Perispinal Etanercept to improve STroke Outcomes (PESTO): Protocol for a multicenter, international, randomized placebo-controlled trial.

RATIONALE: A large proportion of stroke survivors will have long-lasting, debilitating neurological impairments, yet few efficacious medical treatment options are available. Etanercept inhibits binding of tumor necrosis factor to its receptor and is used in the treatment of inflammatory conditions. Perispinal subcutaneous injection followed by a supine, head down position may bypass the blood brain barrier. In observational studies and one small randomized controlled trial the majority of patients showed improvement in multiple post stroke impairments. AIM: Perispinal Etanercept to improve STroke Outcomes (PESTO) investigates whether perispinal subcutaneous injection of etanercept improves quality of life and is safe in patients with chronic, disabling, effects of stroke. METHODS AND DESIGN: PESTO is a multicenter, international, randomized placebo-controlled trial. Adult participants with a history of stroke between 1 and 15 years before enrollment and a current modified Rankin scale between 2 and 5 who are otherwise eligible for etanercept are randomized 1:1 to single dose injection of etanercept or placebo. STUDY OUTCOMES: The primary efficacy outcome is quality of life as measured using the Short Form 36 Health Inventory at day 28 after first injection. Safety outcomes include serious adverse events. SAMPLE SIZE TARGET: A total of 168 participants assuming an improvement of the SF-36 in 11% of participants in the control arm and in 30% of participants in the intervention arm, 80% power and 5% alpha. DISCUSSION: PESTO aims to provide level 1 evidence on the safety and efficacy of perispinal etanercept in patients with long-term disabling effects of stroke.

A phase III, multi-arm multi-stage covariate-adjusted response-adaptive randomized trial to determine optimal early mobility training after stroke (AVERT DOSE).

RATIONALE: The evidence base for acute post-stroke rehabilitation is inadequate and global guideline recommendations vary. AIM: To define optimal early mobility intervention regimens for ischemic stroke patients of mild and moderate severity. HYPOTHESES: Compared with a prespecified reference arm, the optimal dose regimen(s) will result in more participants experiencing little or no disability (mRS 0-2) at 3 months post-stroke (primary), fewer deaths at 3 months, fewer and less severe complications during the intervention period, faster recovery of unassisted walking, and better quality of life at 3 months (secondary). We also hypothesize that these regimens will be more cost-effective. SAMPLE SIZE ESTIMATES: For the primary outcome, recruitment of 1300 mild and 1400 moderate participants will yield 80% power to detect a 10% risk difference. METHODS AND DESIGN: Multi-arm multi-stage covariate-adjusted response-adaptive randomized trial of mobility training commenced within 48 h of stroke in mild (NIHSS < 7) and moderate (NIHSS 8-16) stroke patient strata, with analysis of blinded outcomes at 3 (primary) and 6 months. Eligibility criteria are broad, while excluding those with severe premorbid disability (mRS > 2) and hemorrhagic stroke. With four arms per stratum (reference arm retained throughout), only the single treatment arm demonstrating the highest proportion of favorable outcomes at the first stage will proceed to the second stage in each stratum, resulting in a final comparison with the reference arm. Three prognostic covariates of age, geographic region and reperfusion interventions, as well as previously observed mRS 0-2 responses inform the adaptive randomization procedure. Participants randomized receive prespecified mobility training regimens (functional task-specific), provided by physiotherapists/nurses until discharge or 14 days. Interventions replace usual mobility training. Fifty hospitals in seven countries (Australia, Malaysia, United Kingdom, Ireland, India, Brazil, Singapore) are expected to participate. SUMMARY: Our novel adaptive trial design will evaluate a wider variety of mobility regimes than a traditional two-arm design. The data-driven adaptions during the trial will enable a more efficient evaluation to determine the optimal early mobility intervention for patients with mild and moderate ischemic stroke.

AVERT2 (a very early rehabilitation trial, a very effective reproductive trigger): retrospective observational analysis of the number of babies born to trial staff.

OBJECTIVE: To report the number of participants needed to recruit per baby born to trial staff during AVERT, a large international trial on acute stroke, and to describe trial management consequences. DESIGN: Retrospective observational analysis. SETTING: 56 acute stroke hospitals in eight countries. PARTICIPANTS: 1074 trial physiotherapists, nurses, and other clinicians. OUTCOME MEASURES: Number of babies born during trial recruitment per trial participant recruited. RESULTS: With 198 site recruitment years and 2104 patients recruited during AVERT, 120 babies were born to trial staff. Births led to an estimated 10% loss in time to achieve recruitment. Parental leave was linked to six trial site closures. The number of participants needed to recruit per baby born was 17.5 (95% confidence interval 14.7 to 21.0); additional trial costs associated with each birth were estimated at 5736 Australian dollars on average. CONCLUSION: The staff absences registered in AVERT owing to parental leave led to delayed trial recruitment and increased costs, and should be considered by trial investigators when planning research and estimating budgets. However, the celebration of new life became a highlight of the annual AVERT collaborators' meetings and helped maintain a cohesive collaborative group. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry no 12606000185561. DISCLAIMER: Participation in a rehabilitation trial does not guarantee successful reproductive activity.