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Matching-adjusted indirect comparison of fruquintinib versus ramucirumab in advanced gastric or gastroesophageal junction adenocarcinoma.

Aim: Fruquintinib (Fruq), a selective VEGFR 1/2/3 inhibitor, showed a significant progression-free survival (PFS) benefit in the Phase III FRUTIGA trial for advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Ramucirumab (RAM), an anti-VEGFR2 antibody, demonstrated efficacy in the RAINBOW-Asia trial. This anchored matching-adjusted indirect comparison (MAIC) evaluated Fruq plus paclitaxel versus RAM plus paclitaxel as second-line therapy for G/GEJ adenocarcinoma in the absence of head-to-head trials. Materials & methods: Data from individual patients in the FRUTIGA study (N&#xa0;=&#xa0;703) and aggregated data from the RAINBOW-Asia study (N&#xa0;=&#xa0;440) were analyzed. Baseline characteristics were balanced using entropy balancing. The placebo plus paclitaxel (PBO&#xa0;+&#xa0;PTX) groups served as the common comparators. The primary outcome was PFS; secondary outcomes included overall survival, objective response rate (ORR) and disease control rate (DCR). Rates of treatment-emergent adverse events (TEAEs) were also compared as an exploratory outcome using an adjusted indirect risk difference. Sensitivity analyses included restricted mean survival time and simulated treatment comparison. Results: After weighting (effective sample size&#xa0;=&#xa0;564), baseline covariates were balanced. The anchored MAIC demonstrated that Fruq&#xa0;+&#xa0;PTX significantly improved PFS compared with RAM&#xa0;+&#xa0;PTX (HR: 0.70; 95% CI: 0.51-0.96; p&#xa0;=&#xa0;0.0280), corresponding to a 30% reduction in progression risk, with a significant restricted mean survival time benefit of 1.18&#xa0;months at 20&#xa0;months (95% CI: 0.08-2.27; p&#xa0;=&#xa0;0.024). Fruq achieved significantly higher ORR (OR: 1.76, 95% CI: 1.16-2.68; p&#xa0;=&#xa0;0.008) and DCR (OR: 1.94, 95% CI: 1.33-2.83; p&#xa0;<&#xa0;0.001). Overall survival was similar (0.97; 95% CI: 0.73-1.30; p = 0.8640). Subgroup analyses showed PFS benefits with Fruq in patients with ECOG PS 1, peritoneal metastases and two or fewer metastatic sites. In sensitivity analysis, the simulated treatment comparison also suggested a PFS benefit for Fruq&#xa0;+&#xa0;PTX (HR: 0.40, 95% CI: 0.32-0.50; p&#xa0;<&#xa0;0.0001). For any-grade TEAEs, the indirect comparison showed higher adjusted relative incidences of increased bilirubin with Fruq&#xa0;+&#xa0;PTX than with RAM&#xa0;+&#xa0;PTX (RD: 12.3%; 95% CI: 2.3-22.4%, p&#xa0;<&#xa0;0.05) and of hypokalemia (RD: 9.0%; 95% CI: 1.5-16.4%, p&#xa0;<&#xa0;0.05). For grade &#x2265;3 TEAEs, the adjusted relative incidence of decreased body weight was higher with Fruq&#xa0;+&#xa0;PTX than with RAM&#xa0;+&#xa0;PTX (RD: 2.9%; 95% CI: 0.6-5.2%, p&#xa0;<&#xa0;0.05). The adjusted relative incidences of increased AST, ALT and hypocalcemia were numerically lower in the fruquintinib group than in the RAM group. Conclusion: This MAIC indicates that Fruq&#xa0;+&#xa0;PTX may be more effective than RAM&#xa0;+&#xa0;PTX in second-line advanced G/GEJ adenocarcinoma, with potentially improved PFS, ORR and DCR, and similar overall survival. Safety analyses suggested generally comparable safety profiles across the two regimens. Fruq&#xa0;+&#xa0;PTX remains a valuable treatment option, offering important comparative evidence for clinical and health technology assessment decisions. Trial Registration: Clinicaltrials.gov identifiers: NCT07144995.

Adult

The glucagon and GLP-1 receptor dual agonist DD01 for metabolic dysfunction-associated steatotic liver disease and steatohepatitis (DD01-DN-02): 12-week results from a randomised, double-blind, multicentre, placebo-controlled, phase 2 trial.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a major public health problem arising in the context of metabolic syndrome and obesity. DD01 is a liver-targeted GLP-1 receptor and glucagon dual agonist being investigated for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD) and MASH. The DD01-DN-02 trial aimed to evaluate the efficacy and safety of DD01 in adults with MASLD or MASH; this initial analysis reports prespecified 12-week outcomes to assess early hepatic effects. METHODS: DD01-DN-02 is an ongoing, randomised, double-blind, multicentre, placebo-controlled, phase 2 trial conducted at 12 outpatient clinical sites in the USA. Adults aged 18-70 years with obesity or who were overweight (BMI &#x2265;25 kg/m2) were included in the study. Patients with MASLD or MASH underwent liver biopsy and MRI-proton density fat fraction (PDFF) and were eligible if liver fat content was 10% or higher with metabolic risk factors, or if the biopsy confirmed MASH with a non-alcoholic fatty liver disease activity score of at least 4. Participants were randomly assigned (1:1) to receive once-weekly subcutaneous DD01 40 mg or matched placebo over 48 weeks, dose-escalated over 2 weeks, using a centrally administered interactive response technology system. The randomisation sequence was computer-generated by an independent statistician. Participants, investigators, study staff, outcome assessors, and the sponsor were masked to treatment assignment. The primary endpoint was the proportion of participants having at least a 30% relative reduction in liver fat by MRI-PDFF at week 12, which was analysed in all randomly assigned participants receiving at least one dose of study drug or placebo. Safety analyses included all participants who received at least one dose of study drug. Missing primary endpoint data were handled using multiple imputation under a missing-at-random assumption. This trial is registered with ClinicalTrials.gov (NCT06410924) and is ongoing but closed to new participants. FINDINGS: Between June 13, 2024, and Jan 30, 2025, 67 eligible participants were enrolled, of whom 33 were randomly assigned to DD01 and 34 to placebo. The mean age of participants was 48&#xb7;4 years (SD 10&#xb7;6), 42 (63%) were female, 25 (37%) were male, 57 (85%) were White, and 52 (78%) participants had biopsy-confirmed MASH. At week 12, 25 (76%) of 33 participants receiving DD01 had a 30% or higher reduction in liver fat versus four (12%) of 34 participants receiving placebo (adjusted common odds ratio 28&#xb7;8 [95% CI 7&#xb7;2-115&#xb7;2]; adjusted relative risk 6&#xb7;3 [95% CI 2&#xb7;5-15&#xb7;9]; p<0&#xb7;0001). Treatment-emergent adverse events occurred in 28 (85%) of 33 participants receiving DD01 and 23 (68%) of 34 participants receiving placebo. The most common adverse events were nausea (18 [55%] of 33 participants assigned DD01; six [18%] of 34 participants assigned placebo), diarrhoea (nine [27%] of 33; six [18%] of 34), and vomiting (ten [30%] of 33; four [12%] of 34). Treatment-emergent adverse events led to treatment discontinuation in four (12%) of 33 participants in the DD01 group and one (3%) of 34 participants in the placebo group. Two (6%) treatment-emergent serious adverse events occurred in the DD01 group (abdominal pain and acute cholecystitis) and zero in the placebo group. No deaths occurred. INTERPRETATION: In this prespecified 12-week primary analysis, DD01 produced rapid reductions in liver fat compared with placebo, supporting further evaluation in long-term studies. FUNDING: D&D Pharmatech, Neuraly.

Humans

Neurological effects of encapsulated dexamethasone sodium phosphate in children aged 6-9 years with ataxia telangiectasia (NEAT): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Ataxia telangiectasia is a rare, multisystem disorder with progressive cerebellar neurodegeneration and no approved treatments. The efficacy of corticosteroids, including erythrocyte encapsulated dexamethasone sodium phosphate (eDSP), which have been studied for two decades in this disease, has not yet been proven in randomised trials. We aimed to investigate the safety and efficacy of eDSP in children aged 6-9 years with ataxia telangiectasia. METHODS: NEAT was a multicentre, randomised, double-blind, placebo-controlled phase 3 study, conducted at 20 sites across nine countries (Denmark, Germany, Italy, Norway, Poland, Spain, Switzerland, UK, and USA). Eligible participants were children aged 6 years or older weighing at least 15 kg, with a genetic diagnosis of ataxia telangiectasia and presence of neurological symptoms. Participants were randomly assigned (1:1) to the eDSP or placebo group via an independent interactive web response system and were stratified by age (6-9 years or &#x2265;10 years), sex, and region (USA vs other countries). All participants, investigators, sponsors, and raters were masked to treatment assignments. eDSP was given intravenously every 21-30 days for six doses. All randomly assigned participants were included in the intention-to-treat (ITT) and safety populations; the primary and secondary efficacy analyses were conducted in participants aged 6-9 years in the ITT population. The primary efficacy endpoint was the change in Rescored Modified International Cooperative Ataxia Rating Scale (RmICARS) score between baseline and month 6, and a mixed-model-repeated-measures analysis was used. The trial was registered at ClinicalTrials.gov, NCT06193200, and is completed. FINDINGS: Between June 24, 2024, and Dec 17, 2025, we screened 125 participants for eligibility, of whom 105 (84%) were randomly assigned to the eDSP group (n=51 [49%]) or the placebo group (n=54 [51%]) and received at least one dose of treatment. The mean age was 8&#xb7;5 years (SD 1&#xb7;9) in the eDSP group and 8&#xb7;6 years (2&#xb7;3) in the placebo group (overall age range 6-17 years). In the eDSP group, 24 (47%) of 51 participants were girls and 27 (53%) were boys and, in the placebo group, 26 (48%) of 54 were girls and 28 (52%) were boys. Of ITT participants aged 6-9 years, 38 (95%) of 40 in the eDSP group and 41 (95%) of 43 in the placebo group completed the study. Compared with the placebo group, no significant differences were identified in change in RmICARS score from baseline to 6 months in participants aged 6-9 years: least squares mean difference -1&#xb7;30 (95% CI -2&#xb7;77 to 0&#xb7;18; p=0&#xb7;085). Adverse events were reported in 47 (92%) of 51 participants in the eDSP group and in 50 (93%) of 54 participants in the placebo group. The most common treatment-emergent adverse events were vomiting, pyrexia, pruritus, nasopharyngitis, cough, headache, and fatigue. There were no reports of treatment-related serious adverse events or deaths. Safety laboratory parameters did not identify adverse effects on growth, metabolism, bone mineral density, or endocrine function in any of the treatment groups. INTERPRETATION: The primary efficacy endpoint was not achieved, because the effect of eDSP on neurological symptoms did not reach statistical significance. The favourable safety profile of eDSP, previously described in a large study of children with ataxia telangiectasia, was confirmed in this trial. The eDSP programme, comprising two randomised studies and treating the largest cohort of patients with ataxia telangiectasia to date, underscores the need for rigorously designed trials of sufficient duration to detect sustained clinical benefit. FUNDING: Quince Therapeutics.

Humans

Chemoradiotherapy versus short-course radiotherapy for response-adapted organ preservation in early-stage and intermediate-stage rectal cancer (STAR-TREC): 12-month results of an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial.

BACKGROUND: Total mesorectal excision (TME) is the standard treatment for most early-stage and intermediate-stage rectal cancer but can cause substantial perioperative morbidity, functional impairment, and reduced quality of life. We assessed whether long-course chemoradiotherapy (LCCRT) or short-course radiotherapy (SCRT) could increase organ preservation and reduce surgery, toxicity, and quality-of-life harms without compromising oncological outcomes. METHODS: STAR-TREC is an international, multicentre, open-label, parallel-group, randomised, phase 2/3 trial in five European countries. Eligible patients were aged 16 years or older in the UK or aged 18 years or older elsewhere, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and rectal adenocarcinoma (&#x2264;40 mm staged as mrT1-T3bN0). In phase 2, participants were randomly assigned (1:1:1) to LCCRT-based organ preservation (LCCRT-OP; 50 Gy in 25 fractions plus oral capecitabine 825 mg/m2 twice daily), SCRT-based organ preservation (SCRT-OP; 25 Gy in five fractions), or primary TME. Phase 2 assessed feasibility, with recruitment at months 12 and 24 as the primary endpoint and feasibility thresholds of four or more and six or more randomisations per month, respectively. Phase 3 adopted a partially randomised patient-preference design, allowing participants to choose either organ preservation or TME. Participants that chose organ preservation were randomly assigned (1:1) to receive LCCRT-OP or SCRT-OP using centralised, computer-generated assignment, with stratification by country and MRI T category (&#x2264;T3a vs T3b) using minimisation. The phase 3 primary endpoint was organ-preservation 30 months after treatment initiation, defined as absence of TME, stoma, or local recurrence, which was assessed in the modified intention-to-treat population, which included participants in phase 2 and phase 3. After a planned interim analysis of unmasked phase 2 data, the trial steering committee and independent data monitoring committee recommended reporting a 12-month, modified intention-to-treat analysis of implementation outcomes for participants recruited before Aug 8, 2023. This study is registered with ISRCTN (14240288) and is closed. FINDINGS: Between June 14, 2017, and April 8, 2024, 503 participants were enrolled at 37 sites. Phase 2 enrolled 120 participants, with recruitment rates of three and six participants per month at months 12 and 24, respectively. Overall, 12-month TME-free survival was 60% (47 of 78 participants). After phase 3 recruitment ended, interim analysis of unmasked phase 2 data showed an early TME-free survival benefit with LCCRT versus SCRT (12-month median TME-free survival not reached [95% CI not reached-not reached] vs 7&#xb7;6 months [95% CI 6&#xb7;4-not reached]; hazard ratio [HR] 3&#xb7;7 [95% CI 1&#xb7;7-8&#xb7;0]; posterior probability of superiority >99&#xb7;5%). The trial steering committee and independent data monitoring committee therefore recommended expanded analysis of 426 participants recruited before Aug 8, 2023: 120 from phase 2 and 306 from phase 3. 17 participants withdrew before treatment, leaving 409 in the modified intention-to-treat population: 163 allocated to LCCRT, 168 to SCRT, and 78 to primary TME. 116 (28%) participants were female and 293 (72%) were male. Among participants who opted for organ preservation, 12-month TME-free survival was 78&#xb7;5% (95% CI 72&#xb7;4-85&#xb7;1) with LCCRT and 60&#xb7;6% (53&#xb7;6-68&#xb7;4) with SCRT (HR 1&#xb7;90 [95% CI 1&#xb7;29-2&#xb7;81]). The most common grade 3-4 serious adverse events were gastrointestinal disorders (four [2%] with LCCRT vs six [4%] with SCRT vs six [8%] with TME) and procedural complications (three [2%] with LCCRT vs five [3%] with SCRT vs five [6%] with TME). One participant allocated to primary TME died after an anastomotic leak. INTERPRETATION: These early results support a response-adapted organ-preservation approach, with LCCRT appearing more effective than SCRT at 12 months. Organ-preservation might also reduce treatment-related toxicity compared with primary TME. Longer follow-up is needed for the prespecified 30-month endpoint and definitive functional and oncological outcomes. FUNDING: Cancer Research UK, Stand Up to Cancer, Dutch Cancer Society, Danish Cancer Society, Kom Op Tegen Kanker, Cancerfonden, ALF Region Stockholm, RCC Region Stockholm.

Humans

Strategies to improve recruitment to randomised trials.

BACKGROUND: Recruiting participants to randomised controlled trials (RCTs) is challenging. Identifying effective recruitment strategies would benefit health research: poor recruitment leads to underpowered trials, reducing the reliability of findings and increasing the risk of wasted resources, ethical concerns, and trial failure. Evidence to inform recruitment strategies is increasingly generated through Studies Within A Trial (SWATs), which are methodological studies embedded within host RCTs. This is an update of a review last published in 2018. OBJECTIVES: Primary: to quantify the effects of strategies to improve recruitment of participants to RCTs. Secondary: to evaluate recruitment strategies' cost-effectiveness and impact on retention, and the equity, diversity, and inclusion (EDI) characteristics of recruited participants. SEARCH METHODS: We used MEDLINE, Embase, and six other databases to identify the studies included in the review. We also sought unpublished recruitment SWATs through social media and targeted email dissemination to trial methodology networks. The latest search date was 16 February 2023. SELECTION CRITERIA: We included randomised SWATs evaluating trial recruitment strategies embedded in healthcare and non-healthcare trials. We excluded quasi-randomised, hypothetical, questionnaire-only, retention-only, or clinician incentive studies. DATA COLLECTION AND ANALYSIS: Primary outcome: proportion of eligible participants or centres recruited. SECONDARY OUTCOMES: cost-effectiveness, retention rates, and EDI characteristics of included participants. We conducted random-effects meta-analysis for strategies evaluated in at least two studies; otherwise, we synthesised results narratively. We reported effects as risk differences (RDs) with 95% confidence intervals (CIs), and assessed between-trial heterogeneity. We used GRADE to assess the certainty of evidence for the primary outcome. We expressed cost-effectiveness as the incremental cost per additional participant recruited in pounds sterling (GBP). MAIN RESULTS: We identified 91 eligible studies (53 new to this update), providing 94 comparisons and involving at least 176,747 participants. Eighty-one studies involved strategies aimed at trial participants, while 10 evaluated strategies aimed at recruiters. All were healthcare studies. We found 65 recruitment strategies; 49 were evaluated in a single study. Only five strategies were supported by high-certainty evidence according to GRADE criteria, and we focus on these strategies in the summary below. Open-label trials versus blinded, placebo trials. Open-label trials recruited more participants than blinded trials (RD 10%, 95% CI 8% to 12%; 3 studies, 9004 participants), corresponding to approximately 10 additional participants per 100 approached. The studies involved mostly women in the UK and Estonia. No cost or retention data were reported. Telephone reminder versus no telephone reminder. Telephone reminders to people who did not respond to an initial postal invitation boosted recruitment by 6% (95% CI 3% to 9%; 2 studies, 1450 participants), in trials with low underlying recruitment (we are less certain for trials with over 10% recruitment). The studies involved people with a mean age of 58 years in Canada and Norway. No cost or retention data were reported. Recruitment primer letter versus no letter. Pre-recruitment letters and leaflets designed to encourage participation made little or no difference to recruitment (absolute improvement 1%, 95% CI -1% to 2%; 2 studies, 5376 participants), and were associated with increased costs compared to not sending a primer (incremental cost: GBP 2.08). The studies involved mostly older white people in the UK and Ireland. Multimedia information via a digital link/QR code plus paper participant information leaflet (PIL) versus paper PIL alone. This made little or no difference to recruitment (absolute improvement 0%, 95% CI -1% to 1%; 7 studies, 11,612 participants) and retention (absolute improvement 0%, 95% CI -2% to 3%; 5 studies, 7403 participants), and increased costs compared to not including multimedia information (incremental cost: GBP 0.78). The studies involved people in the UK. Optimised, user-tested PIL versus standard PIL. Optimising participant information leaflets (e.g. through user-testing the leaflet with the target population to shape its content, format, and appearance) made little or no difference to recruitment: absolute improvement was 0% (95% CI 0% to 1%; 6 studies, 27,805 participants). The studies involved people in the UK. Only one study reported EDI data; participants were mostly older women. No cost or retention data were reported. We had moderate-certainty evidence for 13 other strategies; confidence was often reduced because the results came from single studies. Seven strategies involved changes to how potential participants received information; four involved changes to trial conduct; one targeted the recruiter or recruitment site; and one tested non-monetary incentives. We had much less confidence in the other 47 comparisons because the studies had design flaws, were single studies, or had very uncertain results. Costs were reported in only 17 of 91 studies. Strategy impact on retention was reported in 15 studies. All but one study (99%) were from high-income countries. The most reported demographics were age (49 studies), sex (32 studies), gender (27 studies), and education level (16 studies). AUTHORS' CONCLUSIONS: The evidence on strategies to improve trial recruitment remains broad but lacks depth. Of 65 strategies evaluated, only five were supported by high-certainty evidence. Open-label trial designs and telephone reminders to non-responders increased recruitment, while optimised participant information leaflets, recruitment primer letters, and multimedia information provided alongside a paper participant information leaflet had little or no effect. Reporting of participant characteristics was poor, limiting assessment of equity, diversity, and inclusion across most studies. Evidence is heavily skewed toward high-income countries. Future research must prioritise evaluations in low-to-middle-income settings and consistently report cost, retention, and EDI outcomes. We strongly urge the methodology research community to strengthen the evidence base by prioritising replications of existing strategies over the development and testing of new ones. FUNDING: National Institute for Health and Care Research (Advanced Fellowship, Adwoa Parker, reference:NIHR302256). Health Research Board, Republic of Ireland, Evidence Synthesis Ireland (grant ESI-2021-001) REGISTRATION: This review updates an earlier Cochrane review, which was first published in 2002 and subsequently updated in 2007, 2010, and 2018. Previous versions of the review and their protocols are available at: https://doi.org/10.1002/14651858.MR000013.pub2 https://doi.org/10.1002/14651858.MR000013.pub3 https://doi.org/10.1002/14651858.MR000013.pub4 https://doi.org/10.1002/14651858.MR000013.pub5 https://doi.org/10.1002/14651858.MR000013.pub6.

Randomized Controlled Trials as Topic