RAMPART Statistical Analysis Plan Valerie Durkalski NETT Statistical and Data Management Center Department of Biostatistics, Bioinformatics & Epidemiology Medical University of South Carolina This award is funded with support of NINDS, BARDA and the NIH CounterACT program.

Study Design Parallel Arm (IV lorazepam/IM midazolam) Double-Blind Randomized Non-inferiority Study

Question 1 The FDA wants to see more non-inferiority studies conducted by investigators: A. True B. False

Question 1 The FDA wants to see more non-inferiority studies conducted by investigators: A. True B. False

Question 2 The primary goal of a non-inferiority study is to show that the efficacy of the experimental treatment is: A. ‘superior’ to that of the standard treatment (active control). B. ‘the same’ as that of the standard treatment. C. ‘no worse than’ that of the standard treatment. D. All of the above.

Question 2 The primary goal of a non-inferiority study is to show that the efficacy of the experimental treatment is: A. ‘superior’ to that of the standard treatment (active control). B. ‘the same’ as that of the standard treatment. C. ‘no worse than’ that of the standard treatment. D. All of the above.

Question 3 Researchers choose the non-inferiority study design because: A. Proving two treatments are ‘similar’ is simpler than proving two treatments are ‘different’. B. They need a smaller sample size. C. They do not think the efficacy of the new treatment is superior to the active control but the new treatment offers other superior qualities (safer, less cost, etc). D. All of the above.

Question 3 Researchers choose the non-inferiority study design because: A. Proving two treatments are ‘similar’ is simpler than proving two treatments are ‘different’. B. They need a smaller sample size. C. They do not think the efficacy of the new treatment is superior to the active control but the new treatment offers other superior qualities (safer, less cost, etc). D. All of the above.

Primary Objective To determine if the efficacy of IM midazolam is not less than the efficacy of IV lorazepam by more than a pre-specified absolute amount (i.e., the non-inferiority margin). Efficacy = % subjects with termination of seizure prior to ED arrival (p IM and p IV ).

Primary Analysis Test the difference between two independent binomial proportions (Dunnett & Gent, 1977; 1996). Reject the null (H0) if the 1-sided p-value is <  H 0 : p IM - p IV  -  (inferior) H A : p IM - p IV > -  (non-inferior)

Primary Analysis 0 -- Non-inferior Inferior (p IM – p IV )

Non-inferiority Margin Placebo IV Efficacy Scale IM Statistical & Clinical Judgment. Statistical: Retains at least a certain amount (at least 50%) of the superiority of the active control over placebo. = = PHTSE Trial: Fraction of the lower limit 0.38 (95% CI: 0.23, 0.52)  ≤ X(.23) where X=(1 -.5);  =.12.

Sample Size 1:1 Simple Randomization Scheme Assume p IV = 0.70  = One-sided alpha = Power = 80% Inflation factor = 15% (re-enrollers; drop outs)  800 subjects (400 per treatment arm)

Interim Analysis Two tests for futility of the primary efficacy outcome. 1/3 subjects reach primary outcome (N= 230). ~ ending Year 1 of enrollment (month 11).

Analysis Population Modified ITT: All subjects who are randomized; study box open and autoinjector in thigh. Missing Data: termination of seizure as determined by the ED attending physician is missing. 1.determined from the paramedic records; or, 2.determined from the hospital record.

RAMPART Safety Monitoring Plan

DSMB Reports Open and Closed Reports distributed by SDMC. –After first 10 randomized; 40 randomized; every 50 randomized. Open Reports (blinded): –Trial metrics plus safety (AE/SAE) summary tables –Distributed to DSMB, Trial Steering Committee. Closed Reports: –Open Report by treatment arm (A/B) –Detailed safety tables –Planned interim analysis when specified –Distributed to DSMB only.

AE/SAE Monitoring Monthly Reports to MSM and DSMB. By treatment group (A/B) and dose tier. Immediate report of death to MSM and DSMB.