II), cancer type (hematologic malignancy vs solid tumor), and PS (0 vs ≥1). Among 117 included patients, valid step count and 6MWT measurements were available for 96.6% and 76.7% of patients at T0, 74.4% and 53.3% at T1, and 89.7% and 54.4% at T2, respectively. Patients experiencing step count decline between T0 and T1 had higher odds of trial discontinuation at 8 weeks (odds ratio, 8.67; 95% CI, 1.94-61.43), and decline between T1 and T2 was associated with discontinuation at 90 days (odds ratio, 5.20; 95% CI, 1.43-21.14). Step count decline was significantly associated with shorter PFS (hazard ratio, 3.54; 95% CI, 2.06-6.08) and OS (hazard ratio, 2.31; 95% CI, 1.26-4.23). Declines in 6MWT distance or deterioration in ECOG PS were not associated with trial discontinuation or survival. Repeated smartphone measurements of physical activity are feasible in patients participating in EPCTs. Additionally, physical activity decline is significantly associated with trial discontinuation, PFS, and OS. Hence, we envision that objective smartphone measurements of physical activity will contribute to optimal treatment development for patients with cancer.

Kinetics of BCR::ABL1 transcript levels and molecular relapse after tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia patients: preliminary results from the DES-CML study.

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

Fragile points method for Euler–Bernoulli beams

In this paper, the recently introduced Fragile Points Method (FPM) is extended to study the static bending, free vibration, and mechanical buckling of isotropic and homogeneous case as well as functionally graded Euler–Bernoulli beams. The beam kinematics is based on the Euler–Bernoulli theory that assumes plane sections remain plane and perpendicular to the neutral axis of the deformed beam. The salient feature of the FPM is that it is a truly meshless method that employs simple local point-based polynomial test and trial functions. The key distinction is that the polynomial test and trial functions are discontinuous and constructed using radial basis functions, in contrast to the conventional Galerkin framework. Further, as the trial and test functions are discontinuous, the continuity requirement imposed by the continuous Galerkin framework is circumvented. The discontinuous trial and test functions lead to inconsistency; to alleviate this, we employ numerical flux corrections inspired by the discontinuous Galerkin method. The efficiency and robustness of the approach are tested with a few standard benchmark examples.

Retrospective cohort of in-office backfill-assisted voiding trial versus at-home catheter discontinuation with autofill voiding trial on the day after urogynecologic surgery

Retrospective cohort of in-office backfill-assisted voiding trial versus at-home catheter discontinuation with autofill voiding trial on the day after urogynecologic surgery

Treatment discontinuation in pharmacological clinical trials for gambling disorder

BackgroundGambling disorder affects 0.5–2% of the population, and of those who receive treatment, dropout tends to be relatively high. Very little is known about participant-specific variables linked to treatment discontinuation/dropout in gambling disorder, especially in pharmacological clinical trial settings. MethodsData were pooled from eight previous randomized, controlled pharmacological clinical trials conducted in people with gambling disorder. Demographic and clinical variables were compared between those who did versus did not subsequently dropout from those treatment trials. ResultsThe sample comprised data from 635 individuals, and the overall rate of treatment dropout was 40%. Subsequent treatment dropout was significantly associated with the following: positive family history of gambling disorder in one or more first degree relatives (relative risk [RR] of dropout in those with positive history vs not = 1.30), preference for mainly strategic vs non-strategic gambling activities (RR = 1.43), lower levels of education (Cohen's D = 0.22), and higher levels of functional disability (Cohen's D = 0.18). These variables did not differ significantly as a function of treatment condition (medication versus placebo). Dropouts and completers did not differ significantly in terms of the other demographic or clinical variables that were considered. ConclusionsThis study identified several candidate participant-specific predictors of pharmacological treatment dropout in gambling disorder. The findings highlight the need for future studies to address a wider range of contextual variables at large scale (including also study-specific variables e.g. trial/intervention duration), including in naturalistic treatment and clinical trial settings, with a view to developing algorithms that might usefully predict dropout risk.

Discontinuation of long-term growth hormone treatment in adults with growth hormone deficiency: a survey of UK practice.

We conducted a survey of UK endocrine clinicians between June 2022 and August 2022 to understand current practices regarding GH treatment discontinuation in adults with growth hormone deficiency. Using Survey Monkey®, a web-based multiple-choice questionnaire was disseminated to the UK Society for Endocrinology membership. It consisted of 15 questions on demographics, number of patients receiving GH and current practice on GH treatment discontinuation. In total, 102 endocrine clinicians completed the survey. Of these, 65 respondents (33 endocrinologists and 32 specialist nurses) indicated active involvement in managing patients with growth hormone deficiency. In total, 27.7% of clinicians were routinely offering a trial of GH discontinuation to adults receiving long-term GH therapy. Only 6% had a clinical guideline to direct such practice. In total, 29.2% stated that GH discontinuation should be routinely offered as an option to patients on long-term treatment, whilst 60% were not clearly in favour or against this approach but stated that it should probably be considered, and 9.2% were against. During the GH withdrawal period, most clinicians monitor signs and symptoms (75.4%), measure IGF-1 (84.6%), and complete a quality-of-life assessment (89.2%). The practice of offering a trial of GH discontinuation in growth hormone deficiency adults on long-term GH therapy is highly variable, reflecting the lack of high-quality evidence. Around a quarter of clinicians offer GH withdrawal for a number of reasons, but only a few have a local clinical guidance. A further 60% of clinicians stated they would probably consider such an approach. Methodologically sound studies underpinning the development of safe and cost-effective guidance are needed. In this UK survey of endocrine clinicians managing adults with growth hormone deficiency on long-term GH therapy, we explored for the first-time current practice and views on offering GH treatment discontinuation. In total, 27.7% of clinicians were routinely offering this option for a variety of reasons. Only 6% have local clinical guideline available to direct their practice on this. The majority of clinicians (60%), were not clearly in favour or against this approach but indicated it should probably be considered. In the absence of robust evidence on consequences of GH withdrawal, clinicians proposed monitoring of various clinical, biochemical and quality-of-life parameters during the period of discontinuation. Methodologically sound studies that will underpin the development of a safe, cost-effective guidance are needed.

A fragile points method with a numerical-flux-based interface debonding model to simulate the delamination migration in composite laminates

Predicting damage in composite laminates is essential for a better utilization of the material, but it is challenging especially when the inter- and intra-ply damages are coupled. In this paper, a Fragile Points Method (FPM) with a numerical-flux-based interface debonding model is proposed to simulate the laminates’ damage. The FPM is a novel meshless method using the discontinuous Galerkin weak formulations and the point-based discontinuous polynomial trial functions. In this work, an orthotropic interface debonding model has been developed based on the numerical fluxes to simulate the mixed-mode inter- and intra-ply damage. For any interior interface in an FPM model, the interface damage is triggered when the damage criterion is satisfied and the interface is separated when the fracture energy is reached. Due to the discontinuous characteristics of the FPM, the inter- and intra-ply damage modes are introduced explicitly, and thus the coupling between them can be naturally captured. In this paper, the proposed FPM is verified by four benchmark examples for Mode I, Mode II and Mixed Mode delamination. Then the proposed method is applied to simulate the delamination migration, used as an example for the inter- and intra-ply damage. The FPM results show that this method is able to provide reliable prediction on the load–displacement curves as well as the damage and crack patterns, and the mechanism governing the delamination migration is also discussed based on the FPM results.

The Contemporary Role of Hematopoietic Stem Cell Transplantation in the Management of Chronic Myeloid Leukemia: Is It the Same in All Settings?

Hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) patients has transitioned from the standard of care to a treatment option limited to those with unsatisfactory tyrosine kinase inhibitor (TKI) responses and advanced disease stages. In recent years, the threshold for undergoing HSCT has increased. Most CML patients now have life expectancies comparable to the general population, and therefore, the goal of therapy is shifting toward achieving treatment-free remission (TFR). While TKI discontinuation trials in CML show potential for achieving TFR, relapse risk is high, affirming allogeneic HSCT as the sole curative treatment. HSCT should be incorporated into treatment algorithms from the time of diagnosis and, in some patients, evaluated as soon as possible. In this review, we will look at some of the recent advances in HSCT, as well as its indication in the era of aiming for TFR in the presence of TKIs in CML.

514 - Tapinarof cream 1% once daily: significant efficacy in the treatment of atopic dermatitis in two pivotal phase 3 trials in adults and children down to 2 years of age

Abstract Introduction Tapinarof cream 1% once daily (QD) demonstrated efficacy versus vehicle and was well tolerated in adults and adolescents with moderate to severe atopic dermatitis (AD) in a previously reported phase 2 trial. Objective Here, we report pivotal phase 3 efficacy and safety results for tapinarof cream 1% QD in the treatment of adults and children down to 2 years of age with AD. Materials and Methods ADORING 1 and 2 were two identical phase 3, randomized, double-blind, vehicle-controlled trials. Eligibility criteria included a Validated Investigator Global Assessment for Atopic DermatitisTM (vIGA-ADTM) score of ≥3, Eczema Area and Severity Index (EASI) score of ≥6, and body surface area (BSA) involvement of 5–35%. Patients were randomized 2:1 to receive tapinarof cream 1% or vehicle cream QD for 8 weeks. The primary efficacy endpoint was vIGA-ADTM response, defined as a score of clear (0) or almost clear (1) and ≥2-grade improvement from baseline at Week 8. Secondary efficacy endpoints included ≥75% improvement in EASI score (EASI75) and proportion of patients (aged ≥12 years) with a baseline Peak Pruritus-Numerical Rating Scale (PP-NRS) score of ≥4 who achieved a ≥4-point reduction at Week 8. Adverse events (AEs) included rates of AEs of special interest (AESIs): contact dermatitis, follicular event, and headache. Results 407 and 406 patients aged 2–81 years were randomized in ADORING 1 and 2, respectively. At baseline, 84.0–89.9% of patients had a vIGA-ADTM score of 3 (moderate), mean EASI score of 12.5–13.3, and mean BSA affected of 16.7–16.9% across trials. At Week 8, both the primary and all secondary efficacy endpoints were met with statistical significance in the tapinarof groups versus vehicle: vIGA-ADTM response rates were 45.4% vs 13.9% and 46.4% vs 18.0% (both P&amp;lt;0.0001); EASI75 response rates were 55.8% vs 22.9% and 59.1% vs 21.2% (both P&amp;lt;0.0001); and a ≥4-point reduction in PP-NRS was achieved by 55.8% vs 34.2% (P=0.0366) and 52.8% vs 24.1% (P=0.0015), in ADORING 1 and 2, respectively. AEs were mostly mild or moderate; the most frequent (≥5% in any group) were folliculitis, headache, and nasopharyngitis. Trial discontinuation rates due to AEs were lower with tapinarof versus vehicle (ADORING 1: 1.9% vs 3.6%; ADORING 2: 1.5% vs 3.0%, respectively). Rates of AESIs with tapinarof versus vehicle were: contact dermatitis 1.5% vs 2.2% and 1.1% vs 1.5%; follicular events 10.0% vs 0.7% and 8.9% vs 1.5%; and headache 7.0% vs 2.2% and 1.5% vs 0%, in each trial, respectively. Conclusions Tapinarof cream 1% QD demonstrated statistically significant efficacy compared with vehicle for primary and secondary efficacy endpoints in adults and children down to 2 years of age with AD. Tapinarof was well tolerated, with no new safety or tolerability signals. AEs were mostly mild to moderate and led to low rates of trial discontinuation, demonstrating the predictable safety profile of tapinarof cream 1% QD.

Discontinuation and nonpublication of clinical trials in orthopaedic oncology

BackgroundDespite the pivotal role of clinical trials in advancing orthopaedic oncology knowledge and treatment strategies, the persistent issues of trial discontinuation and nonpublication are significant problems. This study conducted an analysis examining clinical trial discontinuation rates, associations between intervention types and discontinuation/nonpublication, and the role of funding, enrollment size, and their implications for trial success and completion.MethodsThis study, conducted on May 1, 2023, utilized a cross-sectional design to comprehensively analyze phase 3 and 4 randomized controlled trials within the realm of orthopaedic oncology. We specifically incorporated Phase 3 and 4 trials as they are designed to evaluate prolonged outcomes in human subjects and are more likely to reach publication. Study characteristics of interest included the intervention utilized in the clinical trial, presence of funding, whether the trial was published, completed, and trial enrollment size. The investigation involved an examination of ClinicalTrials.gov, a prominent online repository of clinical trial data managed by the National Library of Medicine of the USA. Descriptive statistics and multivariate logistic regressions were used to determine statistical significance.ResultsAmong the cohort of 130 trials, 19.2% were prematurely discontinued. Completion rates varied based on intervention type; 111 pharmaceutical trials demonstrated a completion rate of 83.8%, whereas 19 non-pharmaceutical trials exhibited a completion rate of 8.0% (P < .001). Surgical trials, totaling 10, showed a completion rate of 90%. The overall trial publication rate was 86.15%, with pharmaceutical interventions achieving a publication rate of 91.96%. Larger-scale trials (≥ 261 participants) emerged as a protective factor against both discontinuation (Adjusted Odds Ratio [AOR]: 0.85, 95% Confidence Interval [CI] 0.42–0.95) and nonpublication (AOR: 0.19, 95% CI 0.13–.47), compared to smaller-scale trials.ConclusionThis study accentuates the heightened vulnerability of non-pharmaceutical interventions and trials exhibiting lower rates of enrollment to the issues of discontinuation and nonpublication. Moving forward, the advancement of clinical trials necessitates a concerted effort to enhance trial methodologies, especially concerning nonpharmaceutical interventions, along with a meticulous refinement of participant enrollment criteria.

The death of a neurotrauma trial lessons learned from the prematurely halted randomized evaluation of surgery in elderly with traumatic acute subdural hematoma (RESET-ASDH) trial

IntroductionAcute subdural hematoma (ASDH) due to traumatic brain injury (TBI) constitutes an increasing global health problem, especially in the elderly population. Treatment decisions on surgical versus conservative management pose a neurosurgical dilemma. Large practice variation exists between countries, hospitals, and individual neurosurgeons, illustrating the presence of ‘clinical equipoise’. The RESET-ASDH trial aimed to address this dilemma but was terminated prematurely due to insufficient patient recruitment. Research questionWhat factors may have contributed to the premature discontinuation of the RESET-ASDH trial? Materials and methodsThe RESET-ASDH was a multicenter randomized controlled trial (RCT) comparing functional outcome at 1 year after early surgery or an initial conservative treatment in elderly patients (≥65 years) with a traumatic ASDH. Logs of registry data, medical-ethical approval timelines and COVID-19 related research documents were analyzed. Furthermore, non-structured interviews with involved clinical research personnel were conducted. ResultsThe concept of clinical equipoise was broadly misinterpreted by neurosurgeons as individual uncertainty, hampering patient recruitment. Also, the elderly target population complicated the inclusion process as elderly and their informal caregivers were hesitant to participate in our acute surgical trial. Moreover, the COVID-19 pandemic added additional hurdles like delayed medical-ethical approval, a decline in eligible patients and repeated trial halts during the peaks of the pandemic. Discussion and conclusionThe premature termination of the RESET-ASDH study may have been related to the trial’s methodology and target population with an additional impact of COVID-19. Future acute neurosurgical trials in elderly may consider these challenges to prevent premature trial termination.