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Biomolecules Sep 2023Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor... (Review)
Review
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials.
Topics: Humans; Female; Breast Neoplasms; Progression-Free Survival; Cyclin-Dependent Kinase 4; Clinical Trials, Phase II as Topic
PubMed: 37759823
DOI: 10.3390/biom13091422 -
JCO Clinical Cancer Informatics Jul 2023Matching patients to clinical trials is cumbersome and costly. Attempts have been made to automate the matching process; however, most have used a trial-centric...
PURPOSE
Matching patients to clinical trials is cumbersome and costly. Attempts have been made to automate the matching process; however, most have used a trial-centric approach, which focuses on a single trial. In this study, we developed a patient-centric matching tool that matches patient-specific demographic and clinical information with free-text clinical trial inclusion and exclusion criteria extracted using natural language processing to return a list of relevant clinical trials ordered by the patient's likelihood of eligibility.
MATERIALS AND METHODS
Records from pediatric leukemia clinical trials were downloaded from ClinicalTrials.gov. Regular expressions were used to discretize and extract individual trial criteria. A multilabel support vector machine (SVM) was trained to classify sentence embeddings of criteria into relevant clinical categories. Labeled criteria were parsed using regular expressions to extract numbers, comparators, and relationships. In the validation phase, a patient-trial match score was generated for each trial and returned in the form of a ranked list for each patient.
RESULTS
In total, 5,251 discretized criteria were extracted from 216 protocols. The most frequent criterion was previous chemotherapy/biologics (17%). The multilabel SVM demonstrated a pooled accuracy of 75%. The text processing pipeline was able to automatically extract 68% of eligibility criteria rules, as compared with 80% in a manual version of the tool. Automated matching was accomplished in approximately 4 seconds, as compared with several hours using manual derivation.
CONCLUSION
To our knowledge, this project represents the first open-source attempt to generate a patient-centric clinical trial matching tool. The tool demonstrated acceptable performance when compared with a manual version, and it has potential to save time and money when matching patients to trials.
Topics: Child; Humans; Eligibility Determination; Leukemia; Natural Language Processing; Patient Selection; Patient-Centered Care; Clinical Trials as Topic
PubMed: 37428994
DOI: 10.1200/CCI.23.00009 -
Journal of Clinical Epidemiology Jun 2024The restricted Net Treatment Benefit (rNTB) is a clinically meaningful and tractable estimand of the overall treatment effect assessed in randomized trials when at...
OBJECTIVES
The restricted Net Treatment Benefit (rNTB) is a clinically meaningful and tractable estimand of the overall treatment effect assessed in randomized trials when at least one survival endpoint with time restriction is used. Its interpretation does not rely on parametric assumptions such as proportional hazards, can be estimated without bias even in the presence of independent right-censoring, and can include a prespecified threshold of minimal clinically relevant difference. To demonstrate that the rNTB, corresponding to the NTB during a predefined time interval, is a meaningful and adaptable measure of treatment effect in clinical trials.
METHODS
In this simulation study, we tested the impact on the rNTB value, estimation, and power of several factors including the presence of a delayed treatment effect, minimal clinically relevant difference threshold value, restriction time value, and the inclusion of both efficacy and toxicity in the rNTB definition. The impact of right censoring on rNTB was assessed in terms of bias. rNTB-derived statistical tests and log rank (LR) tests were compared in terms of power.
RESULTS
RNTB estimates are unbiased even in case of right-censoring. rNTB may be used to estimate the benefit/risk ratio of a new treatment, for example, taking into account both survival and toxicity and include several prioritized outcomes. The estimated rNTB is much easier to interpret in this context compared to NTB in the presence of censoring since the latter is intrinsically dependent on the follow-up duration. Including toxicity increases the test power when the experimental treatment is less toxic. rNTB-derived test power increases when the experimental treatment is associated with longer survival and lower toxicity and might increase in the presence of a cure rate or a delayed treatment effect. Case applications on the PRODIGE, Checkmate-066, and Checkmate-067 trials are provided.
CONCLUSIONS
RNTB is an interesting alternative to describe and test the treatment's effect in a clear and understandable way in case of restriction, particularly in scenarios with nonproportional hazards or when trying to balance benefit and safety. It can be tuned to take into consideration short- or long-term survival differences and one or more prioritized outcomes.
Topics: Humans; Randomized Controlled Trials as Topic; Neoplasms; Computer Simulation; Treatment Outcome; Medical Oncology; Survival Analysis; Minimal Clinically Important Difference; Bias
PubMed: 38570079
DOI: 10.1016/j.jclinepi.2024.111340 -
BMJ Open Oct 2023Many adolescents and young adults with emerging mood disorders do not achieve substantial improvements in education, employment, or social function after receiving...
EMPOWERED trial: protocol for a randomised control trial of digitally supported, highly personalised and measurement-based care to improve functional outcomes in young people with mood disorders.
OBJECTIVES
Many adolescents and young adults with emerging mood disorders do not achieve substantial improvements in education, employment, or social function after receiving standard youth mental health care. We have developed a new model of care referred to as 'highly personalised and measurement-based care' (HP&MBC). HP&MBC involves repeated assessment of multidimensional domains of morbidity to enable continuous and personalised clinical decision-making. Although measurement-based care is common in medical disease management, it is not a standard practice in mental health. This clinical effectiveness trial tests whether HP&MBC, supported by continuous digital feedback, delivers better functional improvements than standard care and digital support.
METHOD AND ANALYSIS
This controlled implementation trial is a PROBE study (Prospective, Randomised, Open, Blinded End-point) that comprises a multisite 24-month, assessor-blinded, follow-up study of 1500 individuals aged 15-25 years who present for mental health treatment. Eligible participants will be individually randomised (1:1) to 12 months of HP&MBC or standardised clinical care. The primary outcome measure is social and occupational functioning 12 months after trial entry, assessed by the Social and Occupational Functioning Assessment Scale. Clinical and social outcomes for all participants will be monitored for a further 12 months after cessation of active care.
ETHICS AND DISSEMINATION
This clinical trial has been reviewed and approved by the Human Research Ethics Committee of the Sydney Local Health District (HREC Approval Number: X22-0042 & 2022/ETH00725, Protocol ID: BMC-YMH-003-2018, protocol version: V.3, 03/08/2022). Research findings will be disseminated through peer-reviewed journals, presentations at scientific conferences, and to user and advocacy groups. Participant data will be deidentified.
TRIAL REGISTRATION NUMBER
ACTRN12622000882729.
Topics: Adolescent; Young Adult; Humans; Mood Disorders; Follow-Up Studies; Prospective Studies; Mental Health; Treatment Outcome; Randomized Controlled Trials as Topic
PubMed: 37821139
DOI: 10.1136/bmjopen-2023-072082 -
BMJ Open Dec 2023Attention deficit hyperactivity disorder (ADHD) affects 5%-10% of paediatric population and is reportedly more common in children with type 1 diabetes (T1D),...
Lisdexamphetamine versus methylphenidate for paediatric patients with attention-deficit hyperactivity disorder and type 1 diabetes (LAMAinDiab): protocol for a multicentre, randomised cross-over clinical trial in an outpatient telemedicine-supported setting.
INTRODUCTION
Attention deficit hyperactivity disorder (ADHD) affects 5%-10% of paediatric population and is reportedly more common in children with type 1 diabetes (T1D), exacerbating its clinical course. Proper treatment of ADHD in such patients may thus provide neurological and metabolic benefits. To test this, we designed a non-commercial second phase clinical trial comparing the impact of different pharmacological interventions for ADHD in children with T1D.
METHODS AND ANALYSIS
This is a multicentre, randomised, open-label, cross-over clinical trial in children and adolescents with ADHD and T1D. The trial will be conducted in four reference paediatric diabetes centres in Poland. Over 36 months, eligible patients with both T1D and ADHD (aged 8-16.5 years, T1D duration >1 year) will be offered participation. Patients' guardians will undergo online once-weekly training sessions behaviour management for 10 weeks. Afterward, children will be randomised to methylphenidate (long-release capsule, doses 18-36-54 mg) versus lisdexamphetamine (LDX, 30-50-70 mg). Pharmacotherapy will continue for 6 months before switching to alternative medication. Throughout the trial, the participants will be evaluated every 3 months by their diabetologist and online psychological assessments. The primary endpoint (ADHD symptom severity, Conners 3.0 questionnaire) will be assessed by a blinded investigator. Secondary endpoints will include HbA1c, continuous glucose monitoring indices and quality-of-life (PedsQL).
ETHICS AND DISSEMINATION
The trial is approved by Bioethical Committee at Medical University of Lodz and Polish regulatory agency (RNN/142/22/KE, UR/DBL/D/263/2022). The results will be communicated to the research and clinical community, and Polish agencies responsible for healthcare policy. Patient organisations focused on paediatric T1D will be notified by a consortium member. We hope to use the trial's results to promote collaboration between mental health professionals and diabetes teams, evaluate the economic feasibility of using LDX in patients with both diseases and the long run improve ADHD treatment in children with T1D.
TRIAL REGISTRATION NUMBERS
EU Clinical Trials Register (EU-CTR, 2022-001906-24) and NCT05957055.
Topics: Adolescent; Humans; Child; Attention Deficit Disorder with Hyperactivity; Methylphenidate; Lisdexamfetamine Dimesylate; Diabetes Mellitus, Type 1; Outpatients; Blood Glucose Self-Monitoring; Blood Glucose; Central Nervous System Stimulants; Treatment Outcome; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 38086595
DOI: 10.1136/bmjopen-2023-078112 -
Kidney360 Sep 2023
Topics: Humans; Kidney Diseases; Patient Acuity; Clinical Trials as Topic
PubMed: 37768808
DOI: 10.34067/KID.0000000000000256 -
American Journal of Clinical Dermatology Nov 2023Two phase III trials, ECZTRA 1 and 2, confirmed the efficacy and safety of tralokinumab versus placebo in adults with moderate-to-severe atopic dermatitis (AD). To...
BACKGROUND
Two phase III trials, ECZTRA 1 and 2, confirmed the efficacy and safety of tralokinumab versus placebo in adults with moderate-to-severe atopic dermatitis (AD). To further explore the long-term efficacy of tralokinumab for AD, a pooled analysis of these trials was conducted.
METHODS
ECZTRA 1 and 2 patients (n = 1596 total) were randomized to tralokinumab 300 mg or placebo every 2 weeks (q2w) over 16 weeks. Patients achieving Investigator's Global Assessment of clear/almost clear skin (IGA 0/1) and/or 75% improvement in the Eczema Area and Severity Index (EASI-75) at Week 16, were re-randomized to tralokinumab q2w, every 4 weeks (q4w), or placebo (tralokinumab withdrawal) for another 36 weeks. Patients not achieving the response criteria at Week 16 received open-label tralokinumab q2w plus optional topical corticosteroids (TCS). A pooled, prespecified analysis assessed the proportions of Week 16 responders that maintained IGA 0/1 and/or EASI-75 at Week 52. Pooled data from all patients initiated with tralokinumab, regardless of the response at Week 16 or dosing regimen received thereafter, were analyzed post hoc.
RESULTS
In patients who achieved the primary endpoints at Week 16, IGA 0/1 responses were maintained at Week 52 without rescue treatment (including TCS) by 55.9%, 42.4%, and 34.0% of patients re-randomized to tralokinumab q2w, q4w, or placebo (tralokinumab withdrawal), respectively, while EASI-75 responses were maintained by 57.3%, 50.4%, and 26.4%, respectively (prespecified analysis). In a post hoc analysis of all patients initiated with tralokinumab, response rates improved over time with continued tralokinumab treatment beyond Week 16 to Week 52 for EASI-50 (63.1-82.7%), EASI-75 (37.6-61.8%), EASI-90 (20.4-37.3%), and IGA 0/1 (23.0-36.2%).
CONCLUSIONS
Tralokinumab treatment provides progressive and sustained improvement over 1 year in the extent and severity of AD in patients with moderate-to-severe AD.
CLINICAL TRIAL REGISTRATION
NCT03131648 (ECZTRA 1); study start date: 30 May 2017; primary completion date: 7 August 2018; study completion date: 10 October 2019. NCT03160885 (ECZTRA 2); study start date: 12 June 2017; primary completion date: 4 September 2019; study completion date: 14 August 2019. INFOGRAPHIC.
Topics: Adult; Humans; Antibodies, Monoclonal, Humanized; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Glucocorticoids; Immunoglobulin A; Injections, Subcutaneous; Severity of Illness Index; Treatment Outcome; Clinical Trials, Phase III as Topic; Randomized Controlled Trials as Topic
PubMed: 37682422
DOI: 10.1007/s40257-023-00806-3 -
BMJ Open Sep 2023spp is responsible for 8%-15% of total bacteraemias with an associated global mortality around 23%-30%. Regarding the clinical management of enterococcal bacteraemia,...
Randomised, open-label, non-inferiority clinical trial on the efficacy and safety of a 7-day vs 14-day course of antibiotic treatment for uncomplicated enterococcal bacteraemia: the INTENSE trial protocol.
INTRODUCTION
spp is responsible for 8%-15% of total bacteraemias with an associated global mortality around 23%-30%. Regarding the clinical management of enterococcal bacteraemia, the evidence on the duration of antibiotic treatment is scarce and the studies do not discriminate between complicated and uncomplicated bacteraemia.
METHODS
The INTENSE study is a multicentre, open-label, randomised, pragmatic, phase-IV clinical trial to demonstrate the non-inferiority of a 7-day vs 14-day course for the treatment of uncomplicated enterococcal bacteraemia and incorporating the early switching to oral antibiotics when feasible. The primary efficacy endpoint is the clinical cure at day 30±2 after the end of the treatment. Secondary endpoints will include the rate of relapse or infective endocarditis, length of stay, duration of intravenous therapy, infection and the evaluation of the safety of both treatment arms through the recording and analysis of adverse events. For a 6% non-inferiority margin and considering a 5% withdrawal rate, 284 patients will be included.
ANALYSIS
The difference in proportions with one-sided 95% CIs will be calculated for the clinical cure rate using the control group as reference. For secondary categorical endpoints, a similar analysis will be performed and Mann-Whitney U-test will be used to compare median values of quantitative variables. A superiority analysis applying the response adjusted for days of antibiotic risk will be performed if there were incidents in recruitment; will allow obtaining results with 194 patients recruited.
ETHICS AND DISSEMINATION
The study has obtained the authorisation from the Spanish Regulatory Authority, the approval of the ethics committee and the agreement of the directors of each centre. Data will be published in peer-reviewed journals.
TRIAL REGISTRATION NUMBER
NCT05394298.
Topics: Humans; Bacterial Infections; Bacteremia; Anti-Bacterial Agents; Endocarditis; Control Groups; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase IV as Topic
PubMed: 37673453
DOI: 10.1136/bmjopen-2023-075699 -
BMC Cancer Oct 2023Laparoscopic gastrectomy (LG) is considered a standard treatment for clinical stage I gastric cancer. Nevertheless, LG has some drawbacks, such as motion restriction and...
Randomized controlled phase III trial to investigate superiority of robot-assisted gastrectomy over laparoscopic gastrectomy for clinical stage T1-4aN0-3 gastric cancer patients (JCOG1907, MONA LISA study): a study protocol.
BACKGROUND
Laparoscopic gastrectomy (LG) is considered a standard treatment for clinical stage I gastric cancer. Nevertheless, LG has some drawbacks, such as motion restriction and difficulties in spatial perception. Robot-assisted gastrectomy (RG) overcomes these drawbacks by using articulated forceps, tremor-filtering capability, and high-resolution three-dimensional imaging, and it is expected to enable more precise and safer procedures than LG for gastric cancer. However, robust evidence based on a large-scale randomized study is lacking.
METHODS
We are performing a randomized controlled phase III study to investigate the superiority of RG over LG for clinical T1-2N0-2 gastric cancer in terms of safety. In total, 1,040 patients are planned to be enrolled from 46 Japanese institutions over 5 years. The primary endpoint is the incidence of postoperative intra-abdominal infectious complications, including anastomotic leakage, pancreatic fistula, and intra-abdominal abscess of Clavien-Dindo (CD) grade ≥ II. The secondary endpoints are the incidence of all CD grade ≥ II and ≥ IIIA postoperative complications, the incidence of CD grade ≥ IIIA postoperative intra-abdominal infectious complications, relapse-free survival, overall survival, the proportion of RG completion, the proportion of LG completion, the proportion of conversion to open surgery, the proportion of operation-related death, and short-term surgical outcomes. The Japan Clinical Oncology Group Protocol Review Committee approved this study protocol in January 2020. Approval from the institutional review board was obtained before starting patient enrollment in each institution. Patient enrollment began in March 2020. We revised the protocol to expand the eligibility criteria to T1-4aN0-3 in July 2022 based on the results of randomized trials of LG demonstrating non-inferiority of LG to open surgery for survival outcomes in advanced gastric cancer.
DISCUSSION
This is the first multicenter randomized controlled trial to confirm the superiority of RG over LG in terms of safety. This study will demonstrate whether RG is superior for gastric cancer.
TRIAL REGISTRATION
The protocol of JCOG1907 was registered in the UMIN Clinical Trials Registry as UMIN000039825 ( http://www.umin.ac.jp/ctr/index.htm ). Date of Registration: March 16, 2020. Date of First Participant Enrollment: April 1, 2020.
Topics: Humans; Stomach Neoplasms; Robotics; Treatment Outcome; Robotic Surgical Procedures; Gastrectomy; Postoperative Complications; Laparoscopy; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Clinical Trials, Phase III as Topic
PubMed: 37845660
DOI: 10.1186/s12885-023-11481-2 -
Medicine Aug 2023Tezepelumab is a human thymic stromal lymphopoietin (TSLP) antibody with effects in asthma. Therefore, our study aimed to evaluate the overall efficacy and safety of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Tezepelumab is a human thymic stromal lymphopoietin (TSLP) antibody with effects in asthma. Therefore, our study aimed to evaluate the overall efficacy and safety of tezepelumab for the treatment of uncontrolled asthma.
METHODS
The databases Cochrane Library, PubMed, Embase, Web of Science, and Clinical Trials were searched from inception to April 1, 2022. Only randomized controlled trial (RCTs) that evaluated tezepelumab and a comparator for treating uncontrolled asthma were included. Additionally, articles were limited to English. The primary outcome was clinical efficacy, and the secondary outcome was adverse events. The risk of bias and quality were assessed by the Cochrane Collaboration bias assessment tool. The meta-analysis was performed using Review Manager Version 5.3.
RESULTS
Four RCTs with a total of 1600 patients were included in the study. Pooled analysis indicated that tezepelumab had significantly decreased annualized asthma exacerbations (odds ratio [OR] = 0.67, 95% confidence interval [CI] = [0.57, -0.80], P < .00001) and the asthma control questionnaire score of 6 (ACQ-6) among the patients (standard mean difference [SMD] = -0.29, 95% CI = [-0.39, -0.20], P < .00001) compared to placebo. Furthermore, tezepelumab treatment significantly improved forced expiratory volume in 1 second (FEV1, SMD = 0.28, 95% CI = [0.11, 0.45], P = .001). Regarding safety, the pooled analysis indicated that patients treated with tezepelumab showed no significant difference in adverse events that led to discontinuation of the treatment, but they experienced some other (non-serious) adverse events compared to the placebo group. However, there was a significant decrease in the incidence of serious adverse events and any adverse events in the tezepelumab group. Tezepelumab use was associated with adverse events, including nasopharyngitis, headache, and bronchitis, despite effectively treating asthma.
CONCLUSION
Tezepelumab effectively improved FEV1, reduced the disease symptom score, and decreased the risk of exacerbations in uncontrolled asthma patients. Tezepelumab was associated with some adverse events compared to placebo. This suggests that careful management of adverse events is required if tezepelumab is used to treat asthma patients.
Topics: Humans; Randomized Controlled Trials as Topic; Asthma; Antibodies, Monoclonal, Humanized; Treatment Outcome
PubMed: 37565847
DOI: 10.1097/MD.0000000000034746