Trial Arms Research Articles

A novel intrauterine estrogen-releasing system for preventing the postoperative recurrence of intrauterine adhesion: a multicenter randomized controlled study

BackgroundTranscervical resection of adhesions (TCRA) is the standard treatment for intrauterine adhesion (IUA). Previous studies have shown that postoperative oral estrogen or an intrauterine physical barrier could reduce the recurrence of IUA by promoting the proliferation of the endometrium or inhibiting the reformation of adhesions. Our team designed an intrauterine stent that can release estrogen within the uterine cavity slowly. In this study, we aimed to investigate the efficacy and safety of the estrogen-releasing intrauterine system in preventing the recurrence of moderate to severe IUA.MethodsThis was a multicenter prospective randomized controlled 2-arm parallel trial that included patients who were diagnosed with moderate to severe IUA and who received TCRA. A total of 250 patients were randomly assigned, at a 1:1 ratio, to receive the intrauterine estrogen-releasing system or a Foley catheter balloon combined with oral estrogen therapy after surgery. The primary outcome was the rate of adhesion reduction in the two groups. The secondary outcomes included endometrial thickness at the ovulation period, menstrual improvement rates, and other reported adverse events during follow-up.ResultsThe average daily drug release amount for all the tested stents was 0.21 mg/day. At 60 days postoperatively, the rate of adhesion reduction was significantly greater in the experimental group than in the control group (93.33% vs. 58.56%, p < 0.001). The endometrium of the experimental group was thicker than that of the control group (p < 0.001). Consistently, the rate of improvement in menstruation was greater in the experimental group than in the control group (p = 0.010). No grade 3–4 adverse events were found in the two groups during the 1-year follow-up.ConclusionsIn the cohort of patients with moderate to severe IUA, the intrauterine estrogen-releasing system was more effective at reducing adhesion than traditional oral estrogen combined with an intrauterine Foley catheter after TCRA. This novel intrauterine system provides a new option for the management of IUA after surgery.Trial registrationThe registration number is NCT04972032. Date of registration: August 15, 2021.

Abstract C007: Quemliclustat (CD73 Inhibitor) reduces adenosine-regulated NR4A gene expression and increases mPDAC inflammation in patients from the ARC-8 trial

Abstract Background: Metastatic pancreatic ductal adenocarcinomas (mPDACs) express high levels of the adenosine-generating enzyme CD73 and therapeutically represent a significant unmet medical need, with median patient overall survival (OS) of &amp;lt;1 year. The small-molecule quemliclustat (quemli; AB680) was designed to inhibit soluble and cell-bound CD73 enzymatic activity, thereby providing the capability of reversing adenosine-mediated anti-tumor immune suppression. Quemli, in combination with gemcitabine/nab-paclitaxel (G/nP) ± anti-PD-1 antibody zimberelimab (zim), demonstrated encouraging clinical activity in the first line (1L) mPDAC study ARC-8 (NCT04104672), with median OS ranging from 14.6-19.4 months. Methods and Results: We began by identifying surrogates for tumor adenosine levels, given that it is not possible to measure adenosine levels directly in clinical samples. Cell culture experiments indicated that the stable adenosine analogue NECA can drive upregulation of the NR4A family of transcription factors (NR4A1, NR4A2, and NR4A3) in cancer cells as well as cancer-associated stromal cells (fibroblasts). Treatment with quemli reversed NR4A gene family upregulation, supporting a model in which high baseline levels of NR4A expression in tumors may be reflective of tumors with higher levels of adenosine. Next, we investigated quemli’s mechanism of action (MoA) by transcriptomic assessment of 37 matched pairs of pre- compared to post-treated mPDACs from ARC-8 patients dosed with 100mg of quemli. Treatment with quemli-containing regimens led to a significant reduction in tumor expression levels of the NR4A gene family. Decreased NR4A family tumor expression after treatment was accompanied by a significant increase in tumor inflammation, as measured by a T-cell activation gene signature. Analysis of a published transcriptional dataset from the nivolumab + G/nP control arm of the PRINCE trial in front-line mPDAC (NCT03214250) indicated that high levels of tumor NR4A1, 2, and 3 expression portend significantly worse clinical outcomes in patients treated with this IO/chemotherapy regimen, highlighting a potential opportunity for quemli to provide clinical benefit by reversing adenosine-mediated immunosuppression in mPDAC. Conclusion:Quemli + G/nP treatment was associated with a reduction in tumor expression levels of adenosine-regulated NR4A gene family and was accompanied by an increase in tumor inflammation. Given the adenosine-modulating MoA, patients with mPDACs expressing high levels of NR4A in baseline tumor tissue, which portended poor prognosis in 1L mPDACs treated with G/np-containing regimen from the PRINCE study, may benefit from treatment with quemli. A phase 3 trial (PRISM-1) of G/nP +/- quemli in the 1L mPDAC setting is being planned. Citation Format: Ji Yun Kim, Ning Wang, Ben Weeder, Enzo Stagnaro, Karim Mrouj, Jose Aquino, Xian He, Eileen M O’Reilly, Shubham Pant, Gulam A Manji, Zev A Wainberg, Joon Rhee, Brandon Beagle, Daniel DiRenzo, Matthew J Walters, Angelo Kaplan, Sean Cho, Omar Kabbarah. Quemliclustat (CD73 Inhibitor) reduces adenosine-regulated NR4A gene expression and increases mPDAC inflammation in patients from the ARC-8 trial [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C007.

Increasing power in screening trials by testing control-arm specimens: application to multicancer detection screening.

Cancer screening trials have required large sample sizes and long time-horizons to demonstrate cancer mortality reductions, the primary goal of cancer screening. We examine assumptions and potential power gains from exploiting information from testing control-arm specimens, which we call the "intended effect" (IE) analysis that we explain in detail herein. The IE analysis is particularly suited to tests that can be conducted on stored specimens in the control arm, such as stored blood for multicancer detection (MCD) tests. We simulated hypothetical MCD screening trials to compare power and sample size for the standard vs IE analysis. Under two assumptions that we detail herein, we projected the IE analysis for 3 existing screening trials (National Lung Screening Trial [NLST], Minnesota Colon Cancer Control Study [MINN-FOBT-A], and Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial-colorectal component [PLCO-CRC]). Compared with the standard analysis for the 3 existing trials, the IE design could have reduced cancer-specific mortality P values 6-fold (NLST), 33-fold (MINN-FOBT-A), or 260 000-fold (PLCO-CRC) or, alternately, reduced sample size (90% power) by 25% (NLST), 47% (MINN-FOBT-A), or 63% (PLCO-CRC). For potential MCD trial designs requiring 100 000 subjects per arm to achieve 90% power for multicancer mortality for the standard analysis, the IE analysis achieves 90% power for only 37 500-50 000 per arm, depending on assumptions concerning control-arm test-positives. Testing stored specimens in the control arm of screening trials to conduct the IE analysis could substantially increase power to reduce sample size or accelerate trials and could provide particularly strong power gains for MCD tests.

Navigating the barriers to multi-regional research administrative data access: Forward thinking solutions

In 2021, aware of both the importance of pan-Canadian data access for advancing health research and the conditions and requirements that make administrative data access onerous, HDRN Canada worked with CATCO the Canadian arm of an international COVID-19 clinical trial to create a roadmap for navigating the barriers to multi-regional administrative data access in Canada. While developing the roadmap, data access request processes were studied in real time for a multi-region study seeking access to link administrative data to clinical trial data, at the individual level. The intent was to move beyond anecdotal evidence and document the specific nature of policy and processes that hamper data access. The case study allowed the study team to define the barriers permitting application of tangible mitigating measures. In 2022, barriers such as the lack of ability to share data across provincial borders became too great to continue the study. Although the roadmap was not completed, insights were gained for waypoints along the path enabling HDRN Canada to make important process improvement to harmonize data access across regions. Solutions to challenges with data access request forms, regional data flows, data sharing partner relationships, data sharing agreements, and REB and project reviews were identified. Recently pan-Canadian initiatives have released important guidance for addressing data access challenges. The adoption of this guidance is paramount to ensure Canada continues to meaningfully contribute to health research. Forward thinking solutions to data access challenges today will establish the necessary infrastructure for a future with minimal data access barriers.

Assessing the effect of anthocyanins through diet and supplementation on cognitive function in older adults at risk for dementia: protocol for a randomised controlled trial

IntroductionPromising evidence is emerging for the procognitive, anti-inflammatory and neuroprotective properties of dietary flavonoids, particularly anthocyanins that provide red, purple and blue plant pigments.Methods and analysisThe ‘Food for Thought’ study...

Approved medicines for paediatric solid tumours in Europe: Lessons from the life cycle of a paediatric investigation plan

BackgroundDespite the positive changes brought by the Paediatric Regulation in the European Union (EU) in 2007, drug development in children remains challenging. MethodsTo better understand the issues encountered to reach an authorisation for paediatric patients, we reviewed the pathway of the 11 Paediatric Investigational Plans (PIPs) with indications targeting paediatric solid tumours granted by the Committee for Medicinal Products for Human Use (CHMP) between 2007 and 2022. ResultsOn average 5,5 years were necessary to reach approval after a PIP was agreed. All the PIPs underwent at least one modification (median 3 modifications per PIP). The use of single arm trials, in the context of refractory/relapsed disease in absence of standard of care treatment, was supportive for granting a paediatric indication in the majority of the cases. In 6 out of 11 approved products, extrapolation from adults was used. For 2/11 the approval focused on an older population first compared to the initial age group agreed in the PIP due to the development of a suitable formulation for younger children still ongoing at the time of first approval. Scientific advice sought on paediatric development use of extrapolation from adults, major objections raised by CHMP and post-marketing requirements were examined. ConclusionAnalysing the process necessary to reach an authorisation for paediatric patients, we highlight the major challenges faced in the paediatric approval process and the positive examples of successful drug development that reached final approval. Our analysis is expected to provide useful insights to drug developers, investigators and regulators.

Randomized clinical trial on accelerated preoperative hyperfractionated radiotherapy versus preoperative hyperfractionated radio-chemotherapy in locally advanced rectal cancer.

The aim of this study was to compare pathological response rates after preoperative hyperfractionated radiotherapy with co-administration of chemotherapy based on 5FU (HART-CT) versus preoperative hyperfractionated radiotherapy (HART) in patients with resectable rectal cancer. Patients with T2/N+ or T3/any N rectal cancer were randomized either to HART twice a day (28 fractions of 1.5 Gy) to total dose 42 Gy or to HART-CT. Tumour regression grade was postoperatively assessed according to the 4-point scale as recommended by the American Joint Committee on Cancer (AJCC). The secondary endpoints included overall survival (OS), disease-free survival (DFS), toxicity of preoperative treatment, locoregional, and distant failure rates. There were 187 patients eligible for analysis: 95 in HART and 92 in the HART-CT. Median follow-up was 5.6 years. The analysis demonstrated a significantly higher chance of achieving pathologic complete response in HART-CT arm: complete response was achieved in 4/95, 4% (HART) and 11/92, 12% (HART-CT) (P = .045). The differences in OS and DFS, while tending to favour HART-CT, were not significant: OS (P = .13, hazard ratio [HR] = 0.82, 95% CI, 0.63-1.06) and DFS (P = .32; HR = 0.88, 95% CI, 0.69-1.13). The locoregional failure and distant metastases rates did not statistically differ between the trial arms. The rate of late complications was similar (P = .51), grade 3+ being 8% versus 11% in the HART/HART-CT group, respectively. The hyperfractionated preoperative radiotherapy with concurrent 5-Fu-based chemotherapy (HART-CT) improved pathological response rate compared to HART. This translated into favourable OS and DFS in HART-CT, but the differences did not reach the threshold for significance. A new hyperfractionated chemo-RT scheme is proposed. Histopathological major response (TRG 0-1) is associated with better clinical outcome.

The impact of different doses of oral iron supplementation during pregnancy: a pilot randomized trial

AbstractOral iron is first-line medication for iron deficiency anemia in pregnancy. We conducted a pilot randomized trial to investigate the impact of different doses of oral iron supplementation started early in pregnancy on women without anemia for 4 main outcomes: recruitment and protocol compliance, adherence, maintenance of maternal hemoglobin, and side effects. At antenatal clinic visits, participants were allocated to 1 of 3 trial arms in a 1:1:1 ratio: 200 mg ferrous sulfate daily, alternate days, or 3 times per week. The participants were followed to delivery. Baseline characteristics of 300 recruited participants were well matched between trial arms. The mean proportion of tablets taken as expected per participant was 82.5% overall (72.3%, 89.6%, and 84.5% for the daily, alternate days, and 3 times a week arm, respectively). There was a lower overall adherence rate in the daily arm (47%) than in the alternate days (62%) and the 3 times per week (61%) arms. A reduction in hemoglobin between randomization and 28 weeks’ gestation seemed smaller for the daily arm. A range of side effects were commonly reported at baseline before starting interventions and at later antenatal visits. Many side effects of iron overlapped with normal pregnancy symptoms. A daily iron dosing schedule might give the best opportunity for delivering an adequate iron load during pregnancy in women without anemia. Further randomized trials powered on clinical outcomes are needed to establish the clinical effectiveness of oral iron supplementation to prevent iron deficiency anemia. This study was registered (#ISRCTN12911644).

The SAInT study: a protocol for a randomized controlled trial of steroid injection for subacromial pain syndrome using the anterolateral versus posterior approach.

Steroid injections are used for subacromial pain syndrome and can be administered via the anterolateral or posterior approach to the subacromial space. It is not currently known which approach is superior in terms of improving clinical symptoms and function. This is the protocol for a randomized controlled trial (RCT) to compare the clinical effectiveness of a steroid injection given via the anterolateral or the posterior approach to the subacromial space. The Subacromial Approach Injection Trial (SAInT) study is a single-centre, parallel, two-arm RCT. Participants will be allocated on a 1:1 basis to a subacromial steroid injection via either the anterolateral or the posterior approach to the subacromial space. Participants in both trial arms will then receive physiotherapy as standard of care for subacromial pain syndrome. The primary analysis will compare the change in Oxford Shoulder Score (OSS) at three months after injection. Secondary outcomes include the change in OSS at six and 12 months, as well as the Pain Numeric Rating Scale (0 = no pain, 10 = worst pain), Disabilities of Arm, Shoulder and Hand questionnaire (DASH), and 36-Item Short-Form Health Survey (SF-36) (RAND) at three months, six months, and one year after injection. Assessment of pain experienced during the injection will also be determined. A minimum of 86 patients will be recruited to obtain an 80% power to detect a minimally important difference of six points on the OSS change between the groups at three months after injection. The results of this trial will demonstrate if there is a difference in shoulder pain and function after a subacromial space steroid injection between the anterolateral versus posterior approach in patients with subacromial pain syndrome. This will help to guide treatment for patients with subacromial pain syndrome.

Evaluating analytic models for individually randomized group treatment trials with complex clustering in nested and crossed designs.

Many individually randomized group treatment (IRGT) trials randomly assign individuals to study arms but deliver treatments via shared agents, such as therapists, surgeons, or trainers. Post-randomization interactions induce correlations in outcome measures between participants sharing the same agent. Agents can be nested in or crossed with trial arm, and participants may interact with a single agent or with multiple agents. These complications have led to ambiguity in choice of models but there have been no systematic efforts to identify appropriate analytic models for these study designs. To address this gap, we undertook a simulation study to examine the performance of candidate analytic models in the presence of complex clustering arising from multiple membership, single membership, and single agent settings, in both nested and crossed designs and for a continuous outcome. With nested designs, substantial type I error rate inflation was observed when analytic models did not account for multiple membership and when analytic model weights characterizing the association with multiple agents did not match the data generating mechanism. Conversely, analytic models for crossed designs generally maintained nominal type I error rates unless there was notable imbalance in the number of participants that interact with each agent.

Can we counterbalance restricted access to innovation through specialized breast cancer care? The REAL-NOTE study

IntroductionThe KEYNOTE-522 (KN-522) trial showed that the addition of pembrolizumab to standard chemotherapy improved pathological complete response (pCR) and event-free survival (EFS) for patients with early triple negative breast cancer (TNBC). We analyzed results of a real-world cohort of patients treated in a certified Breast Unit, before the introduction of pembrolizumab, to see if high quality care can match outcomes brought by the addition of an innovative anticancer therapy. MethodsObservational, retrospective, single-center cohort study, with real-world data from an ongoing institutional database with prespecified variables. Inclusion criteria matched the ones from KN-522: previously untreated stage II or III TNBC, diagnosed between 2012 and 2022, who received neoadjuvant chemotherapy. The primary endpoints were pCR at the time of definitive surgery and EFS; overall survival (OS) was a secondary endpoint. ResultsTotal of 168 patients were included, median age 55 years, 55 % received neoadjuvant chemotherapy with dose dense anthracyclines and taxanes and 25 % carboplatin + paclitaxel, sequenced with dose dense anthracyclines. Most had Stage II disease (82.7 %), 47 % node + disease. pCR was achieved in 52.7 % cases. At 36 months, EFS was 83.3 % (95 % CI 75.1–89.0) and OS 89 % (95 % CI, 81.6 to 93.5). ConclusionsNotwithstanding the study limitations, outcomes of patients treated with chemotherapy without immunotherapy were numerically similar to the experimental arm of KN-522 trial. These data highlight that providing care by a specialized multidisciplinary team in a certified unit might be just as impactful as the incorporation of new technologies.

Predictors of pulmonary embolism in chronic obstructive pulmonary diseases patients admitted for worsening respiratory symptoms: An individual participant data meta-analyses

BackgroundPulmonary embolism (PE) and acute exacerbation of chronic obstructive pulmonary disease (COPD) have similar clinical symptoms, making PE diagnosis challenging. Previous studies have shown that the prevalence of PE among COPD patients admitted with worsening respiratory symptoms was not negligible, but that systematic search for PE did not provide a clinical benefit. Predictive factors for PE remain unknown. Objectiveto identify predictive factors for PE among COPD patients with worsening respiratory symptoms. MethodsWe conducted an individual participant data meta-analysis which included the patients from the prospective PEP cohort and those randomized to the intervention arm in the SLICE trial which included a systematic search for PE in COPD patients admitted for worsening respiratory symptoms. Univariable and multivariable analysis were used to assess factors associated with the diagnosis of PE during the initial management. ResultsAmong 1110 COPD patients, PE was diagnosed in 61 (5.49 %; 95 %CI 4.15 %-6.84 %). In univariable analysis, BNP (Brain natriuretic peptide) (odds ratio [OR] 1.02 per 100 ng/L increase, 95 %CI 1.01–1.04), prothrombin time (OR 0.78, 95 %CI 0.65–0.94), fibrinogen (OR 0.80, 95 %CI 0.64–0.98), atrial fibrillation (OR 4.74, 95 %CI 1.84–10.80), respiratory rate ≥30 min (OR 2.34, 95 %CI 1.13–4.6) and recent medical immobilization (OR 1.79, 95 %CI 0.99–3.13]) were associated with the risk of PE diagnosed during the initial management. In multivariable analysis, respiratory rate ≥30 (OR 2.77, 95 %CI 1.08–6.71) was a predictive factor for PE, as well as BNP (OR 1.02, 95 %CI 1.00–1.05) with an area under the curve =0.64, negative predictive value =0.15 (95 %CI 0.09–0.23), sensitivity =0.78 (95 %CI 0.74–0.82) and specificity =0.46 (95 %CI 0.29–0.63). ConclusionAmong patients with COPD admitted for worsening respiratory symptoms, respiratory rate and BNP levels are predictor of PE, but with limited discriminatory power.

Percentage area reduction at week 4 as a prognostic indicator of complete healing in patients treated with standard of care: a post hoc analysis.

Early indicators of healing provide valuable information on the potential benefit of treatment. In patients with hard-to-heal (chronic) diabetic foot ulcers (DFUs), timely intervention is critical. Ulcers that fail to show measurable progress within four weeks of treatment are considered recalcitrant. These ulcers increase the risk of soft tissue infection, osteomyelitis and lower extremity amputation. A prognostic indicator or surrogate marker allows for rapid evaluation of treatment efficacy and safety. An inverse correlation between a percentage area reduction (PAR) of ≤50% at week 4 and complete healing by week 12 has been previously established; however, the data were derived from a standard of care (SoC) arm of clinical trials that are over a decade old. In this post hoc analysis, data from a large multicentre prospective randomised controlled trial were reviewed to assess PAR at week 4 as a prognostic indicator in patients treated with SoC. Overall, 65.4% (17/26) of patients with PAR >50% at week 4 achieved complete closure at week 12. The receiver operating characteristic (ROC) curve for area reduction by week 4 showed strong discrimination for predicting non-healing (area under the ROC curve: 0.92; p<0.001; positive predictive value: 70.6%; negative predictive value: 87.2%). These findings are consistent with previous studies and support the use of four-week PAR as a prognostic indicator.

Atrial Fibrillation Burden on a 14-Day ECG Monitor: Findings From the GUARD-AF Trial Screening Arm

BackgroundThe “burden” of atrial fibrillation (AF) detected by screening likely influences stroke risk, but the distribution of burden is not well described. ObjectivesThis study aims to determine the frequency of AF and the distribution of AF burden found when screening individuals ≥70 years of age with a 14-day electrocardiograph monitor. MethodsThis is a cohort study of the screening arm of a randomized AF screening trial among those ≥70 years of age without a prior AF diagnosis (between 2019 and 2021). Screening was performed with a 14-day continuous electrocardiogram patch monitor. ResultsAnalyzable patches were returned by 5,684 (95%) of screening arm participants; the median age was 75 years (Q1-Q3: 72-78 years), 57% were female, and the median CHA2DS2-VASc score was 3 (Q1-Q3: 2-4). AF was detected in 252 participants (4.4%); 29 (0.5%) patients had continuous AF and 223 (3.9%) had paroxysmal AF. Among those with paroxysmal AF, the average indices of AF burden were of low magnitude with right-skewed distributions. The median percent time in AF was 0.46% (Q1-Q3: 0.02%-2.48%), or 75 (Q1-Q3: 3-454) minutes, and the median longest episode was 38 (Q1-Q3: 2-245) minutes. The upper quartile threshold of 2.48% time in AF corresponded to 7.6 hours. Age greater than 80 years was associated with screen-detected AF in our multivariable model (OR: 1.46; 95% CI: 1.06-2.02). ConclusionsMost AF detected in these older patients was very low burden. However, one-quarter of those with AF had multiple hours of AF, raising concern about stroke risk. These findings have implications for targeting populations for AF screening trials and for responding to heart rhythm alerts from mobile devices (GUARD-AF [A Study to Determine if Identification of Undiagnosed Atrial Fibrillation in People at least 70 Years of Age Reduces the Risk of Stroke]; NCT04126486)

Palbociclib in Solid Tumor Patients With Genomic Alterations in the cyclinD-cdk4/6-INK4a-Rb Pathway: Results From National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice Trial Arm I (APEC1621I).

The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib. Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years. The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival. Twenty-three patients (median age, 15 years; range, 8-21) were enrolled; 20 received protocol therapy and were evaluable for toxicity and response. Of the evaluable patients, the most common diagnoses were osteosarcoma (n = 9) and rhabdomyosarcoma (n = 6). A single actionable gene amplification was found in 19 tumors (CDK4, n = 11, CDK6, n = 2, CCND3, n = 6), with one tumor harboring two amplifications (CDK4 and CCND2). Hematologic toxicities were the most common treatment-related events. No objective responses were seen. Two patients with tumors harboring CDK4 amplifications (neuroblastoma and sarcoma) had best response of stable disease for six and three cycles. Six-month progression was 10% (95% CI, 1.7 to 27.2). The CDK4/6 inhibitor palbociclib at 75 mg/m2 orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.

Addressing the Evidence Gap in Aneurysmal Subarachnoid Hemorrhage: The Need for a Pragmatic Randomized Trial Platform.

Aneurysmal subarachnoid hemorrhage (aSAH) occurs less often than other stroke types but affects younger patients, imposing a disproportionately high burden of long-term disability. Although management advances have improved outcomes over time, relatively few aSAH treatments have been tested in randomized clinical trials (RCTs). One lesson learned from COVID-19 is that trial platforms can facilitate the efficient execution of multicenter RCTs even in complex diseases during challenging conditions. An aSAH trial platform with standardized eligibility criteria, randomization procedures, and end point definitions would enable the study of multiple targeted interventions in a perpetual manner, with treatments entering and leaving the platform based on predefined decision algorithms. An umbrella institutional review board protocol and clinical trial agreement would allow individual arms to be efficiently added as amendments rather than stand-alone protocols. Standardized case report forms using the National Institutes of Health/National Institute of Neurological Disorders and Stroke common data elements and general protocol standardization across arms would create synergies for data management and monitoring. A Bayesian analysis framework would emphasize frequent interim looks to enable early termination of trial arms for futility, common controls, borrowing of information across arms, and adaptive designs. A protocol development committee would assist investigators and encourage pragmatic designs to maximize generalizability, reduce site burden, and execute trials efficiently and cost-effectively. Despite decades of steady clinical progress in the management of aSAH, poor patient outcomes remain common, and despite the increasing availability of RCT data in other fields, it remains difficult to perform RCTs to guide more effective care for aSAH. The development of a platform for pragmatic RCTs in aSAH would help close the evidence gap between aSAH and other stroke types and improve outcomes for this important disease with its disproportionate public health burden.

Bridged Treatment Comparisons: an Illustrative Application in HIV Treatment.

Comparisons of treatments, interventions, or exposures are of central interest in epidemiology, but direct comparisons are not always possible due to practical or ethical reasons. Here, we detail a fusion approach to compare treatments across studies. The motivating example entails comparing the risk of the composite outcome of death, AIDS, or greater than a 50% CD4 cell count decline in people with HIV when assigned triple versus mono antiretroviral therapy, using data from the AIDS Clinical Trial Group (ACTG) 175 (mono versus dual therapy) and ACTG 320 (dual versus triple therapy). We review a set of identification assumptions and estimate the risk difference using an inverse probability weighting estimator that leverages the shared trial arms (dual therapy). A fusion diagnostic based on comparing the shared arms is proposed that may indicate violation of the identification assumptions. Application of the data fusion estimator and diagnostic to the ACTG trials indicates triple therapy results in a reduction in risk compared to monotherapy in individuals with baseline CD4 counts between 50 and 300 cells/mm3. Bridged treatment comparisons address questions that none of the constituent data sources could address alone, but valid fusion-based inference requires careful consideration of the underlying assumptions.

Pharmacokinetics of extended-release clarithromycin in patients with Mycobacterium ulcerans infection

Clarithromycin extended-release (CLA-ER) was used as companion drug to rifampicin (RIF) for Mycobacterium ulcerans infection in the intervention arm of a WHO drug trial. RIF enhances CYP3A4 metabolism, thereby reducing CLA serum concentrations, and RIF concentrations might be increased by CLA co-administration. We studied the pharmacokinetics of CLA-ER at a daily dose of 15 mg/kg combined with RIF at a dose of 10 mg/kg in a subset of trial participants, and compared these to previously obtained pharmacokinetic data. Serial dried blood spot samples were obtained over a period of ten hours, and analyzed by LC–MS/MS in 30 study participants—20 in the RIF-CLA study arm, and 10 in the RIF-streptomycin study arm. Median CLA Cmax was 0.4 mg/L—and median AUC 3.9 mg*h/L, following 15 mg/kg CLA-ER. Compared to standard CLA dosed at 7.5 mg/kg previously, CLA-ER resulted in a non-significant 58% decrease in Cmax and a non-significant 30% increase in AUC. CLA co-administration did not alter RIF Cmax or AUC. Treatment was successful in all study participants. No effect of CLA co-administration on RIF pharmacokinetics was observed. Based on our serum concentration studies, the benefits CLA-ER over CLA immediate release are unclear.

A double-masked, sham-controlled trial of rose bengal photodynamic therapy for the treatment of fungal and acanthamoeba keratitis: Rose Bengal Electromagnetic Activation with Green Light for Infection Reduction (REAGIR) study

BackgroundInfectious keratitis secondary to fungus or acanthamoeba often has a poor outcome despite receiving the best available medical therapy. In vitro rose bengal photodynamic therapy (RB-PDT) appears to be effective against fungal and acanthamoeba isolates (Atalay HT et al., Curr Eye Res 43:1322–5, 2018, Arboleda A et al. Am J Ophthalmol 158:64-70, 2014). In one published series, RB-PDT reduced the need for therapeutic penetrating keratoplasty in severe bacterial, fungal, and acanthamoeba keratitis not responsive to medical therapy.MethodsThis international, randomized, sham and placebo controlled 2-arm clinical trial randomizes patients with smear positive fungal and acanthamoeba and smear negative corneal ulcers in a 1:1 fashion to one of two treatment arms: 1) topical antimicrobial plus sham RB-PDT or 2) topical antimicrobial plus RB-PDT.DiscussionWe anticipate that RB-PDT will improve best spectacle-corrected visual acuity and also reduce complications such as corneal perforation and the need for therapeutic penetrating keratoplasty. This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Our results will be disseminated via ClinicalTrials.gov website, meetings, and journal publications. Our data will also be available upon reasonable request.Trial registrationNCT, NCT05110001, Registered on November 5, 2021.

Defining non-inferiority margins in randomised controlled surgical trials: a protocol for a systematic review

BackgroundThe reporting of randomised controlled non-inferiority (NI) drug trials is poor with less than 50% of published trials reporting a justification of the NI margin. This is despite the introduction...