Discontinuation Trial Research Articles

Perceived Impact on Alzheimer's Disease Clinical Trial Participants After Study Termination

<h3>Introduction</h3> Many pharmaceutical companies are working to identify novel treatments to slow or stop the progression of Alzheimer's Disease (AD), which they test through use of multi-site clinical trials. The Geriatric Psychiatry Research Program at McLean Hospital has been a study site in 8 clinical trials over the past 10 years, enrolling over 30 participants and their caregivers, or study partners. During the monthly, multi-hour study visits, McLean study staff accompanied participants and study partners and thus became familiar with the patient's clinical care. Two of the disease-modifying clinical trials conducted at McLean between 2012 and 2019 were terminated by the sponsors after interim analyses revealed study endpoints were not being met. Participants at McLean were immediately discontinued and required to stop infusions of study drug (or placebo) in both placebo-controlled and long-term extension phases of the trials. This abrupt discontinuation broke the pattern of regular study visits and consistent care the participants and study partners had come to expect, especially for those who had been involved in the same study for over 6 years. This observational, qualitative study seeks to examine the effects of study termination on participants and study partners and to provide insight into potential benefits of regular interaction with a consistent research care team. The primary goals of this study are to identify and characterize the impact that sponsor-initiated Alzheimer's clinical trial termination had on participants and their caregivers at McLean Hospital. <h3>Methods</h3> Study aims were accomplished by collecting mood, memory, function, and study satisfaction surveys from participants or study partners who were enrolled in Eli Lilly's LZAO, Eli Lilly's LZAX, or Biogen's Emerge trials at McLean when discontinued. For this one-time study visit, 7 subject and 8 caregiver surveys were administered to eligible individuals. Participants were asked to reflect on their experiences and mood at the time of study termination, 4-weeks after termination, and at the time of this visit. We evaluated qualitative trends in reported changes in mood, memory, function, social support and overall study experience for former subjects and caregivers. <h3>Results</h3> There were 17 participants enrolled in the study - 12 caregivers and 5 subjects. Caregivers reported that the aspects of trial participation they valued most were social interactions with staff, sense of giving back by contributing to AD research, feelings of hope related to trial participation, access to medical knowledge and experts, consistent health monitoring and structure from scheduled visits, and the safe space created to talk about AD. Caregivers tended to disagree when asked if they had less social contact with others following study termination but were more likely to agree that their study partner had less social contact with others following termination. When asked what resources they hoped would be available but were not offered at study termination, 4 caregivers wished they had longitudinal information about testing, specifically the amyloid PET scan data. Multiple caregivers wished the sponsor had provided more information about the rationale for study termination and offered other trial options or support resources. The majority of caregivers would have appreciated more help getting enrolled in other trials. Participants valued the social interaction with and quality of staff, transparent communication, interaction with experts, feeling more connected to others, and the hope of potential benefit from the study medication. Like caregivers, participants desired more specific information about their results and brain amyloid status and wished there had been additional clinical support offered at trial termination, such as facilitated group discussions with other participants. Two caregivers and one participant mentioned that the relationship between the sponsor and site should be closer for a better flow of information. Subjects and caregivers expressed feelings of disappointment, frustration, anger, and sadness at the abrupt ending of the trial, and two caregivers said they would not enroll another family member in a placebo-controlled trial. <h3>Conclusions</h3> Termination of a clinical trial had a significant qualitative impact on both participants and caregivers who were enrolled. Two themes, empowerment and support, emerged regarding the meaning of trial participation to subjects and study partners. When trials were ended abruptly, participants and caregivers were left without a source for the sense of empowerment and support previously provided by study participation. Increased attention should be directed to services provided by both the sponsor and site at the time of termination. Sponsors and study sites should focus on providing resources for emotional support and information to participants and study partners to ease negative feelings that may arise with trial discontinuation. <h3>This research was funded by</h3> Unfunded.

Monoclonal antibody BTT1023 targeting vascular adhesion protein 1 for treating primary sclerosing cholangitis: BUTEO single-arm Phase II trial

Background Primary sclerosing cholangitis is a progressive and fibrotic liver disease. Treatments remain inadequate, and patients with persistent elevations in activity of alkaline phosphatase are at greatest risk of disease progression. Studies in patient cohorts have implicated the serum amine oxidase vascular adhesion protein 1 in the pathophysiology of disease, including liver fibrogenesis. We hypothesised that blockade of serum amine oxidase by a monoclonal antibody would result in a reduction in liver fibrosis/injury, as evaluated by serum liver tests and other non-invasive markers of liver injury. Objectives To evaluate the open-label effect on liver injury markers of treatment with the anti-vascular adhesion protein 1 monoclonal antibody BTT1023 in patients with primary sclerosing cholangitis over a 78-day treatment period. Design A single-arm, two-stage, open-label, multicentre, Phase II clinical trial. Setting Ambulatory liver disease practices in tertiary care hospitals. Participants Patients with primary sclerosing cholangitis at risk of disease progression, based on elevated activity of serum alkaline phosphatase, and without evidence of infection, liver failure or advanced disease. Intervention Seven intravenous infusions of BTT1023 (8 mg/kg of timolumab) over a 78-day treatment period. The intervention was split into a dose-confirmatory stage (to confirm pharmacokinetics), followed by a confirmed expansion cohort stage. Main outcome measures Our primary outcome measure was patient response to treatment at day 99, measured by a reduction in activity of serum alkaline phosphatase of ≥ 25% from baseline to day 99. Secondary markers of efficacy were assessed based on evaluation of changes in markers of liver injury and liver fibrosis. Safety assessments were performed throughout. Results Thirty-five patients were consented and screened for eligibility. Twenty-three patients were treated across the two stages of the trial. Interim assessment demonstrated a failure to meet the primary end point, leading to trial discontinuation on the grounds of futility. Multiple exploratory markers were evaluated in a final cohort of 22 patients (modified intention-to-treat analysis). No treatment-related effects were evident. No new safety concerns were seen. Conclusions No preliminary evidence for disease modification was demonstrated. Limitations It is clear that this study is limited in its design. Even if there were a better biomarker of fibrosis turnover that could be considered the ‘gold standard’, the design and duration would have had real-world resource limitations. With limited opportunity to test a new agent in large numbers of patients over a prolonged period, it was necessary to aim to see efficacy in a small cohort over a short period. Given the absence of any proven biochemical surrogate of disease activity in primary sclerosing cholangitis, alkaline phosphatase was chosen as an end point. This remains a difficult end point (yet one that does capture biliary injury) and, therefore, despite limitations, this study did demonstrate short-term safety. Future work Future research will require attention to an ongoing debate regarding the optimal end points for assessing efficacy, as well as consideration of duration of treatment, even in early-phase studies. This raises the challenge of how to fund early experimental trials with ‘high risk of failure’ adequately to ensure that clearer results (negative or positive) arise by the end of the study. Trial registration Current Controlled Trials ISRCTN11233255, EudraCT 2014-002393-37 and NCT02239211. Funding This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 1. See the NIHR Journals Library website for further project information.

Investigators' sense of failure thwarted transparency in clinical trials discontinued for poor recruitment

Background and ObjectiveWhen a randomized clinical trial (RCT) prematurely discontinues, it is essential that stakeholders do the right thing to ensure that lessons can be learnt and trust in clinical research is maintained. There is, however, a lack of evidence exploring this issue. This study aimed to examine clinical trial stakeholders’ practices following trial discontinuation due to poor participant recruitment and their views on implications of such discontinuation. MethodsIndividual semi-structured qualitative interviews were conducted with 49 clinical trial stakeholders from Switzerland (n = 39), Germany (n = 9) and Canada (n = 1) between August 2015 and November 2016. ResultsAfter interviews with 49 clinical trial stakeholders (75% male presenting), it was found that stakeholders were aware of the risks of premature trial discontinuation wasting limited resources, adversely impacting scientific evidence, and having negative personal and professional implications. However, barriers continue to undermine transparency regarding trial discontinuation in practice, with it being reported that most investigators of discontinued trials are failing to notify stakeholders or publishing their results. Investigators sense of failure and associated negative emotions were identified as a key reason why investigators are not more transparent following discontinuation. ConclusionThe decision to notify stakeholders and publish results of a discontinued clinical trial should not rest solely on individual investigators but come from a systemic approach. However, until health research proactively requires the dissemination of results of all clinical trials, much will rest on individual investigators being motivated to do the right thing. Support programs might be helpful for investigators involved in discontinued trials and promote transparency and learning lessons.

The use of telecommunication and virtualization among ongoing and discontinued COVID-19 clinical trials: A cross-sectional analysis

ImportanceThe COVID-19 pandemic has impacted clinical research due to safety measures such as social distancing and lockdowns. However, developing treatments for COVID-19 relies on conducting clinical trials. Using telemedicine or virtual methods may support ongoing trials and limit the pandemic's impact on clinical research. ObjectiveTo examine the use of virtual methods among ongoing and discontinued COVID-19 clinical trials. DesignIn this cross-sectional analysis, we performed a systematic search of ClinicalTrials.gov for COVID-19 related trials registered since the pandemic began. In masked, duplicate fashion, authors extracted data from included studies, noting whether trialists reported using telecommunication, virtualization, or remote data collection to deliver interventions and monitor outcome measures. The authors also coded the use of virtual methods for recruitment, enrollment, or follow-up visits. Chi-square tests and Kruskal-Wallis tests were used to assess differences in the use of virtual methods between ongoing and discontinued studies and differences between intervention types. ResultsOur search returned 2549 clinical trials, of which 2383 were included. Of included studies, 2109 (88.5%) were ongoing and 274 (11.5%) were discontinued. Overall, 519 (24.6%) ongoing COVID-19 trials reported using virtual methods for trial conduct and 43 (15.7%) discontinued trials reported using virtual methods. There was a statistically significant difference in the rate of reporting virtual methods between discontinued and ongoing trials (X21 = 27.2, P < .001). Studies listed as Behavioral or Other were more likely to report using virtual methods for delivering interventions compared to other intervention types (X21 = 751.88, P < .001). Conclusions and relevanceThe COVID-19 pandemic has presented an unprecedented need for safe and efficient clinical trial conduct. Nearly a quarter of ongoing COVID-19 clinical trials in our sample reported using virtual methods for supporting trial progress. Ongoing trials were more likely to report virtual methods compared to discontinued trials. Developing strategies that allow for continuing trials during emergencies may limit trial disruption. Exploring and developing remote trial methods may continue to be valuable in light of emerging COVID-19 variants and may persist beyond the pandemic.

Access to early-phase clinical trials for children with relapsed and refractory neuroblastoma: A multicentre international study.

Neuroblastoma is the most common extracranial tumour in children, and prognosis for refractory and relapsed disease is still poor. Early-phase clinical trials play a pivotal role in the development of novel drugs. Ensuring adequate recruitment is crucial. The primary aim was to determine the rate of participation trials for children with refractory/relapsed neuroblastoma in two of the largest drug development European institutions. Data from patients diagnosed with refractory/relapsed neuroblastoma between January 2012 and December 2018 at the two institutions were collected and analysed. Overall, 48 patients were included. A total of 31 (65%) refractory/relapsed cases were enrolled in early-phase trials. The main reasons for not participating in clinical trials included not fulfilling eligibility criteria prior to consent (12/17, 70%) and screening failure (2/17, 12%). Median time on trial was 4.3months (range 0.6-13.4). Most common cause for trial discontinuation was disease progression (67.7%). Median overall survival was longer in refractory (28months, 95% CI: 20.9-40.2) than in relapsed patients (14months, 95% CI: 8.1-20.1) (p=.034). Although two thirds of children with refractory/relapsed neuroblastoma were enrolled in early-phase trials, recruitment rates can still be improved. The main cause for not participating on trials was not fulfilling eligibility criteria prior to consent, mainly due to performance status and short life expectancy. This study highlights the hurdles to access to innovative therapies for children with relapsed/refractory neuroblastomas, and identifies key areas of development to improve recruitment to early-phase trials.

Rates of discontinuation and non-publication of trials for the pharmacologic treatment of alcohol use disorder

Objective: With approximately 15 million individuals in the United States meeting criteria for Alcohol Use Disorder (AUD), advancing effective medication-assisted treatment options is crucial. This advancement stems from the publication of clinical trial (CT) results. The primary objective of this study was to assess the rates of discontinuation and non-publication of results in CTs focused on the pharmacologic treatment of AUD and to assess associated factors. Design: A cross-sectional study was completed after acquiring trials focused on AUD within the ClinicalTrials.gov database. Inclusion criteria for CTs were the use of a pharmaceutical intervention with an outcome measure of alcohol intake or craving, conducted between October 2008 through September 2018. The primary outcome measures were the frequency of trial discontinuation and non-publication. Discontinuation was assessed as the listed status on ClinicalTrials.gov. Publications were identified through verification of listings on ClinicalTrials.gov, or via searches of PubMed, Embase, and Google Scholar. If publications were not found, correspondence to trial contacts were sent. Data analysis occurred on December 5th, 2020. Results: Of 235 trials returned from the search, 87 met inclusion criteria. Our study found that 12.6% (11) of CTs involving pharmaceutical treatments for AUD were prematurely terminated, and 39.1% (34) had no published results. Recruitment and lower cutoff of targeted age groups were significantly associated with discontinuation and non-publication, respectively. Conclusions: Scientific evidence advances faster when all results are known—furthering the progress of positive studies, while avoiding duplicative efforts to test the same hypotheses with the same methods, thereby reducing scientific waste. Given the number of unpublished AUD trials, potentially useful information regarding treatment for individuals with AUD may be inaccessible to clinicians while also adding to the abundance of research waste. Key points Question: What are the rates of discontinuation or non-publication of clinical trials for pharmacological treatments for AUD and associated factors? Findings: Among 87 trials, 11 (12.6%) were prematurely terminated and 34 (39.1%) did not reach publication, with trials that included participants 21 years and older more likely to reach publication than those with younger participants. Meaning: Low publication rates of CTs for pharmacological treatments of AUD may (1) stunt the advancement of AUD research, (2) decrease the value in funding AUD research from government entities, and (3) needlessly expose participants to potentially harmful interventions.

Multiple Sclerosis: What We Can Learn Even from Failed Approaches to Antibody Therapies

In recent years, the revolutionary effects of monoclonal antibodies on the immune response of patients with multiple sclerosis have been studied extensively. Researchers can gain important insights even from failed or discontinued trials. Yet valuable lessons may be lost when so-called “negative” studies do not publish their results.

Is there resource wastage in the research for spinal diseases? An observational analysis of discontinuation and non-publication in randomised controlled trials

IntroductionThe scale of waste in research funding systems is large and detrimental to research capacity. Both incompleteness and non-publication of Randomised Controlled Trials (RCTs) have been increasingly reported in the literature. This is a serious consequence as RCTs demand monumental amounts of healthcare resources leading to wastage. Most importantly, both under-reporting and non-publication can distort the evidence landscape and obscure rationale behind clinical decisions. Research questionWe, therefore, aimed at conducting the first systematic assessment of registered trial discontinuation and non-publication in the field of spinal disorders. Material and methodsA list of RCTs was obtained from the U.S National Library of Medicine ClinicalTrials.gov database from January 1st, 2013, to December 31st, 2020. Two independent authors excluded all non-RCTs, trials unrelated to spinal diseases, and trials that are in or before the recruitment phase. We extracted the progress status, sources of funding, the number of centres, type of intervention, principal investigator's department affiliation, publication status, location, the reason for discontinuation, publication date, and subtopics. Results112 trials were included in the study. 25 (22%) trials were discontinued early, with slow recruitment being the major reason (38%). Only 56 (50%) of the trials were published in peer-reviewed journals. The publication rate amongst discontinued trials was significantly lower compared to completed trials (P ​< ​0·001). The trial discontinuation rate was much higher in trials registered in the United States (US) compared to other countries (P ​= ​0·009). Industry-sponsored studies had 11 trials (23·4%) that were discontinued whilst there was 20% of non-industry-sponsored studies that were unfinished. Only 20% of the trials were compliant with the FDA reporting requirements over the study period. Discussion and conclusionNearly a quarter of all trials in spinal disorders were discontinued. Half of the trials were unpublished. There was over a third of trials that were completed but not published. These rates remain worrisome from an ethical and financial perspective. Both under-reporting and non-publication adversely affect efforts in evidence synthesis and can compromise clinical guideline development.

Multiple Sclerosis: What We Can Learn Even from Failed Approaches to Antibody Therapies

In recent years, the revolutionary effects of monoclonal antibodies on the immune response of patients with multiple sclerosis have been studied extensively. Researchers can gain important insights even from failed or discontinued trials. Yet valuable lessons may be lost when so-called “negative” studies do not publish their results.

Management of Psychiatric Disorders during the Perinatal Period.

Management of Psychiatric Disorders during the Perinatal Period.

The TKI Era in Chronic Leukemias.

Tyrosine kinases are proteins involved in physiological cell functions including proliferation, differentiation, and survival. However, the dysregulation of tyrosine kinase pathways occurs in malignancy, including hematological leukemias such as chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Particularly, the fusion oncoprotein BCR-ABL1 in CML and the B-cell receptor (BCR) signaling pathway in CLL are critical for leukemogenesis. Therapeutic management of these two hematological conditions was fundamentally changed in recent years, making the role of conventional chemotherapy nearly obsolete. The first, second, and third generation inhibitors (imatinib, dasatinib, nilotinib, bosutinib, and ponatinib) of BCR-ABL1 and the allosteric inhibitor asciminib showed deep genetic and molecular remission rates in CML, leading to the evaluation of treatment discontinuation in prospective trials. The irreversible BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib, tirabrutinib, and spebrutinib) covalently bind to the C481 amino acid of BTK. The reversible BTK inhibitor pirtobrutinib has a different binding site, overcoming resistance associated with mutations at C481. The PI3K inhibitors (idelalisib and duvelisib) are also effective in CLL but are currently less used because of their toxicity profiles. These tyrosine kinase inhibitors are well-tolerated, do have some associated in-class side effects that are manageable, and have remarkably improved outcomes for patients with hematologic malignancies.

Characterization of amyloid‐related imaging abnormality in the DIAN‐TU‐001 trial

AbstractBackgroundAmyloid‐related imaging abnormalities (ARIA), edema (E) or hemorrhagic (H) type, have been reported in trials of anti‐β‐amyloid passive immunotherapies in sporadic and dominantly inherited Alzheimer Disease (DIAD). However, beyond APOE‐ɛ4 the risk factors and clinical implications of ARIA are not well understood, especially in DIAD populations. Here we characterize ARIA, focusing on ARIA‐E in the DIAN‐TU‐001 trial evaluating gantenerumab and solanezumab in DIAD.MethodThe DIAN‐TU‐001 trial enrolled 194 participants, including 144 DIAD mutation‐carriers receiving gantenerumab (n=52), solanezumab (n=52), or a placebo (n=40). Clinical assessments included the Clinical Dementia Rating (CDR). Imaging assessments included PiB‐PET and safety MR, including T2‐FLAIR and T2*‐GRE. Treatment dosage and APOE‐ɛ4 status were also reported.ResultEleven participants developed a total of 14 ARIA‐E episodes (discovered on scheduled safety MR) and three had associated mild symptoms reported in retrospect (e.g. headache, imbalance disorder). Though one ARIA‐E case was observed in the solanezumab arm, the following results focus on the gantenerumab arm to prevent unblinding. Recipients of gantenerumab were more likely to develop ARIA‐E compared to placebo (odds ratio (OR)=9.29, 95% confidence interval (CI)=[1.1,75.9], p‐value&lt;0.05). ARIA‐E participants were PiB‐PET+ and 60% were CDR&gt;0. APOE‐ɛ4 tends to be associated with risk for developing ARIA‐E (OR=5.0, 95%CI=[1.0,30.4], p‐value=0.055). ARIA‐E were not observed at initial 225mg dose and were first observed after a titration step (within 4‐24 weeks, after 1‐6 injections, Table 1). Time‐to‐resolution of ARIA‐E was 10.4±6.2weeks. Seven of ten ARIA‐E patients paused/reduced dose escalation and three discontinued treatment. Overall, developing ARIA‐E did not increase the odds of trial discontinuation (OR=1.57, 95%CI=[0.34,7.33], p‐value=0.57). ARIA‐E occurred primarily in the occipital lobe (71%) with associated incident ARIA‐H (microhemorrhages or superficial siderosis) in 60% of ARIA‐E participants. ARIA‐E size was associated with microhemorrhage count (Spearman’s rho=0.72, p‐value&lt;0.05), rate of change (rho=0.78, p‐value&lt;0.01), and baseline PiB‐PET (rho=0.68, p‐value&lt;0.05). Normalizing by baseline, PiB‐PET decreased similarly in ARIA‐E+ (‐0.21±0.20) and ARIA‐E‐ (‐0.16±0.20) participants.ConclusionIn DIAD, gantenerumab dose over 225mg increased ARIA‐E risk, possibly more for APOE‐ɛ4 carriers. ARIA‐E was reversible, generally asymptomatic, and without increased odds of trial discontinuation. These aspects of drug response give insights for managing ARIA‐E occurrence in future trials.

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

BackgroundConvalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX).MethodsIn this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence.ResultsA total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis.ConclusionsConvalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.

General characteristics and reasons for the discontinuation of drug clinical trials in mainland China

BackgroundAlthough discontinuation is common in clinical trials, no study has been conducted to analyse the current situation and reasons for the suspension or discontinuation of drug clinical trials in China. This study aims to analyse the general characteristics and reasons for the discontinuation of registered clinical trials in mainland China and to identify the associated factors.MethodsWe conducted a cross-sectional observational study of discontinued trials registered in the Drug Trial Registration and Information Publication Platform before March 31, 2020. All trials with a status of terminated or stopped recorded in the platform were classified as discontinued trials and included in the analysis. The basic characteristics of the discontinued trials were recorded, reasons for trial discontinuation were recorded and divided into 4 categories as drug development strategy, trial planning, trial conduct and studied drug. Pearson’s chi-square test and fisher’s exact test were used to compare the differences in reasons for discontinuation between neoplasm trials and non-neoplasm trials, and to examine the associations of trial characteristics with different reasons related to trials discontinuation.ResultsThree hundred twelve discontinued trials were included in this study. The studied drugs were mainly chemical drugs [229 (73.4%)], and indications of the studied drugs were mainly neoplasms [77 (24.7%)]. Geographical location of the discontinued trials were mostly in northern [114 (36.5%)] and eastern [96 (30.8%)] China. Study type of the included trials was mainly bioequivalence studies [97 (31.1%)]. The most common reason for trial discontinuation was commercial or strategic decision [84 (26.9%)], followed by futility/lack of efficacy [70 (22.4%)]. The number of trial centers, sample size and whether participants had been enrolled were significantly associated with trial discontinuation (P < 0.05). Multiple center trials showed a higher rate of trial discontinuation due to trial conduct related reasons than single center trials (P < 0.05), trials with sample size > 500 showed a higher rate of trial discontinuation due to studied drug related reasons (P < 0.05), and trials enrolled participants showed a lower rate of trial discontinuation due to commercial or strategic decision and a higher rate of trial discontinuation due to studied drug related reasons than trials without enrolled participants (P < 0.05). Besides, neoplasm trials showed a higher rate of trial discontinuation due to poor recruitment and safety comparing with non-neoplasm trials (P < 0.05).ConclusionsTrial discontinuation in China mainly occurred because of commercial or strategic decision and futility/lack of efficacy of the studied drug. Clinical trials with multiple centers and a large sample size may more likely be discontinued due to trial conduct related reasons such as good clinical practice. Discontinuation due to drug safety and lack of efficacy in multiple center trials with a large sample size deserves more attention to avoid resources wastes. Full communication with regulatory authorities such as Center for Drug Evaluation and research institutes to develop a feasible protocol is important for sponsors to avoid trial discontinuation due to protocol issues.

Discontinuation and nonpublication of pediatric otolaryngology clinical trials

ObjectivesRandomized controlled trial (RCT) discontinuation and nonpublication are potential mechanisms of waste in resources and lead to decreased advancement of medical science and compromised ethical issues in all specialties. However, the prevalence of discontinued or unpublished RCTs regarding common pediatric otolaryngology disorders and interventions remains unclear. Study designCross-sectional analysis. MethodsRetrospective analysis of common pediatric otolaryngology RCTs registered in ClinicalTrials.gov up until November 2, 2018. Data were collected from the registry, and publication status was identified. If a reason for trial discontinuation or nonpublication was not identified through a systematic search, corresponding trialists were contacted through email. ResultsAfter exclusion, 260 RCTs were included for analysis. Analysis found 198 (76%) RCTs were completed, and 62 (24%) trials were discontinued. The most commonly reported reasons for RCT discontinuation were program termination by sponsor or management (7/24; 29.2%), lack of participant enrollment, difficulty recruiting, or slow accrual (7/24; 29.2%). A total of 192 (192/260; 73.8%) published RCTs and 68 (68/260; 26.2%) unpublished RCTs were identified. Twenty-six (26/62; 42%) of the discontinued RCTs reached publication, while 36 (58%) remained unpublished. Regarding the completed RCTs, 166 of 198 (83.8%) completed trials reached publication, while 32 (32/198; 16.2%) remained unpublished after trial completion. ConclusionsApproximately 1 in 4 of included RCTs were discontinued or did not reach publication. Findings suggest further guidance is needed for RCTs regarding common pediatric otolaryngology disorders and interventions. Level of evidenceNA.

Nilotinib and Dasatinib Evoked Distinct Immune Effects during Tfr Phase of Each Discontinuation Trial

Nilotinib and Dasatinib Evoked Distinct Immune Effects during Tfr Phase of Each Discontinuation Trial

Safety and Efficacy of Tinostamustine in Heavily Pre-Treated Patients with Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)

Safety and Efficacy of Tinostamustine in Heavily Pre-Treated Patients with Relapsed/Refractory (R/R) Hodgkin Lymphoma (HL)

Second Treatment Free Remission after Combination Therapy with Ruxolitinib Plus Tyrosine Kinase Inhibitors in Chronic Phase Chronic Myeloid Leukemia (CML)

Second Treatment Free Remission after Combination Therapy with Ruxolitinib Plus Tyrosine Kinase Inhibitors in Chronic Phase Chronic Myeloid Leukemia (CML)

Updated Efficacy of Eltanexor Monotherapy in Patients with Higher Risk Hypomethylating Myelodysplastic Syndrome Primary Refractory to Hypomethylating Agents

Updated Efficacy of Eltanexor Monotherapy in Patients with Higher Risk Hypomethylating Myelodysplastic Syndrome Primary Refractory to Hypomethylating Agents

A randomized, phase II trial of adjuvant immunotherapy with durable TKI-free survival in patients with chronic phase CML

PurposeChronic myeloid leukemia (CP-CML) patients can achieve undetectable minimal residual disease (UMRD) and discontinue tyrosine kinase inhibitors (TKIs). Cellular immunity plays an important role in CML disease control. We conducted a randomized, non-blinded phase II trial of adjuvant immunotherapy with TKIs to facilitate TKI discontinuation. MethodsTKI-treated patients with CP-CML were randomized to receive the K562/GM-CSF vaccine (vaccine) OR Interferon-α + Sargramostim (IFN). If UMRD was achieved, then all treatment was stopped. Patients who did not achieve UMRD within one year, had a molecular relapse, or discontinued therapy for toxicity could crossover. ResultsThirty-four patients were randomized to IFN (n = 18) or vaccine (n = 16), and 21 patients crossed over (IFN⟶vaccine: n = 9, vaccine⟶IFN, n = 12). TKIs at enrollment included imatinib (n = 31), nilotinib (n = 2), and dasatinib (n = 1). No patients discontinued vaccine due to side effects, while 33 % of IFN-treated patients discontinued treatment. More patients randomized to IFN (47.4 %, 95 % CI: 16.7–66.7 %) versus vaccine (25.0 %, 95 % CI: 0.5–43.5 %) achieved UMRD within one year. Seven patients randomized to IFN discontinued treatment with 28.6 % (95 % CI: 8.9–92.2 %) sustaining treatment-free remission (TFR) at 1 year, while three patients randomized to vaccine discontinued treatment with none sustaining TFR. Including crossover, there was a cumulative discontinuation success rate of 36.4 % (95 % CI: 16.6 %–79.5 %) after adjuvant IFN. Patients who sustained TFR received a median of 29 months of imatinib prior to discontinuation. ConclusionAdjuvant IFN led to durable TFRs with limited prior TKI exposure with comparable success to prior discontinuation trials, but many patients stopped IFN early.