Adopt to adapt: Efforts to Keep the RAMPART Trial of Adjuvant Immunotherapy in Renal Cancer on Track in the COVID-19 Era

Introduction: The RAMPART trial is an international, UCL-led, multi-arm multi-stage (MAMS) platform trial investigating the use of immune checkpoint inhibitors after nephrectomy in patients with renal cell carcinoma. It was initiated with a control (active monitoring) and two research arms (durvalumab monotherapy and durvalumab with tremelimumab) and has been open to recruitment since July 2018. Due to the COVID-19 pandemic, recruitment and treatment delivery was suspended for four months in the Spring/Summer of 2020 and accrual has only recovered in 2022. / Methods/Approach: The RAMPART team provided clear communication to sites on how to manage priorities during the temporary suspension and relaunch of the trial. The protocol was amended to ensure the safe treatment of patients and to offer flexibility to conduct consent and certain assessments remotely. Sites were asked to focus on the submission of high priority data to permit continued oversight of patient safety and allow primary outcome data to be collected. Data completeness has been carefully monitored and targeted data chases have been conducted to maximise data integrity. We have explored the extent to which the pandemic will prolong recruitment and follow-up, and the timelines for our primary analyses. To maximise options for patients and to aid accrual, we examined the impact of re-randomisation of control arm patients within the protocol, an approach that has been employed in other trials within the CTU in other disease areas. / Results Structure & Timelines: This section will contain an update on compliance, recruitment, sites open and timelines for analysis. In order to be able to present these adequately and robustly, we will use data up to September 2022. / Potential Relevance & Impact: The pandemic era has been challenging for clinical trials. Adaptations can be made to prioritise patient safety, to allow activity to continue where there is capacity and to ensure trial integrity is maintained

Effect of small-vessel disease on cognitive trajectory after atrial fibrillation-related ischaemic stroke or TIA

Post-stroke dementia is common but has heterogenous mechanisms that are not fully understood, particularly in patients with atrial fibrillation (AF)-related ischaemic stroke or TIA. We investigated the relationship between MRI small-vessel disease markers (including a composite cerebral amyloid angiopathy, CAA, score) and cognitive trajectory over 12 months. We included patients from the CROMIS-2 AF study without pre-existing cognitive impairment and with Montreal Cognitive Assessment (MoCA) data. Cognitive impairment was defined as MoCA < 26. We defined "reverters" as patients with an "acute" MoCA (immediately after the index event) score < 26, who then improved by ≥ 2 points at 12 months. In our cohort (n = 114), 12-month MoCA improved overall relative to acute performance (mean difference 1.69 points, 95% CI 1.03-2.36, p < 0.00001). 12-month cognitive impairment was associated with increasing CAA score (per-point increase, adjusted OR 4.09, 95% CI 1.36-12.33, p = 0.012). Of those with abnormal acute MoCA score (n = 66), 59.1% (n = 39) were "reverters". Non-reversion was associated with centrum semi-ovale perivascular spaces (per-grade increase, unadjusted OR 1.83, 95% CI 1.06-3.15, p = 0.03), cerebral microbleeds (unadjusted OR 10.86, 95% CI 1.22-96.34, p = 0.03), and (negatively) with multiple ischaemic lesions at baseline (unadjusted OR 0.11, 95% CI 0.02-0.90, p = 0.04), as well as composite small-vessel disease (per-point increase, unadjusted OR 2.91, 95% CI 1.23-6.88, p = 0.015) and CAA (per-point increase, unadjusted OR 6.71, 95% CI 2.10-21.50, p = 0.001) scores. In AF-related acute ischaemic stroke or TIA, cerebral small-vessel disease is associated both with cognitive performance at 12 months and failure to improve over this period

Small vessel disease burden and intracerebral haemorrhage in patients taking oral anticoagulants

OBJECTIVE We investigated the contribution of small vessel disease (SVD) to anticoagulant-associated intracerebral haemorrhage (ICH). METHODS Clinical Relevance of Microbleeds in Stroke-2 comprised two independent multicentre observation studies: first, a cross-sectional study of patients with ICH; and second, a prospective study of patients taking anticoagulants for atrial fibrillation (AF) after cerebral ischaemia. In patients with ICH, we compared SVD markers on CT and MRI according to prior anticoagulant therapy. In patients with AF and cerebral ischaemia treated with anticoagulants, we compared the rates of ICH and ischaemic stroke according to SVD burden score during 2 years follow-up. RESULTS We included 1030 patients with ICH (421 on anticoagulants), and 1447 patients with AF and cerebral ischaemia. Medium-to-high severity SVD was more prevalent in patients with anticoagulant-associated ICH (CT 56.1%, MRI 78.7%) than in those without prior anticoagulant therapy (CT 43.5%, p<0.001; MRI 64.5%, p=0.072). Leukoaraiosis and atrophy were more frequent and severe in ICH associated with prior anticoagulation. In the cerebral ischaemia cohort (779 with SVD), during 3366 patient-years of follow-up the rate of ICH was 0.56%/year (IQR 0.27-1.03) in patients with SVD, and 0.06%/year (IQR 0.00-0.35) in those without (p=0.001); ICH was independently associated with severity of SVD (HR 5.0, 95% CI 1.9 to 12.2,p=0.001), and was predicted by models including SVD (c-index 0.75, 95% CI 0.63 to 0.85). CONCLUSIONS Medium-to-high severity SVD is associated with ICH occurring on anticoagulants, and independently predicts ICH in patients with AF taking anticoagulants; its absence identifies patients at low risk of ICH. Findings from these two complementary studies suggest that SVD is a contributory factor in ICH in patients taking anticoagulants and suggest that anticoagulation alone should no longer be regarded as a sufficient 'cause' of ICH. TRIAL REGISTRATION NCT02513316

Early versus late anticoagulation for ischaemic stroke associated with atrial fibrillation: multicentre cohort study

BACKGROUND AND PURPOSE: The optimal time to start oral anticoagulant (OAC) in patients with ischaemic stroke due to non-valvular atrial fibrillation (AF) is unknown. We reviewed OAC timing in relation to 90-day clinical outcomes as a post hoc analysis from a prospective multicentre observational study. METHODS: We included patients with data on time to initiation of OAC from CROMIS-2 (Clinical Relevence Of Microbleeds In Stroke-2), a prospective observational inception cohort study of 1490 patients with ischaemic stroke or transient ischaemic attack (TIA) and AF treated with OAC. The primary outcome was the composite outcome of TIA, stroke (ischaemic stroke or intracranial haemorrhage) or death within 90 days of the qualifying stroke or TIA. We performed adjusted logistic regression analyses to compare early (0-4 days) and later (≥5 days or never started) OAC initiation. RESULTS: We included 1355 patients, mean age 76 (SD 10), 580 (43%) women. OAC was started early in 358 (26%) patients and later (or not at all) in 997 (74%) patients. The event rate within 90 days was 48/997 (5%) in the late-OAC group (2 intracranial haemorrhages, 18 ischaemic strokes or TIAs and 31 deaths (three deaths were as a result of new ischaemic strokes)) versus 7/358 (2%) in the early-OAC group (5 ischaemic strokes or TIAs and 2 deaths). In adjusted analyses, late OAC was not associated with the composite outcome (adjusted OR 1.17, 95% CI 0.48 to 2.84, p=0.736). CONCLUSION: In adjusted analyses, early OAC after acute ischaemic stroke or TIA associated with AF was not associated with a difference in the rate of the composite outcome of stroke, TIA or death at 90 days, compared with late OAC. However, despite adjustment for important baseline factors, patients selected for early OAC and late OAC might still have differed in important respects; evaluation of OAC timing in adequately powered randomised trials is required. CLINICAL TRIAL REGISTRATION: NCT02513316

RAMPART : a model for a regulatory-ready academic-led phase III trial in the adjuvant renal cell carcinoma setting

AstraZeneca LP have provided an educational grant for the trial and free of charge durvalumab and tremelimumab. A small grant is also provided by Kidney Cancer UK. MRC CTU at UCL provides funding for staff working on the trial.The development of therapeutics in oncology is a highly active research area for the pharmaceutical and biotechnology industries, but also has a strong academic base. Many new agents have been developed in recent years, most with specific biological targets. This has mandated the need to look at different ways to streamline the evaluation of new agents. One solution has been the development of adaptive trial designs that allow the evaluation of multiple agents, concentrating on the most promising agents while screening out those which are unlikely to benefit patients. Another way forward has been the growth of partnerships between academia and industry with the shared goal of designing and conducting high quality clinical trials which answer important clinical questions as efficiently as possible. The RAMPART trial (NCT03288532) brings together both of these processes in an attempt to improve outcomes for patients with locally advanced renal cell carcinoma (RCC), where no globally acceptable adjuvant strategy after nephrectomy currently exist. RAMPART is led by the MRC CTU at University College London (UCL), in collaboration with other international academic groups and industry. We aim to facilitate the use of data from RAMPART, (dependent on outcomes), for a future regulatory submission that will extend the license of the agents being investigated. We share our experience in order to lay the foundations for an effective trial design and conduct framework and to guide others who may be considering similar collaborations.Publisher PDFPeer reviewe

RAMPART : a phase III multi-arm multi-stage trial of adjuvant checkpoint inhibitors in patients with resected primary renal cell carcinoma (RCC) at high or intermediate risk of relapse

AstraZeneca LP have provided an educational grant for the trial and free of charge durvalumab and tremelimumab. A small grant is also provided by Kidney Cancer UK. MRC CTU at UCL also provides funding for staff working on the trial. The TransRAMPART sample collection is being funded by a Prospective Sample Collection award from Cancer Research UK.Background 20–60% of patients with initially locally advanced Renal Cell Carcinoma (RCC) develop metastatic disease despite optimal surgical excision. Adjuvant strategies have been tested in RCC including cytokines, radiotherapy, hormones and oral tyrosine-kinase inhibitors (TKIs), with limited success. The predominant global standard-of-care after nephrectomy remains active monitoring. Immune checkpoint inhibitors (ICIs) are effective in the treatment of metastatic RCC; RAMPART will investigate these agents in the adjuvant setting. Methods/design RAMPART is an international, UK-led trial investigating the addition of ICIs after nephrectomy in patients with resected locally advanced RCC. RAMPART is a multi-arm multi-stage (MAMS) platform trial, upon which additional research questions may be addressed over time. The target population is patients with histologically proven resected locally advanced RCC (clear cell and non-clear cell histological subtypes), with no residual macroscopic disease, who are at high or intermediate risk of relapse (Leibovich score 3–11). Patients with fully resected synchronous ipsilateral adrenal metastases are included. Participants are randomly assigned (3,2:2) to Arm A - active monitoring (no placebo) for one year, Arm B - durvalumab (PD-L1 inhibitor) 4-weekly for one year; or Arm C - combination therapy with durvalumab 4-weekly for one year plus two doses of tremelimumab (CTLA-4 inhibitor) at day 1 of the first two 4-weekly cycles. The co-primary outcomes are disease-free-survival (DFS) and overall survival (OS). Secondary outcomes include safety, metastasis-free survival, RCC specific survival, quality of life, and patient and clinician preferences. Tumour tissue, plasma and urine are collected for molecular analysis (TransRAMPART).Publisher PDFPeer reviewe

Developmental dyslexia in Chinese and English populations: dissociating the effect of dyslexia from language differences

Previous neuroimaging studies have suggested that developmental dyslexia has a different neural basis in Chinese and English populations because of known differences in the processing demands of the Chinese and English writing systems. Here, using functional magnetic resonance imaging, we provide the first direct statistically based investigation into how the effect of dyslexia on brain activation is influenced by the Chinese and English writing systems. Brain activation for semantic decisions on written words was compared in English dyslexics, Chinese dyslexics, English normal readers and Chinese normal readers, while controlling for all other experimental parameters. By investigating the effects of dyslexia and language in one study, we show common activation in Chinese and English dyslexics despite different activation in Chinese versus English normal readers. The effect of dyslexia in both languages was observed as less than normal activation in the left angular gyrus and in left middle frontal, posterior temporal and occipitotemporal regions. Differences in Chinese and English normal reading were observed as increased activation for Chinese relative to English in the left inferior frontal sulcus; and increased activation for English relative to Chinese in the left posterior superior temporal sulcus. These cultural differences were not observed in dyslexics who activated both left inferior frontal sulcus and left posterior superior temporal sulcus, consistent with the use of culturally independent strategies when reading is less efficient. By dissociating the effect of dyslexia from differences in Chinese and English normal reading, our results reconcile brain activation results with a substantial body of behavioural studies showing commonalities in the cognitive manifestation of dyslexia in Chinese and English populations. They also demonstrate the influence of cognitive ability and learning environment on a common neural system for reading

Outcome of intracerebral hemorrhage associated with different oral anticoagulants

Objective: In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non-vitamin K antagonist oral anticoagulation-related ICH (NOAC-ICH) and vitamin K antagonist-associated ICH (VKA-ICH). Methods: We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score 33% or >6 mL from baseline within 72 hours. Results: We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6-38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0-27.9) for VKA-ICH (p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52-1.64] [p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18-1.19 [p = 0.11]). Conclusions: In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH.Peer reviewe

Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation

Objective: We compared outcomes after treatment with direct oral anticoagulants (DOAC) and Vitamin‐K antagonists (VKA) in patients with atrial fibrillation (AF) and a recent cerebral ischemia. Methods: We conducted an individual patient data analysis of 7 prospective cohort studies. We included patients with AF and a recent cerebral ischemia (&lt;3 months before starting oral anticoagulation) and a minimum follow‐up of 3 months. We analyzed the association between type of anticoagulation (DOAC vs. VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HR) with 95% confidence intervals (95% CI). Results: We included 4912 patients (median age 78 years [IQR 71‐84]; 2331 [47.5%] women, median NIHSS at onset 5 [IQR 2‐12]); 2256 (45.9%) patients received VKA and 2656 (54.1%) DOAC. The median time from index event to starting oral anticoagulation was 5 days (IQR 2‐14) for VKA and 5 days (IQR 2‐11) for DOAC (p=0.53). There were 262 AIS (4.4%/year), 71 ICH (1.2%/year) and 439 deaths (7.4%/year) during the total follow‐up of 5970 patient‐years. Compared to VKA, DOAC treatment was associated with reduced risks of the composite endpoint (HR 0.82, 95%CI 0.67‐1.00, p=0.05) and ICH (HR 0.42, 95%CI 0.24‐0.71, p&lt;0.01); we found no differences for the risk of recurrent AIS (HR 0.91, 95%CI 0.70‐1.19, p=0.5) and mortality (HR 0.83, 95%CI 0.68‐1.03, p=0.09). Interpretation: DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly due to lower risks of ICH