The results are in! Now what? Illustrations of results from Delamanid (superiority) and STREAM 1 (non-inferiority) Phase III Trials Carole Mitnick Meredith Brooks

Superiority Example: Time to conversion 95% CI Median days to culture conversion 95% CI Superior H0: time to conversion is not different between the experimental and control regimens 95% CI Control arm Experimental arm Not superior 95% CI

DLM phase III Results: primary analysis Median days to culture conversion 95% CI Treatment arm (mITT) Days to conversion (95% CI) Control (n=101) 57 (56-64) Experimental (n=226) 51 (43-57) Crude difference 6 days P-value 0.056 95% CI H0: time to conversion is equal between the experimental and control regimens

Superiority vs. Non-inferiority: risk difference example H0: difference in unfavorable outcomes between the experimental and control arms=0 HA: difference in unfavorable outcomes between the experimental and control arms<0 Difference in unfavorable outcomes between the experimental and control regimens ∆ 10 Non-inferior Inferior Not superior Inconclusive Superior Difference in unfavorable outcomes between the experimental and control regimens H0: difference in unfavorable outcomes between the experimental and control arms>=10 HA: difference in unfavorable outcomes between the experimental and control arms<10

STREAM Results Adjusted difference Δ = 10 2.1 (95% CI: -6.9, +11.2) Treatment arm (mITT) % unfavorable outcome Experimental (n=210) 21.9% Control (n=108) 19.4% Crude difference 2.5% Adjusted difference Δ = 10 2.1 (95% CI: -6.9, +11.2) Conclusion: 95% CI includes Δ (10%), inconclusive for non-inferiority 95% confident that true difference between the control and experimental treatments is between -6.9% and +11.2% H0 (experimental regimen is >= 10% worse than the control), cannot be ruled out

Simplified example of possible algorithm integrating all new treatment modalities for RR/MDR-TB

Rapid molecular (or conventional) test positive for TB and RR/MDR Known (or suspected) R to FQ and/or inject or HIV infected? Yes Conventional regimen + BDQ and/or DLM No Known R to PZA? >=50% PZA R among FQ-S in jurisdiction? PZA-R, XDR, pre-XDR among known contacts of patient? Known or suspected R to other drugs in shortened regimen? Shortened regimen, pending conventional DST Is R documented? Conventional regimen + 2 of 3: BDQ, LZD, DLM Continue shortened regimen