Remission endpoints in ulcerative colitis: A systematic review

Table 7 Randomised clinical trials measured with the ulcerative colitis disease activity index

Ref.	Year	Drug	Entry criteria	Primary endpoint	Secondary endpoint	Remission/clinical improvement	Length of study
Randomised clinical trials - to induce remission
Mesalazine (5-ASA)
Marteau etal[58]	2005	Pentasa (PR + PO vs PO alone)	UCDAI: 3-8	Remission at week 4	Remission rate at week 8 Improvement at week 4 and 8	Remission: UCDAI ≤ 1 Clinical improvement: A decrease of UCDAI ≥ 2	8 wk
D’Haens etal[59]	2006	SPD476 - MMX mesalazine	UCDAI: 4-10 + endoscopic score ≥1 PGA score ≤ 2	Remission	Change in UCDAI, FS, histology at week 8 Change in symptoms	Remission: UCDAI ≤ 1 (with RB 0, SF ≤ 1 ) at week 8	8 wk
Sandborn etal[60]	2007	MMX Multi Matrix System mesalazine	UCDAI: 4-10 + endoscopic score ≥1 PGA score ≤ 2	Clinical/endoscopic remission at 8 wk	Proportion of clinical improvement Proportion of patients as treatment failure Change in: RB, SF, FS	Clinical remission: UCDAI ≤ 1 Endoscopic remission: UCDAI endoscopic subscore ≤ 1 Clinical improvement: A decrease of UCDAI ≥ 3 Treatment failure: Unchanged or worsened UCDAI	8 wk
Lichtenstein et al[61]	2007	SPD476 - MMX mesalazine OD vs BD	UCDAI: 4-10	Clinical and endoscopic remission at week 8	Comparison of remission rate at week 8	Clinical remission: UCDAI ≤ 1 with RB/SF/EI = 0	8 wk
Kamm et al[62,63] MEZAVANT study	2007 2009	MEZAVANT MMX Mesalamine	Mild - mod UC: UCDAI 4-10 + endoscopic subscore ≥ 1, PGA ≤ 2	Clinical + Endoscopic remission at week 8	Clinical remission Clinical improvement Change in UCDAI	Clinical + endoscopic remission: UCDAI ≤ 1 + subscore RB/SF = 0, No mucosal friability + a ≥ 1 reduction in EI Clinical improvement: Decrease in UCDAI ≥ 3	8 wk
Ito et al[64]	2010	Asacol vs PentasaTime-dependent vs pH dependent Mesalamine	UCDAI: 3-8 and blood stool score ≥ 1	To demonstrate Asacol over Pentasa AND the decrease in UCDAI	Macroscopic changes	Remission: UCDAI ≤ 2 and no blood diarrhoea Clinical improvement: UCDAI decreased by ≥ 2	8 wk
Hiwatashi etal[65]	2010	Mesalazine - dose study	UCDAI: 6-8	Change in UCDAI at week 8	Remission, improvement, efficacy	Remission: UCDAI ≤ 1 Efficacy: Decrease of UCDAI ≥ 2	8 wk
Flourié et al[66] MOTUS study	2013	Mesalazine, Pentasa OD or BD in total of 4 g/d	UCDAI: 3-8	UCDAI ≤ 1 after 8 wk	Complete remission (UCDAI = 0) at 8 wk UCDAI decreased by ≥ 2 at 8 wk Clinical remission at week 4, 8, 12 Mucosal healing at 8 wk	Complete remission: UCDAI = 0 Endoscopic remission: UCDAI endoscopic subscore: 0 or 1 Clinical remission: UCDAI ≤ 1	12 wk
Probert et al[42] PINCE study	2013	Mesalazine (pentasa) enema	UCDAI: 3-8	Remission rate (UCDAI < 2) at 4 wk	Remission rate at 8 wk, improvement at week 2, 4 and 8 Time to cessation of RB QoL (EQ-5D)	Remission: UCDAI ≤ 1 Clinical improvement: UCDAI decreased by ≥ 2	8 wk
Sun et al[67]	2016	Mesalazine (modified-release vs enteric-coated tablets)	UCDAI: 3-8 + bloody stool score > 1	The decrease in UCDAI	Remission rate Efficacy rate	Remission: UCDAI ≤ 2 + bloody stool 0 Clinical improvement: A decrease of UCDAI ≥ 2	8 wk
Suzuki etal[68]	2016	pH dependent release mesalamine, asacol dose	UCDAI: 6 - 10 Rectal bleeding score ≥ 1	Decrease in UCDAI		Remission: UCDAI ≤ 2 Rectal bleeding score: 0 Improvement UCDAI decreased by ≥ 2	8 wk
Thiazole compounds
Mantzaris etal[69]	2004	Azathioprine alone (2.2 mg/kg) vs combination with olsalazine (0.5 g TID)	Steroid-dependent remission	Relapse rate	Time to relapse Time to discontinuation Severity of relapse	Remission: UCDAI ≤ 1 Relapse: New symptoms + UCDAI > 3	2 yr
Schreiber etal[70]	2007	Tetomilast - Thiazole compound	UCDAI: 4-11	Clinical improvement: UCDAI decreased by ≥ 3 at 8 wk	Remission Clinical improvement at week 4 IBDQ-32 score Proportion of pts with improved Flexible Sigmoidscopy score Time to clinical improvement Time to remission	Clinical improvement: UCDAI decreased by ≥ 3 Remission: UCDAI ≤ 1	8 wk
Steroids
Travis et al[71] CORE II study	2012	Budesonide MMX	UCDAI: 4-10	Clinical/endoscopic remission at week 8	Clinical improvement Endoscopic improvement at week 8	Clinical/endoscopic Remission: UCDAI ≤ 1 + RB/SF/EI = 0 Clinical improvement: A decrease of UCDAI ≥ 3 Endoscopic improvement: A decrease of EI ≥ 1	8 wk
Probiotics
Vernia etal[72]	2000	Sodium Butyrate	Mild-moderate UC	Remission or marked improvement		Remission: UCDAI ≤ 2 Positive response: Decrease of UCDAI ≥ 2	6 wk
Mahmood etal[73]	2005	Human recombinant trefoil factor 3 enema	UCDAI: >3	Remission at week 2	Clinical significant improvement in clinical and histological scores at 2 and 4 wk	Remission: UCDAI ≤ 1 without RB Clinical improvement: A decrease of UCDAI >3	4 wk
Lichtenstein et al[74]	2007	Bowman-Birk inhibitor concentrate - soy extract with high protease inhibitor activity	UCDAI: 4-10	Remission at week 8		Remission: UCDAI ≤ 1 + no RB or SF Clinical improvement: UCDAI decrease ≥ 1
Tursi et al[75]	2009	VSL #3 (probiotic)	UCDAI 3-8, endoscopic subscore ≥ 3	Decrease in UCDAI of ≥ 50%	Activity of relapsing UC Remission Improvement Change in objective and subjective symptoms	Remission: UCDAI ≤ 2	8 wk
Sood et al[76]	2009	VSL #3 probiotic	UCDAI 3-9 with endoscopic subscore ≥ 2	Clinical improvement at week 6	Clinical remission	Clinical remission: UCDAI ≤ 2 Clinical improvement: A decrease UCDAI by 50%	12 wk
Tamaki etal[77]	2016	Bifidobacterium longum 536 (probiotic)	UCDAI 3-9	Change in UCDAI	Remission Improvement of Objective and subjective symptoms Endoscopic improvement in Mayo subscore	Remission: UCDAI ≤ 2	8 wk
Helminth therapy Garg etal[78]	2014	Helminth Trichuris suis ova	UCDAI of ≥ 4	Clinical improvement	Clinical remission	Clinical improvement: Decrease in the UCDAI of ≥ 4 Clinical remission: UCDAI of ≤ 2	12 wk
Nicotine therapy
Ingram etal[79]	2005	Nicotine enema 6 mg/d	Confirmed UC with inflamed mucosa grade > 2	Clinical remission	Improvement in the UCDAI	Clinical remission: UCDAI EI ≤ 1 and No RB for 1 wk	6 wk
Randomised clinical trials - to maintain remission
Lichtenstein et al[80-82] and Zakko etal[83]	2010 2012 2015 2016	Mesalamine granules 1.5 g/d, OD	Previously achieved remission with steroids for > 1 mo and < 12 mo	Percentage of patients relapse-free at 6 mo	Mean changes from baseline at month 6	Relapse: UCDAI RB ≥ 1 and EI ≥ 2 Remission: UCDAI RB = 0, EI < 2	6 mo
Bokemeyer et al[43] and Dignass etal[84]	2009 2011	Mesalazine, Pentasa OD or BD in total of 2 g/d	Clinical remission: UCDAI < 2	To demonstrate OD is not inferior to BD	Time to relapse between 2 groups UC-DAI total and subscores between 2 groups	Remain in remission UCDAI ≤ 2	12 mo

RB: Rectal bleeding; SF: Stool frequency; EI: Endoscopic index/subscore; OD: Once daily; BD: Twice daily; TID: Three times daily; UCDAI: Ulcerative colitis disease activity index; QoL: Quality of life.