Supplementary webappendix

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1 Supplementary webappendix This webappendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Kazui H, Miyajima M, Mori E, Ishikawa M, for the SINPHONI-2 Investigators. Lumboperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (SINPHONI-2): an open-label randomised trial. Lancet Neurol 2015; published online April 29.

2 Supplementary table 1. Comparison of changes for 3M after the randomisation in numbers of who improved one point or more on mrs and inphgs between the two groups (additional secondary endpoints) FAS PPA Immediate group (n = 46) Postponed group (n = 42) Immediate group (n = 43) Postponed group (n = 33) 3M After LP shunt After 3M- conservative therapy 3M After LP shunt After 3M-conservative therapy 95% CI 95% CI p* 95% CI 95% CI p* mrs 32 (70) (54 to 82) 2 (5) (1 to 16) < (70) (54 to 83) 1 (3) (0 to 16) < inphgs total 39 (85) (71 to 94) 8 (19) (9 to 34) < (84) (69 to 93) 4 (12) (3 to 28) < inphgs gait 31 (67) (52 to 80) 4 (10) (3 to 23) < (67) (51 to 81) 3 (9) (2to 24) < inphgs cogn 20 (43) (29 to 59) 5 (12) (4 to 26) (40) (25 to 56) 2 (6) (1 to 20) inphgs Urin 26 (57) (41 to 71) 4 (10) (3 to 23) < (54) (38 to 69) 2 (6) (1 to 20) < * Fisher's exact test, Comparison between Immediate group and Postponed group FAS: full analyses set, PPA: per-protocol analyses, No.: number of mrs: modified Rankin Scale inphgs; idiopathic normal pressure hydrocephalus grading scale 1

3 Supplementary table 2. Comparison of changes for 12M after LP shunt in numbers of who improved one point or more on mrs and inphgs between the two groups (main and additional secondary endpoints) PPA FAS Immediate group (n = 45) Postponed group (n = 38) Immediate group (n = 46) Postponed group (n = 40) 95% CI 95% CI p* 95% CI 95% CI p* mrs 30 (67) (51 to 80) 22 (58) (41 to 74) (67) (52 to 80) 23 (58) (41 to 73) inphgs total 36 (80) (65 to 90) 26 (68) (51 to 83) (80) (66 to 91) 26 (65) (48 to 79) inphgs gait 31 (69) (53 to 82) 15 (39) (24 to 57) (67) (52 to 80) 15 (38) (23 to 54) inphgs cogn 25 (56) (40 to 70) 16 (42) (26 to 59) (57) (41 to 71) 16 (40) (25 to 57) inphgs Urin 25 (56) (40 to 70) 18 (47) (31 to 64) (57) (41 to 71) 18 (45) (29 to 62) * Fisher's exact test, Comparison between Immediate group and Postponed group PPA: per-protocol analyses, FAS: full analyses set, No.: number of mrs: modified Rankin Scale inphgs; idiopathic normal pressure hydrocephalus grading scale 2

4 Supplementary table 3. Comparison of changes in clinical variables between the two groups in RCT (PPA) (additional secondary endpoints) Immediate group (PPA) Postponed group (PPA) 3M after Difference of change between groups Baseline 3M after shunt Difference (95%CI) p* Baseline conservative therapy Difference (95%CI) p* Mean (95%CI) p** Variable No. Mean (SD) Mean (SD) No. Mean (SD) Mean (SD) mrs (0 8) 2 0 (0 9) -0 8 (-1.1 to -0.5) < (0 9) 3 0 (0 8) 0 2 (0 0 to 0 4) (0 7 to 1 4) < inphgs total (2 0) 4 3 (2 4) -2 1 (-2 7 to -1 5) < (2 1) 6 5 (2 1) 0 1 (-0 3 to 0 5) (1 5 to 3 0) < inphgs gait (0 8) 1 5 (1 0) -0 9 (-1 2 to -0 6) < (0 7) 2 4 (0 7) 0 1 (-0 1 to 0 3) (-0 6 to 1 3) < inphgs cogn (0 9) 1 8 (1 0) -0 5 (-0 7 to -0 3) < (0 8) 2 3 (0 9) 0 0 (-0 1 to 0 2) (0 2 to 0 8) < inphgs urin (1 0) 1 1 (1 1) -0 7 (-1 1 to -0 4) < (1 1) 1 8 (1 1) 0 0 (-0 2 to 0 2) (0 3 to 1 1) TUG (sec) (41 3) 21 8 (25 1) (-26 0 to -2 9) < (20 8) 26 1 (23 5) 0 6 (-4 1 to 5 2) (-1 3 to 18 3) WT (sec) (17 1) 14 2 (14 6) 5 6 (2 4 to 8 8) < (13 8) 16 8 (14 2) -0 1 (-4 3 to 4 1) (0 1 to 9 2) MMSE (6 3) 21 7 (6 4) -1 4 (-2 4 to -0 3) (6 3) 18 4 (6 9) 0 1 (-0 8 to 0 9) (-2 9 to -0 1) FAB (3 8) 10 6 (4 2) 1 4 (0 6 to 2 1) (3 4) 9 4 (4 1) -0 3 (-1 3 to 0 8) (-2 8 to -0 3) TMT-A (sec) (185 8) (141 3) (-62 2 to 7 7) (82 3) (130 5) 0 3 (-42 6 to 43 2) (-32 6 to 63 7) WAIS-III (6 5) 11 3 (8 0) 2 6 (0 9 to 4 3) (8 7) 10 5 (8 0) -0 3 (-2 5 to 1 8) (-5 2 to 0 1) LTCISJ (1 6) 2 0 (1 5) -1 0 (-1 4 to -0 5) < (1 5) 3 2 (1 6) 0 2 (-0 1 to 0 4) (0 6 to 1 7) < ZBI total (19 5) 21 6 (17 3) -5 3 (-7 8 to -2 7) < (22 5) 30 7 (21 2) -3 1 (-6 8 to 0 5) (-0 7 to 7 1) * Wilcoxon signed rank test, Comparison between baseline and 3M after **analysis of covariance, Comparison between Immediate and Postponed group with being adjusted by baseline value 3

5 PPA: per-protocol analyses, No.: number of, mrs: modified Rankin Scale, inphgs; idiopathic normal pressure hydrocephalus grading scale, TUG: timed 3-meter Up & Go test, WT: 3-meter reciprocating walking test, MMSE: Mini-Mental State Examination, FAB: Frontal Assessment Battery, TMT-A: Trail Making Test-A, WAIS-III: Symbol search subtest of the Wechsler Adult Intelligence Scale-Third Edition, LTCISJ: level of independence in activities of daily living in the Long-term Care Insurance System in Japan, ZBI: Zarit Caregiver Burden Interview, 4

6 Supplementary table 4. Comparison of changes in clinical variables between the two groups in the 12M long-term study (FAS) (additional secondary endpoints) Immediate group Postponed group Variable No. Mean (SD) No. Mean (SD) Difference (95%CI) p* mrs (1 1) (0 7) 0 2 (-0 2 to 0 6) inphgs total (2 5) (1 8) 0 4 (-0 5 to 1 4) inphgs gait (1 0) (0 9) 0 2 (-0 2 to 0 6) inphgs cogn (1 0) (0 7) 0 2 (-0 1 to 0 6) inphgs urin (1 1) (0 9) 0 1 (-0 3 to 0 4) TUG (sec) (40 7) (26 3) 2 0 (-8 8 to 12 9) WT (sec) (12 6) (20 5) 2 4 (-5 4 to 10 2) MMSE (5 8) (2 9) -2 0 (-3 9 to -0 1) FAB (3 5) (3 1) 0 5 (-0 9 to 1 9) TMT-A (sec) (84 7) (148 4) 13 7 (-31 7 to 59 2) WAIS-III (6 9) (4 7) -0 8 (-3 8 to 2 2) LTCISJ (1 8) (1 0) 0 3 (-0 4 to 0 9) ZBI total (14 1) (14 8) 2 0 (-5 1 to 9 1) *analysis of covariance, Comparison between Immediate and Postponed group with being adjusted by baseline value FAS: full analyses set, No.: number of, mrs: modified Rankin Scale, inphgs; idiopathic normal pressure hydrocephalus grading scale, TUG: timed 3-meter Up & Go test, WT: 3-meter reciprocating walking test, MMSE: Mini-Mental State Examination, FAB: Frontal Assessment Battery, TMT-A: Trail Making Test-A, WAIS-III: Symbol search subtest of the Wechsler Adult Intelligence Scale-Third Edition, LTCISJ: level of independence in activities of daily living in the Long-term Care Insurance System in Japan, ZBI: Zarit Caregiver Burden Interview 5

7 Supplementary table 5. Cochrane Library (Wiley) search strategy ID Search Terms Hits #7 #3 and #6 44 #6 #4 or # #5 ventriculo*:ti,ab,kw (Word variations have been searched) 840 #4 shunt*:ti,ab,kw (Word variations have been searched) 1781 #3 #1 and #2 59 #2 hydrocephal*:ti,ab,kw (Word variations have been searched) 355 #1 normal pressure or "low pressure" or normotensive:ti,ab,kw searched) (Word variations have been

8 Supplementary table 6. PubMed search strategy #16 Search (#12 AND #15) 423 #15 Search (#13 OR #14) #14 Search ADL OR "Daily Living" OR QOL OR "quality of life" #13 Search clinical trial OR clinical trials OR randomized controlled OR cohort OR prospective OR "follow up" OR "long term" #12 Search (#8 NOT #11) 1346 #11 Search (#9 NOT #10) #10 Search "Aged"[Mesh] #9 Search "Child"[Mesh] OR "Infant"[Mesh] #8 Search (#3 AND #7) 1436 #7 Search (#4 OR #5 OR #6) #6 Search "Hydrocephalus/surgery"[Mesh] 7102 #5 Search Ventriculo* #4 Search shunt OR shunts OR shunting

9 Supplementary figure. Coronal MRI T2 images of a typical inph patient (a) and two excluded following the central MRI review (b and c) (a) MRI clearly shows ventricular enlargement and tightness of the high convexity/medial subarachnoid space. (ventricular enlargement: white arrow; tightness of the high convexity/medial subarachnoid space: blue line) (b) There is no prominent ventricular enlargement and no tightness of the high convexity/medial subarachnoid space. (no ventricular enlargement: white arrow; no tightness of the high convexity/medial subarachnoid space: blue line) (c) There is ventricular enlargement but no tightness of the high convexity/medial subarachnoid space. (ventricular enlargement: white arrow; no tightness of the high convexity/medial subarachnoid space: blue line) 8