Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 18 appraisals
Lancet (London, England)
Atrasentan in patients with IgA nephropathy (ALIGN): final 2·5-year results from a randomised, double-blind, placebo-controlled, phase 3 trial
BACKGROUND: Atrasentan, a selective endothelin A receptor antagonist, reduced proteinuria in the prespecified interim analysis (week 36) of the ALIGN trial in adults with IgA nephropathy. We assessed whether atrasentan slowed estimated glomerular filtration rate (eGFR) decline after 2·5 years' treatment. METHODS: We performed a randomised, double-blind, placebo-controlled, phase 3 trial (133 sites, 20 countries). Adults with biopsy-proven IgA nephropathy, eGFR of at least 30 mL/min per 1·73 m2, and urinary protein excretion of at least 1·0 g/day while receiving renin-angiotensin system inhibition were enrolled (main stratum). An exploratory stratum enrolled participants also receiving an SGLT2 inhibitor. Participants were randomly assigned (1:1) to oral atrasentan 0·75 mg once daily or placebo for 132 weeks, followed by a 4-week off-treatment follow-up. The key secondary endpoint was change from baseline to week 136 in eGFR in the main stratum, assessed in all randomised patients (excluding data after intercurrent events, defined as initiation of restricted or alternative IgA nephropathy medications or kidney replacement therapy). Safety was assessed in all randomised patients who received at least one dose of study treatment. ALIGN is registered with ClinicalTrials.gov, NCT04573478; the double-blind section is complete, and the open-label extension is ongoing. FINDINGS: Between March 15, 2021, and April 28, 2023, 404 participants were randomly assigned (main stratum: 340; SGLT2 inhibitor stratum: 64). In the main stratum, change from baseline in eGFR at week 136 was -7·5 mL/min per 1·73 m2 (95% CI -9·2 to -5·8) with atrasentan and -9·9 mL/min per 1·73 m2 (-11·7 to -8·1) with placebo (between-group difference 2·4 mL/min per 1·73 m2; 95% CI -0·1 to 4·8; p=0·057). The between-group difference in eGFR change from baseline at end of treatment (week 132) was 2·6 mL/min per 1·73 m2 (95% CI 0·1-5·0), and the difference in total eGFR slope (baseline to week 136) was 1·4 mL/min per 1·73 m2 per year (95% CI 0·5-2·3). In the SGLT2 inhibitor stratum, the difference in eGFR change from baseline at week 136 between atrasentan and placebo was 9·1 mL/min per 1·73 m2 (95% CI 3·0-15·2). Treatment-emergent adverse events were well balanced between atrasentan and placebo, with no new safety signals. In the main stratum, fluid retention adverse events occurred in 24 (14%) of 169 patients receiving atrasentan and 20 (12%) of 170 receiving placebo. INTERPRETATION: Atrasentan reduced proteinuria and preserved kidney function after 2·5 years. This effect was present with or without concomitant SGLT2 inhibitor use. Atrasentan was well tolerated. FUNDING: Novartis.
14 June 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Durvalumab in Combination With Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer: Long-Term Analysis From the GeparNuevo Trial
The phase II GeparNuevo trial investigated whether adding durvalumab to neoadjuvant chemotherapy (NACT) only in patients with early triple-negative breast cancer cT1b-cT4a-d would improve pathologic complete response (pCR) rate and patient survival. Hundred and seventy-four patients were randomly assigned to receive durvalumab or placebo concurrently with nab-paclitaxel once per week and followed by dose-dense epirubicin and cyclophosphamide. With 86.4 months of median follow-up compared with the previously reported 43.7 months, durvalumab showed sustained significant improvements in long-term outcomes as defined by STEEP compared with placebo regarding not only invasive disease-free survival (iDFS; hazard ratio [HR], 0.56 [95% CI, 0.32 to 0.99]; stratified log-rank P = .0431), but also distant disease-free survival (DDFS; HR, 0.41 [95% CI, 0.21 to 0.80]; P = .0069) and overall survival (OS; HR, 0.33 [95% CI, 0.14 to 0.79]; P = .0085). All analyses were stratified by stromal tumor-infiltrating lymphocytes (sTILs) at baseline (low [≤10%], intermediate [11%-59%], high [≥60%]). In exploratory subgroup analysis, patients with nodal involvement at baseline demonstrated a greater iDFS benefit (HR, 0.33 [95% CI, 0.144 to 0.771]; P = .01; Pinteraction = 0.045). sTILs in residual disease (RD) could be assessed in 39/71 patients without pCR. Post hoc analyses by sTILs high (>10%) versus low (≤10%) in RD showed estimated 7-year iDFS rates of 92.3% (95% CI, 56.6 to 98.9) and 51.4% (95% CI, 29.2 to 69.7), respectively. Hence, adding durvalumab to dose-dense NACT without adjuvant continuation of checkpoint inhibition improved long-term survival outcomes, irrespective of the extent of pathologic response. This underscores the necessity to re-evaluate the adjuvant continuation of checkpoint inhibition.
11 June 2026
Read appraisal →JMIR medical informatics
Blockchain Smart Contracts for Automating Clinical Trials: Systematic Review and Proposed System Architecture
BACKGROUND: Blockchain technologies have revolutionized the financial sector through their ability to generate immutable, cryptographically secure records. Clinical trials and health care data possess several synergies with those of the financial sector, specifically pertaining to the importance of tamper-resistant recording of processes. The evolution of blockchain to autonomously execute tasks contingent upon predefined contractual terms via smart contracts (SCs) allows a dynamic chain of interlinked events to unfold independently and in sequence, with time-stamped records. In recent years, mistrust in clinical trial data has grown significantly. Recording the entire clinical trial lifecycle from application, registration, recruitment to conduct, finance management, statistical analysis, and reporting in an immutable, cryptographically secure ledger with SC execution of trial processes could limit the potential for human intervention and tampering. This would produce a time-stamped record of all events within the trial lifecycle. Leveraging the capabilities of SCs could alleviate recruitment challenges and address ongoing concerns regarding data transparency, ownership, and integrity that currently undermine clinical trial processes. OBJECTIVE: This study aimed to review the existing literature on SC applications in clinical trials and propose a system architecture for using SCs to automate key processes throughout the clinical trial lifecycle. METHODS: A systematic search was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, identifying peer-reviewed studies and open-source repositories pertaining to the implementation of SCs in clinical trials. Data were extracted specific to the stage of the trial lifecycle described, SC architecture, and technical specifications for real-world implementation. Data were synthesized to propose an architecture for automating clinical trial processes within the lifecycle using SCs. RESULTS: A total of 144 records were screened; 10 studies met the inclusion criteria. Most implementations used private Ethereum-based networks (7/10, 70%). Reported applications included automated patient matching (5/10, 50%), consent management with dynamic permissioning (6/10, 60%), protocol enforcement and time-stamped audit logs (9/10, 90%), adverse event reporting (3/10, 30%), and financial or workflow automation (3/10, 30%). SC-based recruitment systems demonstrated rapid matching performance (eg, 6000 simulated patients matched in 2.13 s). However, all included systems were prototypes or simulations, and none were tested in real-world regulatory settings. Scalability, interoperability limitations, regulatory ambiguity (eg, General Data Protection Regulation right-to-erasure conflicts), and high infrastructural complexity were common gaps noted across studies. CONCLUSIONS: Current evidence suggests that SCs can enhance transparency, traceability, and automation throughout the clinical trial lifecycle. However, the literature remains dominated by simulation-based prototypes, primarily Ethereum-dependent architectures, and lacks analyses of cost-effectiveness, governance, and integration with institutional workflows. Future research should evaluate hybrid architectures, develop interoperability standards, and assess regulatory and ethical implications in real deployments.
30 May 2026
Read appraisal →Lupus science & medicine
Can disease activity and treatment responses be captured by a core set of domains in SLE clinical trials? An analysis of phase III belimumab trial data.
OBJECTIVE: Outcome measures used in SLE randomised controlled trials (RCTs) have impeded trial success and drug approval. In an ongoing global project to develop a novel outcome measure for SLE RCTs, a 'core set' of domains with which to determine treatment response was chosen via consensus. We investigated the impact of restricting disease activity assessment to this core set on responder classification in RCTs. METHODS: Using pooled baseline and week 52 data from two phase III SLE RCTs (Belimumab in Subjects with Systemic Lupus Erythematosus (BLISS)-52, NCT00424476; BLISS-76, NCT00410384), we divided items from the British Isles Lupus Assessment Group (BILAG) disease activity index into core and non-core sets. The core set included 30 of 86 BILAG items across five domains: mucocutaneous (rash, alopecia, mucosal ulcers), haematological (thrombocytopenia, haemolytic anaemia), arthritis, serositis and nephritis. We analysed baseline disease activity and treatment response at week 52. RESULTS: We analysed 1526 patients. At baseline, the core set captured the majority of disease activity captured using the full BILAG (1426/1526 (93.5%) of patients). Cutaneous vasculitis, non-haemolytic anaemia, leucopenia, dyspnoea and fatigue were the most common non-core set manifestations present. At week 52, about 1278/1426 (89.5%) patients demonstrated concordant treatment responses measured with the core set only versus all BILAG items. Discordance was again driven by cutaneous vasculitis, non-haemolytic anaemia, leucopenia and fatigue. CONCLUSIONS: Limiting the classification of treatment response to a core set of domains has the potential to simplify SLE RCT endpoints without a significant negative impact on patient inclusion or responder classification.
23 May 2026
Read appraisal →Drug discoveries & therapeutics
Artificial intelligence (AI)-assisted ultrasound in clinical trials: Endpoint automation, decentralized monitoring, and regulatory readiness
Ultrasound is among the most widely used imaging modalities in clinical trials, and yet its dependence on operator skill and equipment settings has historically limited the reproducibility of ultrasound-based endpoints in multi-center studies. Artificial intelligence (AI) now addresses this limitation across two complementary dimensions: automated measurement algorithms that quantify cardiac function, organ volume, and vascular parameters with reproducibility approaching or, in select settings, exceeding that of trained human readers and real-time acquisition guidance systems that enable clinicians with no formal sonography training to perform diagnostic-level examinations, making remote and decentralized assessment increasingly feasible. This narrative review synthesizes current evidence and regulatory developments across three interconnected domains. First, use of automated ultrasound to ascertain endpoints has advanced from single-institution validation to prospective and randomized evidence, with deep learning measurement of the left ventricular ejection fraction demonstrating formal equivalence to expert readers across multiple echocardiographic parameters and AI-first workflows shortening the time to diagnosis in a blinded non-inferiority trial. Second, AI-guided ultrasound acquisition by nurses and other non-expert operators has achieved a high rate of diagnostic acceptability in cardiac and pulmonary ultrasound, laying the groundwork for use of ultrasound-based endpoints in decentralized clinical trial designs, as reflected in Food and Drug Administration (FDA) guidance on decentralized trial elements. Third, the regulatory frameworks governing AI-enabled medical devices - including the U.S. FDA's Predetermined Change Control Plan guidance, the EU Artificial Intelligence Act, and internationally harmonized good machine learning practice relevant to Japan and other jurisdictions - increasingly emphasize overlapping principles such as specification of prospective performance, post-marketing oversight, and transparent reporting. Addressing remaining challenges in domain generalization across vendors, subgroup fairness, and algorithm change management during ongoing trials will be essential for AI-assisted ultrasound to fulfill its potential as a robust, scalable endpoint in clinical research worldwide.
18 May 2026
Read appraisal →Neurology
Intrathecal Mesenchymal Stem Cells in Progressive Multiple Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Trial (SMART-MS)
BACKGROUND AND OBJECTIVES: There is an unmet need for neuroregenerative therapies in multiple sclerosis (MS). Mesenchymal stem cells (MSCs) have shown immunomodulatory and regenerative effects in preclinical models and early clinical studies. Intrathecal administration may enhance therapeutic potential by direct delivery to the CNS. However, randomized, placebo-controlled trials are needed to establish safety and efficacy. The objective of this trial was to assess whether a single intrathecal administration of autologous MSCs could provide evidence of a neuroregenerative effect in progressive MS. METHODS: In this randomized, double-blind, placebo-controlled phase I/II trial (NCT04749667), patients with progressive MS enrolled at 4 Norwegian tertiary hospitals received a single intrathecal injection of autologous bone marrow-derived MSCs (1 × 106 cells/kg) in a crossover design. The primary end point was the change in latency of combined evoked potentials at 6 months. Secondary end points included safety, brain MRI measures, functional and ophthalmologic assessments, and serum biomarkers at 6 and 12 months. Exploratory analyses comprised proteomic profiling of CSF. Outcomes were analyzed using baseline-adjusted regression models. RESULTS: A total of 18 patients were included (mean age 46.7 years; 55.6% female). No significant between-group difference was observed for the primary end point (β = -0.31, 95% CI -1.84 to 1.22, p = 0.668). At 6 months, patients in the MSC group showed reduced cerebral atrophy on MRI (β = 9.37, 95% CI 0.29 to 18.45, p = 0.044) and lower serum glial fibrillary acidic protein levels (β = -16.3 pg/mL, 95% CI -33.0 to 0.3, p = 0.054), but neither were sustained at 12 months. Exploratory CSF proteomics revealed reductions in multiple inflammation-related proteins at 6 months. One serious adverse event was deemed probably related to MSC treatment. Common adverse events included fever (n = 9) and low back pain (n = 10) after MSC administration, and spinal MRI abnormalities with fluid loculations and nerve root clumping (n = 7) at 6 months. One patient developed chronic coccygeal pain attributed to arachnoiditis. DISCUSSION: A neuroregenerative effect was not detected, although interpretation may be limited by the small sample size. Adverse events suggest an acute localized inflammatory reaction after MSC administration. Our findings suggest that intrathecal administration of MSCs in progressive MS should be approached with caution in future studies. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, in patients with progressive multiple sclerosis, treatment with a single intrathecal administration of autologous mesenchymal stem cells does not provide neuroregenerative effect, as assessed by a composite evoked potential score. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04749667); registered February 8, 2021; first patient enrolled August 9, 2021.
10 May 2026
Read appraisal →Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
Prevalence of antibody drug conjugated-induced nausea and vomiting (ADCINV) in patients with cancer
INTRODUCTION: Antibody-drug conjugates (ADC) have emerged as an important part of systemic treatment across disease sites. To date, there is no robust pooled prevalence estimate of nausea and vomiting induced by ADCs. Establishing such estimates is essential to determine if ADC-induced nausea and vomiting (ADCINV) represents a clinically significant problem warranting further research into antiemetic prophylaxis. Our aim is to report the prevalence of reported ADCINV across literature. METHODS: A systematic search of Medline, Embase, Cochrane CENTRAL and Web of Science was conducted from database inception until September 24, 2025. Articles were included if they reported nausea and/or vomiting due to ADCs used in cancer treatment, in the abstract. Pooled prevalence was reported. Subgroup analysis was conducted by ADC. Meta-regression was conducted by age and sex. Quality assessment was conducted. Type I error was set at 0.05. RESULTS: A total of 209 studies with 15,493 patients were included. Thirty-nine percent (95%CI, 36-42%) of patients experience any nausea, and 26% (95%CI, 23-29%) experience any vomiting. Younger patients are more likely to experience nausea; each 10-year increase in age is associated with a 12% decrease in nausea rates. Higher emetogenic ADCs include trastuzumab deruxtecan, sacituzumab govitecan, brentuximabvedotin and patritumab deruxtecan. Lower emetogenic agents include disitimab vedotin, telisotuzumab vedotin and rovalpituzumab tesirine. DISCUSSION: This is the first study to report prevalence of ADCINV across ADCs. It is a prevalent adverse effect akin to chemotherapy-induced nausea and vomiting that should be viewed as clinically relevant and further investigated to help develop optimal strategies related to antiemetics.
10 May 2026
Read appraisal →Journal of medical systems
Automated data extraction from electronic medical records for pragmatic clinical trials
Data collection in randomized trials is expensive and labor intensive. With the rise in ongoing pragmatic trials, the use of electronic medical records (EMR) as a source of data has increased. Although potentially faster and cheaper, EMR use can lead to errors. Therefore, to ensure accurate data collection and to avoid systematic errors we performed a study comparing automated data extraction (ADE) with manual data extraction (MDE). We performed a retrospective cohort study to compare the accuracy of ADE using Structured Query Language with MDE by blinded physicians from our EMR. We tested the interrater agreement and intraclass correlation coefficient of clinical baseline data and outcomes of a random sample of 30 patients admitted to the ICU, on mechanical ventilation, requiring opioids for analgosedation for an upcoming pragmatic clinical trial. Key data compared included, but not limited to, patient's demographics, laboratory and vital signs, daily morphine milligram equivalent (MME), days alive and free of mechanical ventilation, days alive and free of hospitalization, days alive and free of ICU, days alive and free of vasopressors, and death. Among 238 patients screened over 1-month period, 72 fulfilled inclusion criteria and 30 were randomly selected to be included in the evaluation. We blindly collected 1320 baseline data, 2160 categorical outcomes and 705 continuous outcomes for a total of 4185 data points. The intraclass correlation coefficient and the Cohen's Kappa were perfect or almost perfect for all data, including outcomes such as daily MME, days alive and free of mechanical ventilation, days alive and free of ICU and days alive and free of hospital with p < 0.001. Among all rechecked data, the ADE was correct in 53 (77.9%) of cases, while MDE in 15 (22.1%). The inaccurate data collected by ADE accounted for 0.36% of the total data-points. The performance of ADE had almost perfect agreement for all outcomes and when rechecking for disagreements, it was more accurate than MDE.
5 May 2026
Read appraisal →The British journal of ophthalmology
Use of patient-reported outcomes in ophthalmology clinical trials between 2014 and 2023.
BACKGROUND/AIMS: Patient-reported outcomes (PROs) evaluate health and functional status, and PRO measures (PROMs) are standardised tools for measuring PROs. Together, they provide valuable insights into treatment efficacy, safety and practicality not captured by traditional clinical endpoints. This cross-sectional analysis with a systematic search component aims to investigate the use, interpretation and reporting of PROs and PROMs in ophthalmic randomised controlled trials (RCTs). METHODS: Ophthalmic RCTs published in the top 10 highest impact factor ophthalmic and medical journals between 2014 and 2023 were systematically reviewed. The frequency of PRO inclusion and adherence to Consolidated Standards of Reporting Trials (CONSORT) PRO guidelines was assessed. The relationship between PRO utilisation and study-level and journal-level characteristics was explored with multivariable regression. RESULTS: Among 9436 records screened, 333 RCTs met eligibility criteria. Of these, 87 (26.1%) included PROs, and 28 (8.4%) used them as primary outcomes. Most studies (83/87, 95.4%) leveraged PROMs, with ophthalmology-specific tools predominating (73.5%). Minimal important differences (MIDs) were rarely used (2.3%) for PRO interpretation. At least 8/13 CONSORT PRO Extension items were reported in 33.3% studies, and trials with primary PRO endpoints had better adherence (p<0.001). PRO utilisation was less likely in trials with lower 5-year journal impact factor (adjusted OR (aOR) 0.99, 95% CI 0.98 to 1.00, p=0.037) and pharmaceutical compared with health service interventions (aOR 0.15, 95% CI 0.03 to 0.67, p=0.013). CONCLUSIONS: PRO integration and interpretation remain limited in high-impact ophthalmic RCTs, despite offering a meaningful adjunct to objective endpoints. Future trials should adopt validated and condition-specific PROMs and establish MIDs to enhance interpretation.
26 Apr 2026
Read appraisal →Journal of medicinal chemistry
The Discovery of RGH-706, a Highly Efficacious MCH1 Receptor Antagonist, for the Treatment of Obesity and Insatiable Hunger
The discovery and characterization of a novel 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole derivative MCH1 receptor antagonist (37) is disclosed. Starting from our previously investigated pyrazino[1,2-a]indole series and utilizing a scaffold hopping strategy, pyrimidine- and 1,4-diazepine-fused indole derivatives were designed and synthesized. Among these, only the prototype molecule containing the 2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole scaffold emerged as a chemically stable and potent MCHR1 antagonist. Previous SAR knowledge coupled with an ex vivo occupancy assay helped us to optimize this advanced lead to our candidate (37). The high MCHR1 potency and excellent receptor occupancy profile of 37 translated into statistically significant body weight loss after 14 days in a DIO mice study, supporting the potential use of this compound as a weight loss agent. Compound 37 (RGH-706) has successfully completed a phase I (SAD & MAD) clinical study in the indication of obesity, followed by an exploratory Phase II study in patients with Prader-Willi Syndrome (PWS).
25 Apr 2026
Read appraisal →Journal of the American College of Cardiology
Using Artificial Intelligence to Adjudicate Major Adverse Cardiovascular Events in Clinical Trials
BACKGROUND: Major adverse cardiovascular events (MACE)-cardiovascular (CV) death, nonfatal myocardial infarction (MI), and nonfatal stroke-are highly relevant clinical outcomes. In global randomized trials, medical records review by a physician clinical events committee (CEC) is the conventional standard for adjudicating MACE but is labor intensive. Automated adjudication with the use of artificial intelligence (AI) could reduce cost and improve reproducibility. OBJECTIVES: In this study, the authors sought to develop and validate an AI-based adjudication system for MACE and compare its performance with CEC adjudication in a large global randomized trial. METHODS: We developed an AI-based system ("Auto-MACE") that uses an iteratively refined prompt of the OpenAI o1-mini language model to adjudicate MACE events, and a Clinical Longformer model trained on adjudicated events to assign a confidence level. We validated Auto-MACE against CEC adjudication in the PARADISE-MI global clinical trial comparing sacubitril/valsartan and ramipril in 5,661 patients with MI complicated by systolic dysfunction or pulmonary congestion. RESULTS: Auto-MACE provided a confident adjudication in 315/455 deaths (69%), 301/659 potential MIs (46%), and 136/167 potential strokes (81%). Auto-MACE agreed with the CEC adjudication in 97%, 89%, and 88% of confident events, respectively. Among all events, Auto-MACE agreed with CEC adjudications in 86% of deaths, 76% of potential MIs, and 84% of potential strokes. The estimated effect of sacubitril/valsartan vs ramipril on composite MACE was similar with Auto-MACE adjudication (HR: 0.91; 95% CI: 0.78-1.07) and CEC adjudication (HR: 0.90; 95% CI: 0.77-1.05). CONCLUSIONS: AI-based adjudication of MACE showed high agreement with human CEC adjudication, especially for CV death and stroke, and where the model was confident. Initial AI-based adjudication with CEC review of uncertain events may reduce workload while maintaining accuracy.
24 Apr 2026
Read appraisal →Journal of neurology, neurosurgery, and psychiatry
Breaking the PROMISE: poor association between brain volume loss and clinical disability worsening over 2 years of follow-up in primary progressive multiple sclerosis.
BACKGROUND: Phase 2 clinical trials in primary progressive multiple sclerosis (PPMS) often use MRI brain volume measures as their primary endpoint. Here, we investigate the longitudinal association between change in MRI outcomes and change in disability over 2 years of follow-up in a large and well-characterised PPMS trial dataset. METHODS: Using the dataset from PROMISE (n=943, mean age of 58.0 years, mean Expanded Disability Status Scale (EDSS) 5.0, and mean disease duration of 10.5 years at baseline), a phase 3 trial of glatiramer acetate in PPMS, we described the change in MRI and disability measures during follow-up and used multivariable logistic regression models to investigate whether change in four MRI outcomes (grey matter volume, white matter volume, brain fraction and total burden of disease) was associated with seven measures of clinical disability worsening (including the EDSS, Timed 25 Foot Walk, Nine-Hole Peg Test and Paced Auditory Serial Addition Test). RESULTS: We found only weak and inconsistent associations between change in MRI and physical and cognitive outcome measures over 2 years of follow-up. Change in MRI measures in year 1 of the trial did not predict change in physical nor cognitive disability in year 2. DISCUSSION: The association of the investigated volumetric MRI measures and clinical disability outcomes was noticeably weak and inconsistent. Our findings question the suitability of brain volume loss and lesion burden accumulation as functionally relevant trial endpoints in PPMS and inform the design and interpretation of clinical trials in PPMS.
17 Apr 2026
Read appraisal →Blood advances
Zamtocabtagene autoleucel in relapsed/refractory B-NHL: 5-year follow-up of a CD20/19 tandem CAR T-cell phase 1 trial
Emerging long-term data indicate relapse rates of >50% after CD19-redirected chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). To reduce selective pressure on the CD19 antigen, we conducted a first-in-human phase 1 clinical trial of zamtocabtagene autoleucel (zamto-cel), a noncryopreserved tandem CD20-CD19-directed CAR T-cell therapy. Two predefined dose levels (dose level 1 [DL1], 1 × 106 and DL2, 2.5 × 106 CAR+ T cells per kg bodyweight) were applied. The primary end point (EP) was the maximum tolerated dose (MTD). Secondary EPs included adverse events, best overall response (BOR), and biomarker assessments. A total of 12 patients, 6 patients per DL, were treated. No dose-limiting toxicity and no cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome of grade ≥3 were observed. Thus, MTD was not reached. The BOR by investigator assessment was 75%, with 5 of 12 patients (42%) achieving complete remission (CR) until month 12 with no relapse in clinical evaluation up to 5 years after infusion. CR was associated with a higher mean maximum observed concentration of zamto-cel and detection of zamto-cel beyond month 6. Additional product characterization revealed increased expression of CD27 and CD127 along with increased expansion of CAR+ central memory T cells in patients with CR, facilitating persistence and improved outcomes in R/R B-NHL treated with zamto-cel. Based on the promising risk-to-benefit ratio, evaluation of zamto-cel at DL2 is ongoing in pivotal phase 2 clinical trials for patients with R/R aggressive B-NHL. This trial was registered at www.ClinicalTrials.gov as NCT03870945.
15 Apr 2026
Read appraisal →Cancer immunology, immunotherapy : CII
A phase I, single-arm, open-label, dose-escalation, multicenter study of SAR445419, an off-the-shelf, ex vivo expanded allogeneic natural killer cell product, in participants with relapsed or refractory acute myeloid leukemia
BACKGROUND: SAR445419 is an investigational, off-the-shelf, allogeneic NK cell therapy derived from donor peripheral blood mononuclear cells and expanded ex vivo using PM21 particles. METHODS: This multicenter, Phase 1, dose-escalation study (NCT05712278) evaluated optimal dose(s), safety, and tolerability of SAR445419 in adults (aged ≥ 18 years) with relapsed/refractory acute myeloid leukemia (R/R AML). Following lymphodepleting chemotherapy (fludarabine 30 mg/m2/day and cytarabine 2 g/m2/day for 5 days), participants received six intravenous SAR445419 (1 × 109 and 3 × 109 NK cells/dose) doses, starting with the lower dose. The primary endpoint was the incidence of dose-limiting toxicities (DLTs), and key secondary endpoints included adverse events (AEs), hematological recovery, hematopoietic stem cell transplantation, and response rate. RESULTS: Of the 12 planned participants, 7 patients were enrolled, of whom 6 received SAR445419 before sponsor decided early study termination for reasons unrelated to safety or efficacy. No DLTs were observed. All participants experienced treatment-emergent adverse events (TEAEs); six had grade ≥ 3 TEAEs; and four had serious adverse events (SAEs). Two SAR445419-related SAEs (infusion-related reactions: both grade 2) were managed with supportive care. All participants experienced grade 3 anemia and grade 4 thrombocytopenia and neutropenia. Five deaths were reported, all due to disease progression, none related to SAR445419. No clinical responses were observed. CONCLUSIONS: This study demonstrated the overall safety of off-the-shelf ex vivo expanded allogeneic NK cells in patients with R/R AML. The successful manufacturing and distribution support the feasibility of donor-derived off-the-shelf NK cells in a clinical setting. Further investigations are required to improve the clinical efficiency of NK cells.
12 Apr 2026
Read appraisal →Journal for immunotherapy of cancer
Anti-TIM-3 antibody TQB2618 in combination with penpulimab in relapsed or refractory classic Hodgkin lymphoma previously treated with PD-1/PD-L1 therapy: a multicenter, open-label, single-arm, phase Ib clinical trial
BACKGROUND: Immune checkpoint inhibitors achieve high response rates in relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL), but few treatment options are available for patients who experience failure after PD-1/PD-L1 blockade. T cell immunoglobulin and mucin-domain containing-3, a key mediator of immune escape from PD-1/PD-L1 inhibition, is targeted by TQB2618, a humanized IgG4 monoclonal antibody. This phase Ib study aimed to evaluate the safety and efficacy of TQB2618 in combination with the anti-PD-1 antibody penpulimab in patients with r/r cHL. METHODS: This multicenter phase 1b study was conducted from June 2022 to September 2024 at 12 sites in China (NCT05400876). The study included a dose-escalation phase in which patients with r/r lymphoma received TQB2618 (600 or 1200 mg, every 3 weeks, Q3W) plus penpulimab (200 mg, Q3W) to evaluate dose-limiting toxicities and determine the recommended phase II dose (RP2D). The subsequent dose-expansion phase enrolled patients with r/r cHL previously treated with PD-1/PD-L1 inhibitors to assess the objective response rate (ORR). RESULTS: 10 patients with r/r lymphoma were enrolled in the dose-escalation phase, and TQB2618 (600 mg, Q3W) plus penpulimab (200 mg, Q3W) was selected as the RP2D. In the dose-expansion phase, 18 additional patients with r/r cHL previously treated with PD-1/PD-L1 inhibitors were enrolled. Among the total 21 r/r cHL patients, the median age was 32 years (range, 22-65), and 12 (57%) were male. The ORR was 52%, including 1 complete response and 10 partial responses. Treatment-related adverse events (TRAEs) occurred in 18 patients (86%), with grade ≥3 TRAEs in 5 (24%). The most common TRAEs (≥20%) were platelet count decreased (24%), anemia (24%), and aspartate aminotransferase increased (24%). As of the data cut-off in December 2024, the median follow-up was 14.1 months, the median duration of response and the median overall survival had not yet been reached. CONCLUSIONS: TQB2618 in combination with penpulimab was well tolerated and demonstrated promising efficacy in patients with cHL who had failed prior anti-PD-1/PD-L1 therapy, supporting its potential as a therapeutic option for this difficult-to-treat population. TRIAL REGISTRATION NUMBER: NCT05400876.
12 Apr 2026
Read appraisal →Trials
The use of complex clinical trials: a regulatory review.
BACKGROUND: Complex clinical trials offer flexibility in evaluating multiple treatments or diseases simultaneously. These trials often feature adaptive designs, common controls, and the potential to add new arms. However, the increased complexity raises methodological challenges particularly regarding multiple testing or the adequate choice of control groups. Despite guidance from regulatory bodies like the European Medicines Agency and the U.S. Food and Drug Administration, uncertainties remain about the regulatory acceptance of these trials. METHODS: This systematic review examines scientific advice procedures of products in the remit of the Paul-Ehrlich-Institut for complex clinical trials to highlight key concerns and regulatory feedback. We identified 30 scientific advice procedures corresponding to 29 different complex clinical trials. RESULTS: Our findings reveal an increasing number of complex trial designs proposed by applicants. A lack of multiplicity control due to multiple arms was generally considered acceptable by regulators in exploratory trials and if cohorts can be considered independent. Additionally, the use of common control groups is frequently proposed by applicants. The review underscores the importance of pre-planning for new treatment arms, appropriate multiplicity control, and the definition of control groups in trial designs. CONCLUSION: Overall, our findings suggest that regulatory concerns regarding complex trials largely align with those in traditional trial designs, though their complexity requires careful, case-by-case consideration. Early engagement with regulatory agencies can be crucial to ensure the successful design and implementation of these trials.
12 Apr 2026
Read appraisal →Signal transduction and targeted therapy
Irinotecan with trifluridine/tipiracil and bevacizumab for second-line metastatic colorectal cancer: a phase II multicenter study
Patients diagnosed with metastatic colorectal cancer (mCRC) face a constrained therapeutic landscape following the failure of initial treatment. This multicenter, single-arm, phase II trial (NCT06202001) aimed to assess the efficacy and safety of a novel second-line regimen comprising trifluridine/tipiracil (TAS-102), irinotecan, and bevacizumab. Patients with mCRC resistant to prior fluoropyrimidine and oxaliplatin-based chemotherapy were enrolled. Based on a preceding phase I trial, patients received biweekly cycles of oral TAS-102 (30 mg/m² twice daily, days 1-5), intravenous irinotecan (150 mg/m²), and intravenous bevacizumab (5 mg/kg). The primary outcome measure was the objective response rate (ORR). From October 2023 to August 2024, 60 patients were enrolled. As of December 2024, the ORR was 18.3% (2 complete and 9 partial responses), and the disease control rate (DCR) was 83.3%. The median progression-free survival (PFS) was 6.6 months (95% CI, 4.39-8.81), and the median overall survival (OS) was 17.3 months (95% CI, 13.55-21.05). Subgroup analyses indicated that prior resection of the primary tumor was associated with significantly longer median OS (21.9 vs. 16.2 months; p = 0.048) and PFS (8.9 vs. 5.2 months; p = 0.004). The most frequently reported treatment-related adverse events (TRAEs) were nausea (100%), neutropenia (86.7%), and anemia (83.3%). The predominant grade 3/4 TRAEs included neutropenia (48.3%), febrile neutropenia (8.3%), and diarrhea (6.7%). In conclusion, the combination of irinotecan, TAS-102, and bevacizumab shows encouraging efficacy and a manageable safety profile as a second-line therapy for mCRC, meriting further investigation.
11 Apr 2026
Read appraisal →Blood
A phase 3 study of intensive chemotherapy with or without dasatinib in core-binding factor acute myeloid leukemia
Core-binding factor acute myeloid leukemia (CBF-AML) is associated with KIT mutations and deregulated expression of KIT. We report results from the randomized, open-label, phase 3 trial of intensive chemotherapy with or without the multikinase inhibitor dasatinib in adult patients with CBF-AML. Patients received "3+7" induction therapy, followed by 4 cycles of high-dose cytarabine; in the investigational arm, patients received dasatinib 100 mg daily on days 8 to 21 in induction, and on days 6 to 28 in consolidation cycles, followed by 12-month single-agent dasatinib 100 mg daily. Primary end point was event-free survival (EFS). Secondary end points included overall survival, relapse-free survival, and cumulative incidence of relapse. A total of 202 patients were randomly assigned to the standard arm (n = 102) and to the dasatinib arm (n = 100). Median age was 49 years (range, 18-77); 94 patients had t(8;21), 108 had inv(16)/t(16;16); and 58 (28.7%) patients had a KIT comutation. There was no statistically significant difference in EFS (hazard ratio, 0.92; 95% confidence interval, 0.63-1.33; P = .66) or secondary end points between treatment arms. There was also no significant difference in EFS in subgroup analyses according to age, CBF-AML type, and KIT mutation status. The incidence of serious adverse events was higher in the investigational arm (64%) than in the standard arm (36%). In patients with CBF-AML, the addition of dasatinib to intensive chemotherapy failed to improve survival outcomes. The addition of dasatinib was associated with an increase in toxicity. This trial was registered at www.ClinicalTrials.gov as NCT02013648.
10 Apr 2026
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