scholarly journals A platform trial in practice: adding a new experimental research arm to the ongoing confirmatory FLAIR trial in chronic lymphocytic leukaemia

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Dena R. Howard ◽  
Anna Hockaday ◽  
Julia M. Brown ◽  
Walter M. Gregory ◽  
Susan Todd ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukaemia ◽  
Type I Error ◽  
Lymphocytic Leukaemia ◽  
Experimental Therapy ◽  
Type I ◽  
Open Label ◽  
Additional Funding ◽  
Trial Structure ◽  
Randomised Controlled ◽  
The Uk

Abstract Background The FLAIR trial in chronic lymphocytic leukaemia has a randomised, controlled, open-label, confirmatory, platform design. FLAIR was successfully amended to include an emerging promising experimental therapy to expedite its assessment, greatly reducing the time to reach the primary outcome compared to running a separate trial and without compromising the validity of the research or the ability to recruit to the trial and report the outcomes. The methodological and practical issues are presented, describing how they were addressed to ensure the amendment was a success. Methods FLAIR was designed as a two-arm trial requiring 754 patients. In stage 2, two new arms were added: a new experimental arm and a second control arm to protect the trial in case of a change in practice. In stage 3, the original experimental arm was closed as its planned recruitment target was reached. In total, 1516 participants will be randomised to the trial. Results The changes to the protocol and randomisation to add and stop arms were made seamlessly without pausing recruitment. The statistical considerations to ensure the results for the original and new hypotheses are unbiased were approved following peer review by oversight committees, Cancer Research UK, ethical and regulatory committees and pharmaceutical partners. These included the use of concurrent comparators in case of any stage effect, appropriate control of the type I error rate and consideration of analysis methods across trial stages. The operational aspects of successfully implementing the amendments are described, including gaining approvals and additional funding, data management requirements and implementation at centres. Conclusions FLAIR is an exemplar of how an emerging experimental therapy can be assessed within an existing trial structure without compromising the conduct, reporting or validity of the trial. This strategy offered considerable resource savings and allowed the new experimental therapy to be assessed within a confirmatory trial in the UK years earlier than would have otherwise been possible. Despite the clear efficiencies, treatment arms are rarely added to ongoing trials in practice. This paper demonstrates how this strategy is acceptable, feasible and beneficial to patients and the wider research community. Trial registration ISRCTN Registry ISRCTN01844152. Registered on August 08, 2014

scholarly journals Cognitive tests used in chronic adult human randomised controlled trial micronutrient and phytochemical intervention studies

2010 ◽  
Vol 23 (2) ◽  
pp. 200-229 ◽  
Author(s):  
Anna L. Macready ◽  
Laurie T. Butler ◽  
Orla B. Kennedy ◽  
Judi A. Ellis ◽  
Claire M. Williams ◽  
...  
Keyword(s):  
Randomised Controlled Trial ◽  
Statistical Power ◽  
Type I Error ◽  
Spatial Working Memory ◽  
Controlled Trial ◽  
Type I ◽  
Cognitive Tests ◽  
Cognitive Domains ◽  
Positive Effects ◽  
Randomised Controlled

In recent years there has been a rapid growth of interest in exploring the relationship between nutritional therapies and the maintenance of cognitive function in adulthood. Emerging evidence reveals an increasingly complex picture with respect to the benefits of various food constituents on learning, memory and psychomotor function in adults. However, to date, there has been little consensus in human studies on the range of cognitive domains to be tested or the particular tests to be employed. To illustrate the potential difficulties that this poses, we conducted a systematic review of existing human adult randomised controlled trial (RCT) studies that have investigated the effects of 24 d to 36 months of supplementation with flavonoids and micronutrients on cognitive performance. There were thirty-nine studies employing a total of 121 different cognitive tasks that met the criteria for inclusion. Results showed that less than half of these studies reported positive effects of treatment, with some important cognitive domains either under-represented or not explored at all. Although there was some evidence of sensitivity to nutritional supplementation in a number of domains (for example, executive function, spatial working memory), interpretation is currently difficult given the prevailing ‘scattergun approach’ for selecting cognitive tests. Specifically, the practice means that it is often difficult to distinguish between a boundary condition for a particular nutrient and a lack of task sensitivity. We argue that for significant future progress to be made, researchers need to pay much closer attention to existing human RCT and animal data, as well as to more basic issues surrounding task sensitivity, statistical power and type I error.

Safety and efficacy of perioperative cisplatin/gemcitabine (cis/gem) and durvalumab (durva) for operable muscle-invasive urothelial carcinoma (MIUC): SAKK 06/17.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 430-430
Author(s):  
Richard Cathomas ◽  
Sacha Rothschild ◽  
Stefanie Hayoz ◽  
Martin Spahn ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Type I Error ◽  
Checkpoint Inhibitors ◽  
Neoadjuvant Treatment ◽  
Upper Urinary Tract ◽  
Pathological Response ◽  
R0 Resection ◽  
Type I ◽  
Open Label ◽  
Perioperative Morbidity

430 Background: The combination of cisplatin-based chemotherapy with immune checkpoint inhibitors is extensively investigated in urothelial carcinoma. Using this combination in the neoadjuvant setting for patients (pts) with MIUC might improve pathological response rate (PaR: <ypT2N0) but carries the risk of increased perioperative morbidity. Methods: SAKK 06/17 is an open-label single arm phase II trial for pts with operable MIUC cT2-T4a cN0-1. Treatment consists of 4 cycles of neoadjuvant cis/gem q3w in combination with 4 cycles durva 1500mg q3w followed by resection. Durva is continued after surgery q4w for 10 cycles. Primary endpoint is event free survival (EFS) at 2 years. 58 pts are needed based on type I error of 10% and a power of 80% for H1 EFS at 2 years ≥ 65% compared to H0 EFS at 2 years ≤ 50%. We report the secondary endoints PaR, pathological complete remission (pCR: ypT0 N0), and safety on the full analysis set (FAS, received at least one dose of durva). Results: 61 pts were included between 7/18 and 9/19 at 12 sites. The FAS consists of 58 pts (79% male, median age 67.5 yrs) with bladder cancer (95%) or upper urinary tract/urethral cancer (5%). Clinical T2, T3, T4 stage were present at diagnosis in 69%, 21%, 10%, respectively, and 17% had cN1. 95% of pts received all 4 doses of neoadjuvant durva, 81% all 4 cycles of cis/gem and 17% switched to carboplatin. In total grade 3 and 4 adverse events (AE) during neoadjuvant treatment occurred in 48% and 27%, respectively. AEs related to durva were G3 in 7 pts (12%) and G4 in one patient (2%). Resection was performed in 53 pts (91%; 51 radical cystectomy, 2 nephroureterectomy), 4 pts refused surgery and one patient was irresectable due to a frozen pelvis. R0 resection was achieved in 52 pts (98%), one had R1. Postoperative complications included Clavien-Dindo III in 13 pts (24%) and IV in 5 pts (9%). PaR was found in 60% (95% CI 46.0%-73.5%) with 18 pts achieving pCR (34%; 95% CI 21.5%-48.3%) and 14 patients (26%) ypT1/ypTis. Conclusions: The first FAS results for neoadjuvant durvalumab in combination with cis/gem for operable MIUC confirm elevated pathological response rates and demonstrate acceptable safety. Postoperative morbidity is relevant but not exceeding the expected frequency or severity. Clinical trial information: NCT03406650.

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