Interim Analyses Clause Samples

Interim Analyses. No interim analysis is planned.

Interim Analyses. No planned interim analysis will be performed. The data safety monitoring board (DSMB) will analyze a proxy endpoint, in-hospital mortality, for subject safety. The stopping guidelines are defined as follows: The primary endpoint will be analyzed for safety reasons if a difference in in-hospital mortality of >6% is found with a p-value <0.005 (Chi square test). The study will only be stopped early for safety reasons if a difference in primary endpoint (28-day mortality) is found of >6% with a p-value of <0.001. Subgroup-analyses are planned to investigate the effects of oxygenation targets on the primary endpoint in the following subgroups: ARDS at ICU admission, patients with sepsis as reason for admission, patients with stroke, patients with myocardial infarction and patients with elevated plasma lactate (> 2 mmol/l). Analysis will primarily be performed following the intention to treat principle. To handle protocol non-adherence a secondary per protocol analysis will be performed. No or minimal losses to follow-up for the primary outcome is anticipated. Complete- case analysis will be carried out for all the outcomes. However, if more than 5% of missing data is found for the primary outcome, a sensitivity analysis using multiple imputations will be carried out. OVERSIGHT AND MONITORING The coordinating center and steering committee will provide trial oversight and is composed of the principal investigator, leading investigators and experts of ventilation who contributed to the design and revision of the study protocol. The leading investigators are responsible for the daily management of the trial and provide assistance to participating ICUs in training in study related procedures for the local staff, trial management, data management and monitoring. Local investigators in each site will screen the patients who require mechanical ventilation and check if they are eligible for participation, perform randomization, supervise data collection and ensure adherence to the ICH-GCP guidelines during the trial. An independent Data Safety and Monitoring Board (DSMB) watches over the ethics of conducting the study in accordance with the Declaration of Helsinki, monitors safety parameters and the overall conduct of the study. The DSMB is composed of three independent individuals. The DSMB will meet at least yearly. No competing interests were reported by the DSMB. Adverse events (AE) are defined as any undesirable experience occurring to a subject during the study,...

Interim Analyses. 1Timeframe and data population Eg., safety data at end of week 12 Business Need Eg., IDMC 1Timeframe can be either relative (at end of week 12) or a specific date (18Jun02) 6 CDS involvement in Investigator/Coordinator Meetings {insert level of involvement in meetings} 7 Study-specific Integrated Data Quality Plan and Data Validation Specification {insert doclink to electronic final Quality Framework if desired} {insert agreements surrounding the QF or the DVS if desired, or note these documents are agreed and their location}

Interim Analyses. No formal interim analyses are planned for this study other than the safety assessments and scheduled external review.

Interim Analyses. Not applicable.

Interim Analyses. An interim analysis will be performed once approximately 50% of the planned patients have enrolled and those patients have either completed the study or discontinued early. The purpose of the interim will be to evaluate the study for futility and potentially increase the sample size to maintain statistical power conditioned on the results of the first 50% of patients. The study team will only be informed of the recommendation to halt the study for futility, maintain the original sample size, or to increase the sample size (by a fixed, pre-specified amount). All recommendations by the statistical review committee are non-binding. For the primary and key secondary outcomes, the results from before and after the interim will be combined with ▇▇▇, ▇▇▇▇, ▇▇▇▇ (CHW) methodology (▇▇▇, 1999). Full details of the interim analysis procedure and steps to maintain treatment blinding of the study team will be described in the SAP and the Interim Analysis Charter and finalized prior to execution of the interim analysis.

Interim Analyses. The first interim analysis will be done when the recruitment of 40 patients have been completed and followed up for 12 weeks (or progressed or died prior to 12 weeks). The interim analysis will be based on efficacy variables i.e. change in tumour size at 12 weeks. The description of statistical analysis at the interim will be same as section 4.2. Additionally, the following variables will be summarised (frequency and percentage) by treatment groups for overall population. • Response rate at week 12 • Best Objective response • Percentage of patients without progression The above stated analysis will be performed for overall population, PIK3CA mutation-positive patients and non-detected patient population separately. The second interim analysis will be conducted when at least 38 PFS events across both PIK3CA mutation subgroups have been achieved and 30 PIK3CA mutation detected patients have completed 12 week follow up period (or progressed prior to 12 weeks). The 2nd interim analysis will be conducted upon the following efficacy endpoints for the overall population, PIK3CA mutation detected and PIK3CA mutation not detected subgroups : • Change in tumour size at week 12 • Progression-free survival • Duration of response Additionally the following variables will be summarised: • Progression status • Progression free survival • Best objective response More details on the interim analysis can be found in the interim SAP.

Interim Analyses. There are no plans to conduct an interim analysis and no criteria by which the study would be terminated early based upon statistical determination. Printed By: Print Date: Document: TDOC-0054838 Status: Effective Serious Adverse Device Effect (USADE) severity or outcome has not been identified in the risk management file. Use Error Act or omission of an act that results in a different medical device response than intended by manufacturer or expected by user. Note: This definition includes slips, lapses, and mistakes. An unexpected physiological response of the subject does not in itself constitute a use error.

Interim Analyses. To ensure that appropriate ethical consideration is given to the welfare of the patients enrolled in the study, NINDS-NIH has appointed a Data and Safety Monitoring Board (DSMB). The DSMB will review the incidences and circumstances of adverse events that occur during the course of the trial. Formal interim analyses will occur after 25%, 50%, and 75% of patients have been enrolled. The objectives of the DSMB are ordered as follows: 1. To monitor the safety of the study subjects. 2. To recommend stopping the trial due to futility. 3. To recommend stopping the trial due to overwhelming efficacy. An efficacy interim analysis will test the null hypothesis that the distribution of scores on the modified ▇▇▇▇▇▇ Scale at Day 90 is identical in the magnesium sulfate and placebo groups versus the one-sided alternative that the distribution of scores is shifted lower in the active magnesium sulfate therapy group. This test will be performed at the 1% alpha level at each interim analysis. This is the same null hypothesis employed in the final primary trial efficacy analysis (evaluating whether patients are benefitted by treatment with magnesium sulfate), and will enter into the Lan and DeMets spending function. A safety interim analysis will test the null hypothesis that the distribution of scores on the modified ▇▇▇▇▇▇ Scale at Day 90 is identical in the magnesium sulfate and placebo groups versus the one-sided alternative that the distribution of scores is shifted lower in the control placebo therapy group. This test will be performed at the 1% alpha level at each interim analysis. This analysis will be conducted to ensure that patients are not being harmed by assignment to the magnesium sulfate group during the course of the trial. As this pure safety, one-sided analysis does not overlap with the final efficacy analysis (evaluating whether patients are benefitted by treatment with magnesium sulfate), it will not enter into the Lan-DeMets spending function. Futility analysis will be conducted at the three interim analyses, calculating the conditional probability of a positive result on the primary efficacy outcome based on the observed treatment effect in the the data collected to that point. If the probability of a positive outcome is below 10%, the DSMB may recommend study termination due to futility.