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

2. 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

3. 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

4. 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

5. 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

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

7. 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