Table of Contents
Supplement Table e-1 ------Page 2
Supplement Methods (Table e-2 and Figure 2) ------Page 3
Supplement Table e-2 ------Page 5
Supplemental References ------Page 10
TreatmentArm / Control
Arm / p
NINDS: Median NIHSS / 14 / 15 / 0.09
NINDS 0-90 Stratum: Median NIHSS / 15 / 14 / 0.82
NINDS 90-180 Stratum: Median NIHSS / 12 / 15 / 0.008
NINDS: Age (Mean±SD) / 68.0±11.3 / 65.9±11.9 / 0.03
CiticolineMedian NIHSS / 13 / 14 / 0.04
ECASS-III: Median NIHSS / 9 / 10 / 0.03
CLEAR: Median NIHSS / 14 / 10 / 0.01
CERELYSE: Median NIHSS / 12 / 9 / NS
SYNTHESIS: Median NIHSS / 17 / 16 / NS
TUCSON Cohort 2: Median NIHSS / 16 / 12 / 0.08
PROACT-II: Glucose (Mean±SD) / 132±45 / 156±73 / 0.007
Table e-1. Imbalances in baseline factors in several randomized controlled stroke trials. These imbalances may contribute to outcomes even if individually not statistically significant.
Supplement Methods (for Table e-2 and Figure 2)
Pubmed was searched for the terms ‘Acute Ischemic Stroke’. Additional filters were applied to limit the search to completed Phase III clinical trials that took place in the prior 20 years (1994-2014) and to those that did not use endovascular treatment. The same keywords and filters were applied to the search engine provided at This was further augmented by repeating the same search in the clinical trial registry database that is maintained at with the same filters. The resultant search results were read and those with preceding early phase trials that provided data on doses used, stroke severity at baseline, baseline demographics and clinical outcomes were selected for analysis. Baseline demographics, stroke severity in terms of NIH stroke scale (NIHSS), and interpretation of outcomes by the authors were tabulated (Tablee-2). Scandinavian Stroke Scale (SSS) and European Stroke Scale (ESS) were accepted as alternate measures of stroke severity if another trial with the same compound presented NIHSS.
When the baseline NIHSS, age and 90 day outcomes in terms of modified Rankin Scale were available the outcomes were plotted onto the pPREDICTS mRS model26. The phase III trials and the preceding early phase trials were classified into categories based on reasons that may have led to failed phase III: 1. Imbalances favoring the treatment arm 2. Subgroup found to be positive without providing baseline information 3.Imbalances corrected with adjustment 4. Futile early phase trials by pooled analysis 5. Noisy endpoint such as ordinal or ‘shift’ analysis and 6. Unrepresentative control arm by pooled analysis. Unrepresentative control arm and futile early phase trial was determined based on comparison with the pPREDICTS model. A control arm was deemed unrepresentative if the functional outcomes (mRS 0-1 or mRS 0-2) for control arm were worse than the -95% prediction interval surface or the mortality was greater than +95% prediction interval surface. Summary table of these findings is provided in Table 2.
Bivariate frequency distributions were calculated for rt-PA and placebo treated subjects from the NINDS trial. The frequency distributions were calculated using an algorithm proposed by Martinez and Martineze55 and shown in Figure 2.
Table e-2
Compound/Trial Name / Reason / Treatment
NIHSS / Control NIHSS / Phase / Author Interpretation / pPREDICTS*
Abciximab
ABISe6
0.15mg/kg,
0.2mg/kg
0.25mg/kg / Dose finding study / Pooled Abciximab patients had higher mRS 0-1 / Cannot plot no baseline
AbESTTe7 / CMH,
Adjusted for NIHSS, Noisy endpoint
Futility / 8 / 9 / II / Abciximab patients had trend of higher mRS 0-1 (p=0.09).Ordinal regression (Shift) showed a trend (p=0.06). CMH tests showed p=0.04 for favorable outcome. / No Benefit
AbESTT-IIe8 / 8 / 8 / III / No Benefit / No Benefit
Albumin
ALIAS 1e9 / Subgroup analysis / 11 / 11 / Increased mortality in albumin treated group. Subgroup analysis showed no increase in mortality
ALIAS 1e10
tPA group reanalyzed / Imbalance, multivariate adjustment
Futility / 11 / 12 / II / Non-significant relative benefit of 20% after multivariate adjustment for baseline factors / No benefit
ALIAS 2e11 / 11 / 11 / III / No benefit / No benefit
Ancrod
ASSIe12 / Imbalance / SSS
24 / SSS
20 / II / Benefit by “meaningful” recovery in terms of SSS (p=0.018). / Cannot plot No NIHSS
No mRS
STATe13 / Covariate adjustment / SSS
23.8 / SSS
24.4 / III / Benefit by Covariate Adjustment / Cannot plot No NIHSS
No mRS
AAISe14 / 9 / 9 / III / No Benefit / Cannot plot
No mRS
Citicoline
Citi-001Ae15
500/1000/2000mg PO 6 weeks / Imbalance,
Covariate adjustment / 11/12/11 / 12 / Dose finding study / Beneficial in 500 and 2000 mg with Covariate Adjustment / Cannot plot not mRS
Citi-007e16
500 mg PO 6 weeks / Subgroup / 12.7 / 13.3 / Beneficial in subgroup with NIHSS> 7 and on global statistic / Cannot plot no mRS
Citi-018e17
2000 mg PO 6 wks / CMH
Imbalance
Futility / 13 / 14 / III / CMH for primary analysis showed no benefit. Secondary Posthoc CMH
Analysis showed benefit in mRS 0-1, NOT for mRS 0-2, BI or NIHSS / No Benefit
ICTUSe18
1000 mg IV X3d
1000 mg PO 6 wk / 15 / 15 / III / No Benefit / No Benefit
Clomethiazole
CLASSe19
75 mg / Subgroup / SSS
27 / SSS
28 / ? / Benefit of treatment in TACS subgroup / Cannot plot
No NIHSS
No mRS
CLASS-Ie20
75 mg / 17 / 17 / III / No benefit / No Benefit
Desmoteplase
DIASe21
Part 1 25 mg/37.5
Part 2 62.5ug/kg;90ug/kg; 125ug/kg / Imbalance / Pt1: 11/11
Pt2: 13/12/12 / Pt 1: 12
Pt 2:9 / Pt1: Increased SICH in all dosing regimens. Favorable trend in low dose (p=0.09).
Pt2: Favorable outcome as dose is increasing (p=.009 in hi dose) / Cannot Plot No mRS
DEDASe22
90 ug/kg; 125ug/kg / Imbalance Subgroup analysis / 10/9 / 12 / No benefit in ITT. Benefit in Target Population with MRI mismatch / Cannot Plot No mRS
DIAS 2e23,e24
90 ug/kg
125 ug/kg / Subgroup analysis
Futility / 9/9 / 9 / II / No benefit.
Combined DIAS, DEDAS, DIAS II subjects with an occlusion had significant benefit / No Benefit
DIAS 3e25 / III / No benefit
DP-b99
DP-b99e26 / Noisy endpoint
Futility / 11.5 / 12 / IIb / Secondary end-points: A. mRS distribution (p=0.04)
B. mRS of <=1 and return to baseline mRS p=0.05 / No Benefit
DP-b99 MACSIe27 / 12.5 / 13 / III / No benefit / No Benefit
Laser
NEST-1e28 / ?Unrepresentative control arm
Adjustment
Noisy endpoint / 11 / 10 / II? / Positive by mRS 0-2 stratified by severity.
Positive by shift / Positive
Control arm nearly worse than lower 95% surface for mRS 0-2
NEST-2e29 / Unrepresent-ative control arm
Futility / 12 / 13 / II? / Trend of benefit p=0.09 / No Benefit
Control arm just below neg 95% surface
NEST-3e30 / 10 / 10 / III / No Benefit / No Benefit
Lubeluzole
Lubeluzole (Int)e31
A.7.5mg bolus IV and 10mg for 5 d
B. 15 mg bolus IV and 20mg for 5 d / Subgroups / 14.0/16.0 / 13.8 / II / Decreased mortality in 10 mg dose and trend to better outcome p=0.05. Mortality higher in high dose p=0.04. Higher Barthel Index in sugbgroups / No mRS. Mortality with low dose lower and higher with hi dose
Lubeluzole USe32
7.5 mg bolus IV + 10 mg for 5 d / Imbalance
Covariate adjustment
Futility / 14.7 / 15.1 / III / Significant improvement in recovery with covariate adjustment / No benefit
Lubeluzole EU+Auste33
7.5 mg bolus IV + 10 mg for 5 d / ESS
40 / ESS
41 / III / Trend for lower mortality p=0.094 / Cannot plot
No NIHSS (ESS)
Lubeluzole Inte34
7.5 mg bolus IV + 10 mg for 5 d / ESS motor
14
ESS non-motor
28.6 / ESS motor 13.4
ESSnon-motor 28.8 / III / No Benefit / Cannot plot
No NIHSS
Nalmefene
Cervenee35
0.05mg/kg bolus & 0.01mg/kg/hr / Imbalance / 9.5 / 14 / II / Trend Benefit / Cannot Plot; BI
Cervenee366/20/60 mg / Subgroup analysis / 11/13.4/11 / 11.4 / IIb / Benefit in subgroups / Cannot Plot; BI
Cervenee3760mg / 12.2 / 12.4 / III / No benefit / Cannot Plot; BI
NXY-059
SA-NXY-0004e38
Dose Esc
420/844 mg / Imbalance,
Adjustment / 9.9/6.9 / 8.4 / IIa / “Encouraging trend in higher dose group by stratified analysis” / Cannot plot mRS 0-2 not given
SAINT Ie39 / Futility
Noisy endpoint / 12 / 12 / III / Benefit by “shift” / No Benefit
SAINT IIe40 / 12 / 12 / III / No benefit / No Benefit
Repinotan
BRAINSe41
0.5mg/1.25mg/2.5mg / CMH test / 13.5/13.3/13.4 / 13.4 / II / Trend toward improvement on NIHSS by CMH test / Incomplete data
mRECTe42 / 15 / 14 / III / No Benefit / No benefit
Selfotel
CGS 19755e43 / Subgroup analysis / Unavailable / Unavailable / IIa / Significant benefit in survivors by BI / Cannot plot BI
ASSISTe44 / 14.2 / 13.9 / III / No Benefit. Trend for increased Mortality / Cannot plot BI
Teneteplase vs tPA
Tenecteplasee45
0.1 mg/kg; 0.2 mg/kg; 0.4 mg/kg; 0.5 mg/kg / Futility
Imbalance / 12/14/10/8 / NINDS 91-180 minutes
tPA: 12.
placebo:15 / Compared results vs NINDS 91-180 minute rtPA and placebo groups. Tenecteplase treated patients “are comparable… to rtPA and generally better than …placebo group”. Doses of 0.1 to 0.4 mg “may be equally or more effective than rtPA”. / No Benefit on pPREDICTS-tPA mRS 0-1
Tenecteplasee46
0.1 mg/kg; 0.25 mg/kg; 0.4 mg/kg / Imbalance / 8/10/9 / 13 / 3.2% increase in good outcome in treated group. / No Benefit on pPREDICTS-tPA mRS 0-1
Tirilizad
STIPASe47
0.6 mg/kg
2.0 mg/kg
6.0 mg/kg / 10/8/8 / 5 / II / Benefit for control group by GOS (treated group did worse) not by BI / Cannot plot
BI and GOS
RANTTASe48
150 mg / 10 / 9 / III / No Benefit / Cannot plot
BI and GOS
RANTTAS-IIe49
Males: 12.5 mg/kg d1, 10 mg/kg d2-3
Females: 15 mg/kg d1, 12 mg/kg d2-3 / Imbalance favoring the treated group / 12 / 13 / III / Stopped prematurely by sponsor due to safety concerns from unpublished European trials. Authors report that treated patients had higher proportion of patients with BI>60. / Cannot Plot BI
UK-279,276
UK-279,276-301e50at doses 0.06/0.1/0.2/0.5/1.0/1.5 mg/kg / Covariate adjustment / 7.8/7.7/6.5/8.3/8.5/6.3 / 7.5 / IIa / Mean change in SSS was significant when covariate adjusted for SSS / Cannot plot
No mRS
ASTINe51 / 13 / 13 / IIb? / No Benefit / Cannot plot no data
Uric Acid + tPA
Uric Acide52,e53
500/1000mg / Futility
Unrepresent-ative control arm. Subgroup analysis / 9.5/14 / 8.5 / Dose finding / No Benefit.
Posthoc subgroup analysis found that those with lower levels of aMMP946 associate with better outcome / No benefit on pPREDICTS-tPA mRS 0-1. Control arm below neg 95%
URICO-ICTUSe54
1000 mg / 13 / 13 / IIb/III / No Benefit p=0.099. By ordinal regression analysis p=0.055 / No benefit on pPREDICTS-tPA mRS 0-1 and mRS 0-2
Supplement Table 2: Phase 3 clinical trials in stroke preceded by early phase trials from 1994-2014.
*pPREDICTS modeling of pooled controls with ± statistical intervals for functional outcome or mortality. Study’s results were superimposed on this model to determine whether there was any early signal of efficacy, mortality and how representative the study’s control arm was with respect to the pooled control sample.
Abbreviations used:
SSS: Scandinavian Stroke Scale (Higher score is better in terms of severity)
TACS: Total Anterior Circulation Stroke
ESS: European Stroke Scale (Higher score is better in terms of severity)
CMH: Cochran MantelHaenszel
BI:Barthel Index
mRS: modified Rankin Scale
ITT: Intention to treat analysis
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