Treatment sequence network meta-analysis in Crohn’s disease: a methodological case study

Figures & data

Figure 1. PRISMA flow diagram.

Figure 2. Placebo response/remission rates for clinical response and clinical remission for maintenance phase trials^{7,25–27,31,32}. Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; IFX, Infliximab; NA, Not available; VDZ, Vedolizumab; UST, Ustekinumab.

Figure 3. Treatment sequence calculation.

Figure 4. Treatment sequence analysis strategy. Abbreviations. CDAI, Crohn’s Disease Activity Index; UST, Ustekinumab.

Table 1. Treatment sequence calculations for the overall population.

Induction studies	Maintenance studies	Treatment	N Induction	Induction CDAI-70 response rate	% CDAI-100 maintenance	% CDAI < 150 maintenance	% CDAI-100 sequence	% CDAI < 150 sequence	1 Year responders (CDAI - 100)	1 Year remission (CDAI < 150)
UNITI 1^5 & UNITI 2^6 & CERTIFI	IM-UNITI^7	Placebo–Placebo	588	33%	51%	42%	17%	14%	100	82
		UST 6–UST 90 q12w	589	52%	58%	49%	30%	26%	177	151
		UST 6–UST 90 q8w	589	52%	59%	53%	31%	28%	181	163
GEMINI II^32 & GEMINI III^29	GEMINI II^32	Placebo–Placebo	354	34%	49%	37%	16%	13%	59	46
		VDZ 300–VDZ 300 q8w	426	47%	44%	39%	21%	18%	88	79
		VDZ 300–VDZ 300 q4w	426	47%	46%	36%	22%	17%	92	71
Classic I^26 & GAIN^28	CHARM^24	Placebo–Placebo	240	35%	49%	37%	17%	13%	42	32
		ADA 160/80–ADA 40 eow	235	54%	41%	36%	23%	20%	53	46
		ADA 160/80–ADA 40 weekly	235	54%	48%	41%	26%	23%	61	53
Watanabe 2012^31	Watanabe 2012^31	Placebo–Placebo	23	30%	49%	37%	17%	13%	4	3
		ADA 160/80–ADA 40 eow	33	70%	38%	38%	27%	27%	9	9
EXTEND^27	EXTEND^27	Placebo–Placebo	65	34%	NA	37%	NA	14%	NA	9
		ADA160/80–ADA eow	64	56%	NA	33%	NA	19%	NA	12
Targan 1997^30	ACCENT I^25	Placebo–Placebo	24	17%	NA	58%	NA	13%	NA	3
		IFX 5	27	81%	NA	32%	NA	26%	NA	7
		IFX 5 & 10	27	81%	NA	38%	NA	33%	NA	9

Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; eow, Every other week; IFX, Infliximab; NA, Not available; q4w, Every 4 weeks; q8w, Every 8 weeks; q12w, Every 12 weeks; UST, Ustekinumab; VDZ, Vedolizumab.

Table 2. Results from treatment sequence network meta-analysis for the overall population, failed conventional and failed anti-TNF-α sub-populations.

Odds ratios (95% CrI) and probability better for UST versus comparator
Dose	UST 90 mg q8w	UST 90 mg q12w	ADA 40 mg weekly	ADA 40 mg eow	VDZ 300 mg q4w	VDZ 300 mg q8w	IFX 5 mg/kg	IFX 5 & 10 mg/kg	PBO
Overall population
CDAI-100	1 p(better) = NA SUCRA = 89%	1.01 (0.87 to 1.19) p(better) = 50% SUCRA = 87%	1.37 (0.85 to 2.19) p(better) = 85% SUCRA = 55%	1.42 (0.88 to 2.26) p(better) = 86% SUCRA = 48%	1.58 (1.03 to 2.43) p(better) = 88% SUCRA = 37%	1.61 (1.04 to 2.47) p(better) = 90% SUCRA = 34%	NA	NA	2.15 (1.66 to 2.80) p(better) = 96% SUCRA = 2%
CDAI <150	1 p(better) = NA SUCRA = 75%	1.03 (0.89 to 1.26) p(better) = 52% SUCRA = 69%	1.29 (0.78 to 2.12) p(better) = 56% SUCRA = 50%	1.34 (0.82 to 2.18) p(better) = 63% SUCRA = 44%	1.55 (0.98 to 2.43) p(better) = 75% SUCRA = 27%	1.60 (1.01 to 2.53) p(better) = 78% SUCRA = 32%	0.73 (0.14 to 2.69) p(better) = 35% SUCRA = 75%	0.72 (0.14 to 2.64) p(better) = 34% SUCRA = 77%	2.27 (1.71 to 3.03) p(better) = 95% SUCRA = 2%
Failed conventional
CDAI-100	1 p(better) = NA SUCRA = 83%	1.01 (0.83 to 1.25) p(better) = 55% SUCRA = 82%	1.32 (0.62 to 2.79) p(better) = 66% SUCRA = 59%	1.38 (0.64 to 2.92) p(better) = 69% SUCRA = 52%	1.66 (0.89 to 3.12) p(better) = 90% SUCRA = 39%	1.71 (0.92 to 3.24) p(better) = 97% SUCRA = 33%	NA	NA	2.60 (1.77 to 3.83) p(better) = 99% SUCRA = 2%
CDAI <150	1 p(better) = NA SUCRA = 80%	1.02 (0.86 to 1.31) p(better) = 52% SUCRA = 65%	1.21 (0.51 to 2.66) p(better) = 67% SUCRA = 60%	1.24 (0.53 to 2.75) p(better) = 69% SUCRA = 49%	1.42 (0.70 to 2.84) p(better) = 86% SUCRA = 46%	1.45 (0.71 to 2.90) p(better) = 89% SUCRA = 37%	0.57 (0.09 to 2.56) p(better) = 36% SUCRA = 78%	0.57 (0.09 to 2.52) p(better) = 35% SUCRA = 80%	2.89 (1.94 to 4.38) p(better) = 99% SUCRA = 1%
Failed anti-TNF-α
CDAI-100	1 p(better) = NA	1.01 (0.84 to 1.24) p(better) = 51%	1.14 (0.60 to 2.15) p(better) = 54%	1.15 (0.60 to 2.18) p(better) = 58%	1.52 (0.81 to 2.73) p(better) = 79%	1.61 (0.86 to 2.90) p(better) = 86%	NA	NA	2.02 (1.40 to 2.94) p(better) = 93% SUCRA = 5%
CDAI <150	1 p(better) = NA	1.01 (0.84 to 1.25) p(better) = 51%	1.03 (0.50 to 1.96) p(better) = 53%	1.05 (0.51 to 2.02) p(better) = 56%	1.40 (0.73 to 2.69) p(better) = 80%	1.40 (0.73 to 2.68) p(better) = 80%	NA	NA	1.71 (1.17 to 2.58) p(better) = 88% SUCRA = 8%

Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; CrI, Credible interval; eow, Every other week; IFX, Infliximab; NA, Not available; PBO, Placebo; q4w, Every 4 weeks; q8w, Every 8 weeks; q12w, Every 12 weeks; TNF-α, Tumor necrosis factor alpha; UST, Ustekinumab; VDZ, Vedolizumab.

Bolded values are statistically significant odds ratios.

Table 3. Results from sensitivity analyses.

Odds ratios (95% CrI), probability better for UST versus comparator and SUCRA										Model fit statistics
Dose	UST 90 mg q8w		UST 90 mg q12w	ADA 40 mg weekly	ADA 40 mg eow	VDZ 300 mg q4w	VDZ 300 mg q8w	IFX 5 mg/kg	IFX 5 & 10 mg/kg
Class	UST			ADA		VDZ		IFX
CDAI-100
Reference case – Bayesian hierarchical NMA	1 p(better) = NA SUCRA = 89%		1.01 (0.87 to 1.19) p(better) = 50% SUCRA = 87%	1.37 (0.85 to 2.19) p(better) = 85% SUCRA = 55%	1.42 (0.88 to 2.26) p(better) = 86% SUCRA = 48%	1.58 (1.03 to 2.43) p(better) = 88% SUCRA = 37%	1.61 (1.04 to 2.47) p(better) = 90% SUCRA = 34%	NA	NA	DIC = 77.22 Totresdev = 8.11 vs. 11
	1 p(better) = NA SUCRA = 89%			1.38 (0.84 to 2.25) p(better) = 73% SUCRA = 10%		1.58 (1.02 to 2.49) p(better) = 87% SUCRA = 2%		NA
Dose-stratified NMA	1 p(better) = NA SUCRA = 89%	1.03 (0.81 to 1.32) p(better) = 53% SUCRA = 84%		1.32 (0.79 to 2.17) p(better) = 78% SUCRA = 62%	1.54 (0.92 to 2.56) p(better) = 81% SUCRA = 40%	1.57 (1.002 to 2.47) p(better) = 84% SUCRA = 39%	1.66 (1.05 to 2.62) p(better) = 85% SUCRA = 3%	NA	NA	DIC = 81.33 Totresdev = 10.10 vs. 11
Dose-pooled NMA	1 p(better) = NA SUCRA = 91%			1.38 (0.88 to 2.16 ) p(better) = 74% SUCRA = 59%		1.59 (1.05 to 2.37) p(better) = 89% SUCRA = 42%		NA		DIC = 58.89 Totresdev = 7.06 vs. 8
Failed conventional Dose-stratified NMA	1 p(better) = NA SUCRA = 84%		1.04 (0.71 to 1.54) p(better) = 59% SUCRA = 79%	1.21 (0.53 to 2.70) p(better) = 67% SUCRA = 68%	1.65 (0.72 to 3.70) p(better) = 88% SUCRA = 41%	1.91 (0.95 to 3.82) p(better) = 97% SUCRA = 29%	1.60 (0.80 to 3.18) p(better) = 91% SUCRA = 46%	NA	NA	DIC = 64.87 Totresdev = 9.05 vs. 9
Failed conventional Dose-pooled	1 p(better) = NA SUCRA = 74%			1.31 (0.64 to 2.68) p(better) = 76% SUCRA = 64%		1.62 (0.88 to 2.97) p(better) =93% SUCRA = 45%		NA		DIC = 44.93 Totresdev = 6.01 vs. 6
Failed conventional Bayesian hierarchical NMA	1 p(better) = NA SUCRA = 83%		1.01 (0.83 to 1.25) p(better) = 55% SUCRA = 82%	1.32 (0.62 to 2.79) p(better) = 66% SUCRA = 59%	1.38 (0.64 to 2.92) p(better) = 69% SUCRA = 52%	1.66 (0.89 to 3.12) p(better) = 90% SUCRA = 39%	1.71 (0.92 to 3.24) p(better) = 97% SUCRA = 33%	NA	NA	DIC = 61.12 Totresdev = 7.70 vs. 9
	1 p(better) = NA SUCRA = 86%			1.34 (0.62 to 2.85) p(better) = 76% SUCRA = 46%		1.68 (0.89 to 3.20) p(better) = 83% SUCRA = 18%		NA
Failed anti-TNF-α Dose-stratified NMA	1 p(better) = NA SUCRA = 79%		1.05 (0.74 to 1.49) p(better) = 55% SUCRA = 73%	1.13 (0.55 to 2.28) p(better) = 54% SUCRA = 66%	1.21 (0.59 to 2.45) p(better) = 65% SUCRA = 58%	1.36 (0.72 to 2.61) p(better) = 80% SUCRA = 49%	1.85 (0.96 to 3.63) p(better) = 93% SUCRA = 18%	NA	NA	DIC = 66.37 Totresdev = 9.03 vs. 9
Failed anti-TNF-α Dose-pooled NMA	1 p(better) = NA SUCRA = 86%			1.14 (0.59 to 2.14) p(better) = 58% SUCRA = 72%		1.61 (0.88 to 2.91) p(better) = 89% SUCRA = 35%		NA		DIC = 45.93 Totresdev = 6.03 vs. 6
Failed anti-TNF-α Bayesian hierarchical NMA	1 p(better) = NA SUCRA = 79%		1.01 (0.84 to 1.24) p(better) = 51% SUCRA = 76%	1.14 (0.60 to 2.15) p(better) = 54% SUCRA = 64%	1.15 (0.60 to 2.18) p(better) = 58% SUCRA = 62%	1.52 (0.81 to 2.73) p(better) = 79% SUCRA = 37%	1.61 (0.86 to 2.90) p(better) = 86% SUCRA = 27%	NA	NA	DIC = 62.70 Totresdev = 7.72 vs. 9
	1 p(better) = NA SUCRA = 78%			1.14 (0.59 to 2.19) p(better) = 56% SUCRA = 57%		1.56 (0.82 to 2.82) p(better) = 78% SUCRA = 14%		NA
CDAI <150
Reference case – Bayesian hierarchical NMA	1 p(better) = NA SUCRA = 75%		1.03 (0.89 to 1.26) p(better) = 52% SUCRA = 69%	1.29 (0.78 to 2.12) p(better) = 56% SUCRA = 50%	1.34 (0.82 to 2.18) p(better) = 63% SUCRA = 44%	1.55 (0.98 to 2.43) p(better) = 75% SUCRA = 27%	1.60 (1.01 to 2.53) p(better) = 78% SUCRA = 32%	0.73 (0.14 to 2.69) p(better) = 35% SUCRA = 75%	0.72 (0.14 to 2.64) p(better) = 34% SUCRA = 77%	DIC = 101.28 Totresdev = 12.51 vs. 16
	1 p(better) = NA SUCRA = 71%			1.29 (0.77 to 2.15) p(better) = 59% SUCRA = 37%		1.54 (0.95 to 2.47) p(better) = 76% SUCRA = 15%		0.71 (0.14 to 2.62) p(better) = 41% SUCRA = 77%
Dose-stratified NMA	1 p(better) = NA SUCRA = 76%		1.11 (0.86 to 1.44) p(better) = 52% SUCRA = 64%	1.22 (0.70 to 2.11) p(better) = 62% SUCRA = 57%	1.44 (0.86 to 2.41) p(better) = 69% SUCRA = 40%	1.53 (0.93 to 2.50) p(better) = 74% SUCRA = 23%	1.74 (1.05 to 2.88) p(better) = 85% SUCRA = 37%	0.62 (0.11 to 2.59) p(better) = 29% SUCRA = 84%	0.90 (0.16 to 3.97) p(better) = 48% SUCRA = 66%	DIC = 106.56 Totresdev = 14.58 vs. 16
Dose-pooled NMA	1 p(better) = NA SUCRA = 79%			1.35 (0.85 to 2.14) p(better) = 69% SUCRA = 49%		1.54 (0.99 to 2.40) p(better) = 78% SUCRA = 36%		0.67 (0.13 to 2.50) p(better) = 43% SUCRA = 85%		DIC = 79.49 Totresdev = 10.57 vs. 12
Failed conventional Dose-stratified NMA	1 p(better) = NA SUCRA = 68%		1.15 (0.78 to 1.71) p(better) = 60% SUCRA = 55%	1.16 (0.47 to 2.77) p(better) = 63% SUCRA = 56%	1.46 (0.59 to 3.52) p(better) = 81% SUCRA = 39%	1.59 (0.74 to 3.37) p(better) = 88% SUCRA = 33%	1.44 (0.67 to 3.05) p(better) = 80% SUCRA = 41%	0.48 (0.06 to 2.44) p(better) = 20% SUCRA = 71%	0.70 (0.08 to 3.67) p(better) = 34% SUCRA = 86%	DIC = 79.30 Totresdev = 12.12 vs. 12
Failed conventional Dose-pooled NMA	1 p(better) = NA SUCRA = 68%			1.20 (0.54 to 2.63) p(better) = 71% SUCRA = 53%		1.40 (0.69 to 2.75) p(better) = 85% SUCRA = 42%		0.52 (0.07 to 2.41) p(better) = 30% SUCRA = 87%		DIC = 54.72 Totresdev = 8.10 vs. 8
Failed conventional Bayesian hierarchical NMA	1 p(better) = NA SUCRA = 80%		1.02 (0.86 to 1.31) p(better) = 52% SUCRA = 65%	1.21 (0.51 to 2.66) p(better) = 67% SUCRA = 60%	1.24 (0.53 to 2.75) p(better) = 69% SUCRA = 49%	1.42 (0.70 to 2.84) p(better) = 86% SUCRA = 46%	1.45 (0.71 to 2.90) p(better) = 89% SUCRA = 37%	0.57 (0.09 to 2.56) p(better) = 36% SUCRA = 78%	0.57 (0.09 to 2.52) p(better) = 35% SUCRA = 80%	DIC = 73.55 Totresdev = 9.74 vs. 12
	1 p(better) = NA SUCRA = 58%			1.21 (0.51 to 2.68) p(better) = 72% SUCRA = 38%		1.41 (0.69 to 2.84) p(better) = 87% SUCRA = 23%		0.56 (0.09 to 2.50) p(better) = 34% SUCRA = 81%
Failed anti-TNF-α Dose-stratified NMA	1 p(better) = NA SUCRA = 74%		1.06 (0.72 to 1.55) p(better) = 54% SUCRA = 67%	0.98 (0.46 to 2.07) p(better) = 50% SUCRA = 73%	1.16 (0.54 to 2.48) p(better) = 66% SUCRA = 55%	1.43 (0.71 to 2.91) p(better) = 84% SUCRA = 35%	1.44 (0.71 to 2.91) p(better) = 84% SUCRA = 35%	NA	NA	DIC = 65.16 Totresdev = 9.05 vs. 9
Failed anti-TNF-α Dose-pooled NMA	1 p(better) = NA SUCRA = 79%			1.03 (0.51 to 2.00) p(better) = 53% SUCRA = 74%		1.40 (0.75 to 2.61) p(better) = 80% SUCRA = 38%		NA		DIC = 45.17 Totresdev = 6.03 vs. 6
Failed anti-TNF-α Bayesian hierarchical NMA	1 p(better) = NA SUCRA = 72%		1.01 (0.84 to 1.25) p(better) = 51% SUCRA = 69%	1.03 (0.50 to 1.96) p(better) = 53% SUCRA = 68%	1.05 (0.51 to 2.02) p(better) = 56% SUCRA = 64%	1.40 (0.73 to 2.69) p(better) = 79% SUCRA = 34%	1.40 (0.73 to 2.68) p(better) = 80% SUCRA = 34%	NA	NA	DIC = 60.54 Totresdev = 6.88 vs. 9
	1 p(better) = NA SUCRA = 68%			1.03 (0.49 to 2.00) p(better) = 53% SUCRA = 63%		1.39 (0.72 to 2.71) p(better) = 79% SUCRA = 19%		NA

Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; CrI, Credible interval; DIC, Deviance information criterion; eow, Every other week; IFX, Infliximab; NA, Not available; q4w, Every 4 weeks; q8w, Every 8 weeks; q12w, Every 12 weeks; SUCRA, Surface Under the Cumulative RAnking curve; Totresdev, Total residual deviance; TNF-α, Tumor necrosis factor; UST, Ustekinumab; VDZ, Vedolizumab.

Bolded values are statistically significant odds ratios.

Appendix 1. Search strategy.MEDLINE and MEDLINE-IN-PROCESS (date of the search: 2 July 2015)

	#	Search terms	Hits
Crohn’s disease	1	“Crohn Disease”[MeSH] OR “Inflammatory Bowel Diseases”[MeSH]	62,276
	2	“Crohn Disease”[TW] OR “Crohns Disease”[TW] OR “Crohn's Disease”[TW] OR “Inflammatory Bowel Diseases”[TW] OR “Inflammatory Bowel Disease”[TW] OR IBD[TW]	63,787
	3	#1 OR #2	80,389
Intervention	4	“Biological Therapy”[MeSH] OR “Antibodies, Monoclonal”[MeSH] OR infliximab[TW] OR remicade[TW] OR adalimumab[TW] OR humira[TW] OR vedolizumab[TW] OR entyvio[TW] OR certolizumab[TW] OR cimzia[TW] OR natalizumab[TW] OR tysabri[TW] OR ustekinumab[TW] OR stelara[TW]	528,522
Study type	5	“Randomized Controlled Trials as Topic”[MeSH]	97,784
	6	“Random Allocation”[MeSH]	82,964
	7	“Double-Blind Method”[MeSH]	128,769
	8	“Single-Blind Method”[MeSH]	20,311
	9	“Clinical Trial, Phase I”[PT]	14,752
	10	“Clinical Trial, Phase II”[PT]	23,851
	11	“Clinical Trial, Phase III”[PT]	9736
	12	“Clinical Trial, Phase IV”[PT]	1024
	13	“Controlled Clinical Trial”[PT]	89,034
	14	“Randomized Controlled Trial”[PT]	390,357
	15	“Multicenter Study”[PT]	182,458
	16	“Clinical trial”[PT]	802,630
	17	“Clinical Trials as Topic”[MeSH]	286,758
	18	#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17	1,074,702
	19	“clinical trial*”[TW]	597,932
	20	“single?blind”[TW] or “double?blind”[TW] or “treble?blind”[TW] or “triple?blind”[TW]	183,132
	21	Placebos[MeSH]	32,632
	22	Placebo?[TW]	168,262
	23	“randomly allocated”[TW]	18,944
	24	#19 OR #20 OR #21 OR #22 OR #23	729,317
	25	#18 OR #24	1,155,213
Exclusion	26	“Case Reports”[PT] OR Comment[PT] OR Editorial[PT] OR “Historical article”[PT] OR Letter[PT] OR “case report”[TI]	3,307,182
	27	Animals[MeSH] NOT Humans[MeSH]	4,016,826
	28	#26 OR #27	7,234,209
Combined	29	#3 AND #4 AND #25	1288
	30	#29 NOT #28	1195
Final results	31	Limit to: English	1097

EMBASE (date of the search: 2 July 2015)

	#	Search terms	Hits
Crohn’s disease	1	Crohn Disease'/ OR 'Inflammatory Bowel Diseases'/	63,132
	2	'Crohn Disease'.mp. OR 'Crohns Disease'.mp. OR 'Inflammatory Bowel Diseases'.mp. OR 'Inflammatory Bowel Disease'.mp. OR IBD.mp.	99,878
	3	1 OR 2	99,878
Intervention	4	Biological Therapy'/ OR 'Antibodies, Monoclonal'/ OR infliximab.mp. OR remicade.mp. OR adalimumab.mp. OR humira.mp. OR vedolizumab.mp. OR entyvio.mp. OR certolizumab.mp. OR cimzia.mp. OR natalizumab.mp. OR tysabri.mp. OR ustekinumab.mp OR stelara.mp	224,640
Study type	5	Clinical trial/	850,725
	6	Randomized controlled trial/	377,685
	7	Randomization/	66,831
	8	Single blind procedure/	20,468
	9	Double blind procedure/	123,874
	10	Crossover procedure/	43,327
	11	Placebo/	270,979
	12	Randomi?ed controlled trial$.tw.	118,784
	13	Rct.tw.	17,421
	14	Random allocation.tw.	1467
	15	Randomly allocated.tw.	22,896
	16	Allocated randomly.tw.	2048
	17	(allocated adj2 random).tw.	810
	18	Single blind$.tw.	16,234
	19	Double blind$.tw.	158,261
	20	((treble or triple) adj (blind$)).tw.	482
	21	Placebo$.tw.	221,397
	22	Prospective study/	296,032
	23	Or/5-22	1,493,693
Exclusion	24	'Case Report'.tw. OR 'Case study'/ OR Abstract report/ OR letter/	1,267,244
	25	animal/ NOT human/	1,259,266
	26	24 OR 25	2,512,180
Combined	27	3 AND 4 AND 23	4121
	28	27 NOT 26	4025
Final results	29	(english).lg.	23,356,142
	30	28 and 29	3776

The Cochrane Library (date of the search: 2 July 2015)

	#	Search terms	Hits
Crohn’s disease	1	MeSH descriptor: [Crohn Disease] explode all trees	1029
	2	MeSH descriptor: [Inflammatory Bowel Diseases] explode all trees	2082
	3	(Crohn Disease):ab,ti,kw OR (Crohns Disease):ab,ti,kw OR (Inflammatory Bowel Diseases):ti,ab,kw OR (Inflammatory Bowel Disease):ti,ab,kw OR (IBD):ti,ab,kw	2501
	4	#1 OR #2 OR #3	3201
Intervention	5	MeSH descriptor: [Biological Therapy] explode all trees	10,978
	6	MeSH descriptor: [Antibodies, Monoclonal] explode all trees	5412
	7	(infliximab):ti,ab,kw OR (remicade):ti,ab,kw OR (adalimumab):ti,ab,kw OR (humira):ti,ab,kw OR (vedolizumab):ti,ab,kw OR (entyvio):ti,ab,kw OR (certolizumab):ti,ab,kw OR (cimzia):ti,ab,kw OR (natalizumab):ti,ab,kw OR (tysabri):ti,ab,kw OR (ustekinumab):ti,ab,kw OR (stelara):ti,ab,kw	1866
	8	#5 OR #6 OR #7	17,084
Final result	9	#4 AND #8	551
	10	Limit: Clinical trials	399

Appendix 2. Treatment doses in moderate-to-severe Crohn’s disease.

Active substance	Induction	Maintenance
Ustekinumab (Stelara)	6 mg/kg	90 mg every 8 weeks (q8w) 90 mg every 12 weeks (q12w)
Infliximab (Remicade)	5 mg/kg	5 mg/kg every 8 weeks (q8w) 5 & 10 mg/kg every 8 weeks (q8w)
Adalimumab (Humira)	160/80 mg and 80/40 mg	40 mg every other week (eow) 40 mg weekly
Vedolizumab (Entyvio)	300 mg IV at 0,2 and 6 weeks	300 mg every 8 weeks (q8w) 300 mg every 4 weeks (q4w)
Conventional therapy	Monotherapy with a conventional glucocorticosteroids or budesonide or 5-ASA	Azathioprine or mercaptopurine as monotherapy when previously used with a conventional glucocorticosteroids or budesonide Methotrexate

Abbreviations. 5-ASA, 5-Aminosalicylic acid; CD, Crohn’s disease; eow, Every other week; IV, Intravenous; q4w, Every 4 weeks; q8w, Every 8 weeks; q12w, Every 12 weeks.

Appendix 3. Detailed rationale for included and excluded studies.Included studies for primary dosage network meta-analysis

Study	Comparison used in NMAs	Analysis
IM-UNITI^7	Maintenance: placebo versus ustekinumab 90 mg q12w vs. ustekinumab 90 mg q8w	Unadjusted NMA Treatment sequence NMA
GEMINI II^32	Induction: placebo versus vedolizumab 300 mg Maintenance: placebo versus vedolizumab 300 mg q8w versus vedolizumab 300 mg q4w	Unadjusted NMA Treatment sequence NMA
CHARM^24	Maintenance: placebo versus adalimumab 40 mg eow versus adalimumab 40 mg Weekly	Unadjusted NMA Treatment sequence NMA
Watanabe 2012^31	Induction: placebo versus adalimumab 160/80 mg Maintenance: placebo versus adalimumab 40 mg eow	Unadjusted NMA Treatment sequence NMA
EXTEND^27	Induction: placebo versus adalimumab 160/80 mg Maintenance: placebo versus adalimumab 40 mg eow	Unadjusted NMA Treatment sequence NMA
ACCENT I^25	Maintenance: placebo versus infliximab 5 mg/kg versus infliximab 5 & 10 mg/kg	Unadjusted NMA Treatment sequence NMA
UNITI-1^5	Induction: placebo versus ustekinumab 6 mg/kg	Treatment sequence NMA
CERTIFI^33	Induction: placebo versus ustekinumab 6 mg/kg	Treatment sequence NMA
UNITI-2^6	Induction: placebo versus ustekinumab 6 mg/kg	Treatment sequence NMA
GEMINI III^29	Induction: placebo versus vedolizumab 300 mg	Treatment sequence NMA
Classic I^26	Induction: placebo versus adalimumab 160/80 mg	Treatment sequence NMA
GAIN^28	Induction: placebo versus adalimumab 160/80 mg	Treatment sequence NMA
Targan 1997^30	Induction: placebo versus infliximab 5 mg/kg	Treatment sequence NMA

Included studies for failed conventional sub-population primary dosage network meta-analyses

Unadjusted NMA	Treatment sequence NMA
IM-UNITI GEMINI II CHARM ACCENT	UNITI-2 IM-UNITI GEMINI II GEMINI III Classic I Watanabe 2012 CHARM Targan 1997 ACCENT I

Included studies for the failed anti-TNF sub-population primary dosage network meta-analyses

Unadjusted NMA	Treatment sequence NMA
IM-UNITI GEMINI II CHARM	UNITI-1 CERTIFI IM-UNITI GEMINI II GEMINI III GAIN CHARM Watanabe 2012

Excluded studies from primary dosage network meta-analysis

Study	Reason for exclusion
D’Haens 1999^36	Lack of reported outcomes of interest & IFX doses not in line with recommendations
Classic II^37	Only included patients in remission at week 4 & 8 (dissimilar to other trials)
SONIC^38	Comparator not of interest
Rutgeerts 1999^39	Retreatment with infliximab (maintenance dissimilar to other trials)
Feagan 2008^40	Comparator not of interest
Hanauer 2013^41	Abstract of GEMINI II
Schreiber 2005^42	Comparator not of interest
Winter 2014^43	Comparator not of interest
PRECISE 1^44	Comparator not of interest
PRECISE 2^45	Comparator not of interest
Rutgeerts 2008^46	Comparator not of interest
WELCOME^47	Comparator not of interest
Feagan 2011^48	Comparator not of interest
Sandborn 2011^49	Comparator not of interest
ENACT-1^50	Comparator not of interest
ENACT-2^50	Comparator not of interest
ENCORE^51	Comparator not of interest
Ghosh 2003^52	Comparator not of interest

Appendix 4. Quality assessment of included studies.

Author(s)	Year	Was randomization carried out appropriately?	Was the concealment of treatment allocation adequate?	Were the groups similar at the outset of the study in terms of prognostic factors?	Were the care providers, participants and outcome assessors blind to treatment allocation?	Were there any unexpected imbalances in drop-outs between groups?	Is there any evidence to suggest that the authors measured more outcomes than they reported?	Did the analysis include an intention-to-treat analysis? If so, was this appropriate?	Were appropriate methods used to account for missing data (LOCF, MMRM)?
Sandborn et al. (CERTIFI)	2012	Yes	Yes	No	Yes	No	No	Yes	Yes
UNITI-1	2015	Yes	Yes	Yes	Yes	No	No	No	Yes
UNITI-2	2015	Yes	Yes	Yes	Yes	No	No	No	Yes
IM-UNITI	2015	Yes	Yes	Yes	Yes	No	No	No	Yes
Hanauer et al. (CLASSIC I)	2006	Yes	Yes	Yes	Yes	Unclear	No	No	Yes
Colombel et al. (CHARM)	2007	Yes	Yes	Yes	Yes	No	No	No	Unclear
Sandborn et al. (GAIN)	2007	Yes	Yes	Yes	Yes	No	Yes	Yes	Unclear
Sandborn et al. (CLASSIC II)	2007	Yes	Yes	Yes	Yes	No	No	No	Unclear
Watanabe et al.	2012	Yes	Unclear	Yes	Yes	No	No	No	Yes
Targan et al.	1997	Yes	Unclear	No	Yes	No	Yes	No	Unclear
Hanauer et al. (ACCENT I)	2002	Yes	Unclear	Yes	Yes	No	No	Unclear	Unclear
Rutgeerts et al. (EXTEND)	2012	Yes	Unclear	Yes	Yes	No	No	Yes	Unclear
Sandborn et al. (GEMINI II)	2013	Yes	Yes	Yes	Yes	No	No	No	Yes
Sands et al. (GEMINI III)	2014	Yes	Yes	Yes	Yes	No	No	Yes	Unclear

Appendix 5. ARisk of bias assessment.

Ref ID	Trial	Random sequence generation	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting
5	UNITI-I^5	+	+	+	+	?	+
6	UNITI-II^6	+	+	+	+	?	+
7	IM-UNITI^7	+	+	+	+	?	+
23	CHARM^24	+	+	+	+	+	+
24	ACCENT I^25	?	?	?	?	+	+
25	CLASSIC I^26	+	+	+	+	+	+
26	EXTEND^27	+	?	?	?	+	+
27	GAIN^28	+	+	+	+	+	+
28	GEMINI III^29	+	+	+	+	+	+
29	Targan 1997^30	+	+	+	+	+	+
30	Watanabe 2012^31	+	?	?	?	+	+
31	GEMINI II^32	+	+	+	+	+	+
32	CERTIFI^33	+	+	+	+	+	+

Abbreviations. +, Low risk of bias; -, High risk of bias; ?, Unclear risk of bias; RCT, Randomized controlled trial.

Appendix 6. Study design of maintenance phase trials.

Treatment	Study	Patient selection	Study design
Ustekinumab	IM-UNITI	Ustekinumab responders at week 8	DB for induction and maintenance
Adalimumab	CHARM Watanabe 2012 EXTEND	Adalimumab responders (CDAI-70) at week 4 Adalimumab responders (CDAI-70) at week 4 Adalimumab responders (CDAI-70) at week 4	OL for induction and DB for maintenance DB for induction and maintenance OL for induction and DB for maintenance
Infliximab	ACCENT I	Infliximab responders (CDAI-70) at week 2	OL for induction and DB for maintenance
Vedolizumab	GEMINI II	Vedolizumab responders (CDAI-70) at week 6	Mix of OL and DB for induction and DB for maintenance

Abbreviations. CDAI, Crohn`s Disease Activity Index; DB, Double blind; OL, Open label.

Appendix 7. Placebo response/remission rates versus treatment response/remission rates and odds ratios.

Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; eow, Every other week; IFX, Infliximab; q4w, Every 4 weeks; q8w, Every 8 weeks; q12w, Every 12 weeks; UST, Ustekinumab; VDZ, Vedolizumab.

Appendix 8. Detailed summary of randomized controlled trial characteristics.Induction

Study	Blinding	Analysis population	Total	Treatments	Prior anti-TNF-α (%)	Sub-population	Primary outcome	Age (mean)	Male (%)	Disease duration (years)	CDAI score
UNITI-1^5	DB	FAS	741	Placebo UST 130 mg UST 6 mg/kg	NR	Failed anti-TNF	Clinical response at week 6 (CDAI 100)	36	42.8	10.1	317
UNITI-2^6	DB	FAS	627	Placebo UST 130 mg UST 6 mg/kg	NR	Failed conventional	Clinical response at week 6 (CDAI 100)	NR	NR	NR	NR
GEMINI II^32	OL	ITT	1115	Placebo VDZ 300 mg	62	Failed conventional & failed anti-TNF	Clinical remission at week 6 (CDAI < 150)	36.1	46.6	9	324
GEMINI III^29	OL	ITT	416	Placebo VDZ 300 mg	76	Failed conventional & failed anti-TNF	Clinical remission at week 6 (CDAI < 150)	37.9	43.3	10.3	307.7
CLASSIC I^26	OL	ITT	299	Placebo ADA 160/80 mg ADA 80/40 mg	NR	Failed conventional	Clinical remission at week 4 (CDAI < 150)	38.25	44.8	NR	297.8
Watanabe 2012^31	DB	FAS	90	Placebo ADA 160/80 mg ADA 80/40 mg	NR	Failed conventional	Clinical remission at week 4 (CDAI < 150)	31.1	57.8	9.5	303.3
GAIN^28	OL	FAS	325	Placebo ADA 160/80 mg	48	Failed anti-TNF	Clinical response at week 4 (CDAI 70/100)	38	45	NR	313
Targan 1997^30	OL	FAS	108	Placebo IFX 5 mg/kg	NR	Failed conventional	Clinical remission at week 4 (CDAI < 150)	37.7	55.8	11.5	300
EXTEND^27	OL	FAS	135	Placebo ADA 160/80 mg	52	Failed conventional & failed anti-TNF	Complete mucosal healing at week 12	37.1	47.2	10.1	319.9

Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; DB, Double blind; FAS, Full analysis set; IFX, Infliximab; ITT, Intention to treat; NR, Not reported; OL, Open label; TNF, Tumor necrosis factor; UST, Ustekinumab; VDZ, Vedolizumab.

Maintenance

Study	Blinding	Analysis population	Total	Treatments	Prior anti-TNF-α (%)	Sub-population	Primary outcome	Age (mean)	Male (%)	Disease duration (years)	CDAI score
IM-UNITI^7	DB	FAS	397	Placebo UST 90 mg q8w UST 90 mg q12w	NR	Failed conventional & failed anti-TNF	Clinical remission at week 52 (CDAI < 150)	36^a	42.8^a	10.1^a	317^a
GEMINI II^32	DB	ITT	778	Placebo VDZ 300 mg q4w VDZ 300 mg q8w	62.00	Failed conventional & failed anti-TNF	Clinical remission at week 52 (CDAI < 150)	37.9^a	43.3^a	10.3^a	307.7^a
CHARM^24	DB	ITT	778	Placebo ADA 40 mg eow ADA 40 mg Weekly	48	Failed conventional & failed anti-TNF	Clinical remission at week 56 (CDAI < 150)	36.7	37.7	NR	316.6
ACCENT I^25	DB	ITT	573	Placebo IFX 5 mg IFX 5 & 10 mg	0	Failed conventional	Clinical remission at week 52 (CDAI < 150)	35^b	39^b	7.5^b	299^b
EXTEND^27	DB	ITT	129	Placebo ADA 40 mg eow	52	Failed conventional & failed anti-TNF	Clinical remission at week 52 (CDAI < 150)	37.1^a	47.2^a	10.1^a	319.9^a

^aBaseline characteristics from induction phase.

^bMedian values.

Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; DB, Double blind; eow, Every other week; FAS, Full analysis set; IFX, Infliximab; ITT, Intention to treat; NR, Not reported; OL, Open label; q4w, Every 4 weeks; q8w, Every 8 weeks; q12w, Every 12 weeks; TNF, Tumor necrosis factor; UST, Ustekinumab; VDZ, Vedolizumab.

Appendix 9. Treatment sequence calculations for sub-populations.

Studies induction	Studies maintenance	Treatment	N Induction	Induction CDAI-70 response rate	% CDAI-100 maintenance	% CDAI < 150 maintenance	% CDAI-100 sequence	% CDAI < 150 sequence	1 Year responders (CDAI-100)	1 Year remission (CDAI < 150)
UNITI 2	IM-UNITI	Placebo–placebo	209	39%	60%	47%	23%	18%	49	39
		UST 6–UST 90 q12w	209	65%	67%	57%	44%	37%	91	77
		UST 6–UST 90 q8w	209	65%	68%	63%	44%	40%	93	84
GEMINI II & GEMINI III	GEMINI II	Placebo–placebo	127	38%	58%	37%	22%	14%	28	18
		VDZ 300–VDZ 300 q8w	163	53%	60%	50%	32%	26%	52	42
		VDZ 300–VDZ 300 q4w	163	53%	53%	45%	28%	24%	46	39
Classic I & Watanabe	CHARM	Placebo–placebo	84	35%	58%	40%	20%	14%	17	12
		ADA 160/80–ADA 40 eow	90	62%	46%	41%	29%	26%	26	23
		ADA 160/80–ADA 40 weekly	90	62%	56%	48%	36%	30%	32	27
Targan 1997	ACCENT I	Placebo–placebo	24	17%	N/A	36%	N/A	8%	0	2
		IFX 5	27	81%	N/A	28%	N/A	26%	0	7
		IFX 5 & 10	27	81%	N/A	38%	N/A	33%	0	9

Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; eow, Every other week; IFX, Infliximab; NA, Not available; q4w, Every 4 weeks; q8w, Every 8 weeks; q12w, Every 12 weeks; UST, Ustekinumab; VDZ, Vedolizumab.

Treatment sequence calculations for failed anti-TNF sub-population

Studies induction	Studies maintenance	Treatment	N Induction	Induction CDAI-70 response rate	% CDAI-100 maintenance	% CDAI < 150 maintenance	% CDAI-100 sequence	% CDAI < 150 sequence	1 Year responders (CDAI-100)	1 Year remission (CDAI < 150)
UNITI 1 & CERFIFI	IM-UNITI	Placebo–placebo	379	30%	39%	35%	12%	11%	45	40
		UST 6–UST 90 q12w	380	45%	47%	39%	21%	16%	79	62
		UST 6–UST 90 q8w	380	45%	48%	41%	22%	17%	82	65
GEMINI II & GEMINI III	GEMINI II	Placebo–placebo	227	31%	38%	34%	12%	11%	27	24
		VDZ 300–VDZ 300 q8w	263	44%	29%	28%	13%	13%	34	33
		VDZ 300–VDZ 300 q4w	263	44%	38%	27%	17%	13%	44	33
GAIN & Watanabe	CHARM	Placebo–placebo	179	34%	36%	30%	12%	11%	22	19
		ADA 160/80–ADA 40 eow	178	53%	36%	31%	19%	15%	34	27
		ADA 160/80–ADA 40 weekly	178	53%	38%	34%	20%	17%	36	31

Abbreviations. ADA, Adalimumab; CDAI = Crohn’s Disease Activity Index; eow, Every other week; IFX, Infliximab; NA, Not available; q4w, Every 4 weeks; q8w, Every 8 weeks; q12w, Every 12 weeks; UST, Ustekinumab; VDZ, Vedolizumab.

Appendix 10. Results from network meta-analysis based on data prior to treatment sequencing adjustments.

Odds ratios (95% CrIs) and probability better for UST versus comparator
Dose	UST 90 mg q8w	UST 90 mg q12w	ADA 40 mg weekly	ADA 40 mg eow	VDZ 300 mg q4w	VDZ 300 mg q8w	IFX 5 mg/kg	IFX 5 & 10 mg/kg	Model fit statistics
Class	UST		ADA		VDZ		IFX
CDAI-100
Reference case – Bayesian hierarchical	1 p(better) = NA	1.01 (0.87 to 1.19) p(better) = 50%	1.37 (0.85 to 2.19) p(better) = 85%	1.42 (0.88 to 2.26) p(better) = 86%	1.58 (1.03 to 2.43) p(better) = 88%	1.61 (1.04 to 2.47) p(better) = 90%	NA	NA	DIC = 77.22 Totresdev = 8.11
Unadjusted maintenance NMA	1 p(better) = NA	1.06 (0.65 to 1.75) p(better) = 53%	0.39 (0.19 to 0.78) p(better) = 20%	0.50 (0.25 to 0.99) p(better) = 25%	0.93 (0.48 to 1.83) p(better) = 44%	1.01 (0.51 to 1.99) p(better) = 50%	NA	NA	DIC = 80.22 Totresdev = 10.47
CDAI <150
Reference case – Bayesian hierarchical	1 p(better) = NA	1.03 (0.89 to 1.26) p(better) = 52%	1.29 (0.78 to 2.12) p(better) = 56%	1.34 (0.82 to 2.18) p(better) = 63%	1.55 (0.98 to 2.43) p(better) = 75%	1.60 (1.01 to 2.53) p(better) = 78%	0.73 (0.14 to 2.69) p(better) = 35%	0.72 (0.14 to 2.64) p(better) = 34%	DIC = 101.28 Totresdev = 12.51
Unadjusted maintenance NMA	1 p(better) = NA	1.20 (0.74 to 1.96) p(better) = 67%	0.37 (0.18 to 0.77) p(better) = 18%	0.46 (0.23 to 0.90) p(better) = 22%	0.99 (0.49 to 2.00) p(better) = 49%	0.89 (0.44 to 1.78) p(better) = 41%	0.81 (0.34 to 1.88) p(better) = 37%	0.52 (0.22 to 1.19) p(better) = 26%	DIC = 104.46 Totresdev = 14.29

Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; CrI, Credible interval; DIC, Deviance information criterion; eow, Every other week; IFX, Infliximab; NA, Not available; q4w, Every 4 weeks; q8w, Every 8 weeks; q12w, Every 12 weeks; Totresdev, Total residual deviance; UST, Ustekinumab; VDZ, Vedolizumab.

Bolded values are statistically significant odds ratios.

Appendix 11. Random effects model results.Results from primary analyses for random effects model

Odds ratios (95% CrIs) for UST versus comparator
Dose	UST 90 mg q8w	UST 90 mg q12w	ADA 40 mg weekly		ADA 40 mg eow		VDZ 300 mg q4w	VDZ 300 mg q8w	IFX 5 mg/kg	IFX 5 & 10 mg/kg	Model fit statistics
Class	UST		ADA				VDZ		IFX
CDAI-100
FE model: overall population	1	1.01 (0.87 to 1.19)	1.37 (0.85 to 2.19)		1.42 (0.88 to 2.26)		1.58 (1.03 to 2.43)	1.61 (1.04 to 2.47)	NA	NA	DIC = 77.22 Totresdev = 8.11 vs. 11
	1		1.38 (0.84 to 2.25)				1.58 (1.02 to 2.49)		NA
RE model: overall population	1	1.01 (0.82 to 1.25)	1.36 (0.63 to 2.74)		1.39 (0.64 to 2.81)		1.59 (0.78 to 3.36)	1.61 (0.78 to 3.38)	NA	NA	DIC = 78.76 Totresdev = 9.10 vs. 11
	1		1.37 (0.63 to 2.79)				1.60 (0.77 to 3.40)		NA
CDAI <150
FE model: overall population	1	1.03 (0.89 to 1.26)	1.29 (0.78 to 2.12)		1.34 (0.82 to 2.18)		1.55 (0.98 to 2.43)	1.60 (1.01 to 2.53)	0.73 (0.14 to 2.69)	0.72 (0.14 to 2.64)	DIC = 101.28 Totresdev = 12.51 vs. 16
	1		1.29 (0.77 to 2.15)				1.54 (0.95 to 2.47)		0.71 (0.14 to 2.62)
RE model: overall population	1	1.02 (0.84 to 1.28)	1.26 (0.61 to 2.40)		1.29 (0.63 to 2.44)		1.52 (0.76 to 3.07)	1.56 (0.77 to 3.13)	0.67 (0.13 to 2.51)	0.66 (0.13 to 2.46)	DIC = 102.45 Totresdev = 13.04 vs. 12
	1		1.25 (0.60 to 2.43)				1.51 (0.75 to 3.12)		0.65 (0.13 to 2.45)

Abbreviations. ADA, Adalimumab; CDAI, Crohn’s Disease Activity Index; CrI, Credible interval; DIC, Deviance information criterion; eow, Every other week; FE, Fixed effects; IFX, Infliximab; NA, Not available; q4w, Every 4 weeks; q8w Every 8 weeks; q12w, Every 12 weeks; RE, Random effects; Totresdev, Total residual deviance; UST, Ustekinumab; VDZ, Vedolizumab.

Bolded values are statistically significant odds ratios.

Appendix 13. PRISMA network meta-analysis checklist.

Section/topic	Item #	Checklist item	Reported on page #
TITLE
Title	1	Identify the report as a systematic review incorporating a network meta-analysis (or related form of meta-analysis).	1
ABSTRACT
Structured summary	2	Provide a structured summary including, as applicable:	1
		Background: main objectives.
		Methods: data sources; study eligibility criteria, participants, and interventions; study appraisal; and synthesis methods, such as network meta-analysis.
		Results: number of studies and participants identified; summary estimates with corresponding confidence/credible intervals; treatment rankings may also be discussed. Authors may choose to summarize pairwise comparisons against a chosen treatment included in their analyses for brevity.
		Discussion/conclusions: limitations; conclusions and implications of findings.
		Other: primary source of funding; systematic review registration number with registry name.
INTRODUCTION
Rationale	3	Describe the rationale for the review in the context of what is already known, including mention of why a network meta-analysis has been conducted.	1
Objectives	4	Provide an explicit statement of questions being addressed, with reference to participants, interventions, comparisons, outcomes and study design (PICOS).	2
METHODS
Protocol and registration	5	Indicate whether a review protocol exists and if and where it can be accessed (e.g. web address); and, if available, provide registration information, including registration number.	2
Eligibility criteria	6	Specify study characteristics (e.g. PICOS, length of follow-up) and report characteristics (e.g. years considered, language, publication status) used as criteria for eligibility, giving rationale. Clearly describe eligible treatments included in the treatment network, and note whether any have been clustered or merged into the same node (with justification).	2
Information sources	7	Describe all information sources (e.g. databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.	2
Search	8	Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.	1
Study selection	9	State the process for selecting studies (i.e. screening, eligibility, included in systematic review and, if applicable, included in the meta-analysis).	2
Data collection process	10	Describe method of data extraction from reports (e.g. piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.	2
Data items	11	List and define all variables for which data were sought (e.g. PICOS, funding sources) and any assumptions and simplifications made.	2
Geometry of the network	S1	Describe methods used to explore the geometry of the treatment network under study and potential biases related to it. This should include how the evidence base has been graphically summarized for presentation, and what characteristics were compiled and used to describe the evidence base to readers.	3
Risk of bias within individual studies	12	Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.	2
Summary measures	13	State the principal summary measures (e.g. risk ratio, difference in means). Also describe the use of additional summary measures assessed, such as treatment rankings and surface under the cumulative ranking curve (SUCRA) values, as well as modified approaches used to present summary findings from meta-analyses.	4
Planned methods of analysis	14	Describe the methods of handling data and combining results of studies for each network meta-analysis. This should include, but not be limited to:  • Handling of multi-arm trials;  • Selection of variance structure;  • Selection of prior distributions in Bayesian analyses; and  • Assessment of model fit.	5
Assessment of inconsistency	S2	Describe the statistical methods used to evaluate the agreement of direct and indirect evidence in the treatment network(s) studied. Describe efforts taken to address its presence when found.	5
Risk of bias across studies	15	Specify any assessment of risk of bias that may affect the cumulative evidence (e.g. publication bias, selective reporting within studies).	2
Additional analyses	16	Describe methods of additional analyses if done, indicating which were pre-specified. This may include, but not be limited to, the following:  • Sensitivity or subgroup analyses;  • Meta-regression analyses;  • Alternative formulations of the treatment network; and  • Use of alternative prior distributions for Bayesian analyses (if applicable).	6
RESULTS*
Study selection	17	Give numbers of studies screened, assessed for eligibility and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.	Figure 1
Presentation of network structure	S3	Provide a network graph of the included studies to enable visualization of the geometry of the treatment network.	Figure 5
Summary of network geometry	S4	Provide a brief overview of characteristics of the treatment network. This may include commentary on the abundance of trials and randomized patients for the different interventions and pairwise comparisons in the network, gaps of evidence in the treatment network, and potential biases reflected by the network structure.	10 6
Study characteristics	18	For each study, present characteristics for which data was extracted (e.g. study size, PICOS, follow-up period) and provide the citations.	6
Risk of bias within studies	19	Present data on risk of bias of each study and, if available, any outcome level assessment.	Figure 2
Results of individual studies	20	For all outcomes considered (benefits or harms), present, for each study: 1) simple summary data for each intervention group; and 2) effect estimates and confidence intervals. Modified approaches may be needed to deal with information from larger networks.	6
Synthesis of results	21	Present results of each meta-analysis done, including confidence/credible intervals. In larger networks, authors may focus on comparisons versus a particular comparator (e.g. placebo or standard care), with full findings presented in an appendix. League tables and forest plots may be considered to summarize pairwise comparisons. If additional summary measures were explored (such as treatment rankings), these should also be presented.	6 Table 2
Exploration for inconsistency	S5	Describe results from investigations of inconsistency. This may include such information as measures of model fit to compare consistency and inconsistency models, p values from statistical tests, or summary of inconsistency estimates from different parts of the treatment network.	10
Risk of bias across studies	22	Present results of any assessment of risk of bias across studies for the evidence base being studied.	Appendix 4
Results of additional analyses	23	Give results of additional analyses, if done (e.g. sensitivity or subgroup analyses, meta-regression analyses, alternative network geometries studied, alternative choice of prior distributions for Bayesian analyses, and so forth).	10 Table 3
DISCUSSION
Summary of evidence	24	Summarize the main findings, including the strength of evidence for each main outcome; consider their relevance to key groups (e.g. healthcare providers, users and policy-makers).	10–11
Limitations	25	Discuss limitations at study and outcome level (e.g. risk of bias), and at review level (e.g. incomplete retrieval of identified research, reporting bias). Comment on the validity of the assumptions, such as transitivity and consistency. Comment on any concerns regarding network geometry (e.g. avoidance of certain comparisons).	11
Conclusions	26	Provide a general interpretation of the results in the context of other evidence, and implications for future research.	11
FUNDING			1
Funding	27	Describe sources of funding for the systematic review and other support (e.g. supply of data); role of funders for the systematic review. This should also include information regarding whether funding has been received from manufacturers of treatments in the network and/or whether some of the authors are content experts with professional conflicts of interest that could affect use of treatments in the network.

Abbreviation. PICOS Population, intervention, comparators, outcomes, study design.

Text in italics indicates wording specific to reporting of network meta-analyses that has been added to guidance from the PRISMA statement.

*Authors may wish to plan for use of appendices to present all relevant information in full detail for items in this section.

Source: Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–784.

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