Spotlight on eluxadoline for the treatment of patients with irritable bowel syndrome with diarrhea

Figures & data

Figure 1 Chemical structure of eluxadoline.

Figure 2 Flowchart of studies.

Table 1 Randomized controlled trials of eluxadoline for IBS-D

Design	Number of participants	Primary and secondary end points	Dose and duration	Inclusion criteria
IBS-2001: randomized, double-blind, placebo-controlled, multicenter study^Citation38	• Total: 807 • Eluxadoline: 635 • Placebo: 172	• Primary outcome: number of composite clinical responses at week 4. A patient was defined as a clinical responder if they completed 5-out-of-7-days of diary entries and met both of the following criteria: an improvement by ≥30% and at least 2 points in average daily pain scores as compared with baseline and achieved a Bristol Stool Scale score of 3 or 4 on >66% of reported days in the past week • Secondary outcomes: composite clinical responders after 12 weeks; abdominal pain responders, stool consistency responders, adequate relief responders, frequency of bowel movements; urgency episodes, incontinence episodes, changes in IBS global symptoms, QoL, and severity scores	Eluxadoline: 5 or 25 or 100 or 200 mg twice per day by mouth vs placebo twice per day for 12 weeks	• Age: 18–65 years old • IBS-D defined by Rome III criteria • Average of daily pain scores of ≥3.0 on a 0–10-point scale • Weekly mean Bristol Stool Scale score equal to or over 5.5 • Colonoscopy within the past 5 years for any alarm feature • Stable diet and no use of rescue medication within 14 days of randomization • Female patients: postmenopausal or surgically sterile or abstinent or receiving contraception, if sexually active
IBS-3001, IBS-3002: prospective, double-blind placebo-controlled, multicenter studies^Citation1,Citation39^–^Citation41	• Total: 2428 • Eluxadoline: 1616 • Placebo: 809	• Primary outcome: number of composite clinical responders over 26 weeks. Clinical responder: if they met the daily response criteria for at least half of the days with diary entries. On a given day, both of the below should be satisfied: daily pain response (worst abdominal pain scores in the past 24 hours improved by ≥30% compared with baseline) and daily stool consistency response (Bristol Stool Scale score < 5 or the absence of a bowel movement if accompanied by ≥30% improvement in worst abdominal pain compared with baseline pain). • Secondary outcomes: abdominal pain responders defined as those patients who met the daily pain response criteria; stool consistency responders, adequate relief responders, frequency of bowel movements; urgency episodes, incontinence episodes, changes in IBS global symptoms, and QoL	Eluxadoline: 75 or 100 mg twice per day by mouth vs placebo twice per day for 26 weeks	• Age: 18–80 years old • IBS-D defined by Rome III criteria • Average of worst abdominal pain scores of ≥3.0 on a 0–10-point scale • Average mean Bristol Stool Scale of ≥5.5 and at least 5 days with a Bristol Stool Consistency Scale score ≥5 on a 1–7-point scale • Average daily IBS-D Global Symptom Score of ≥2.0 on a 0–4-point scale • Stable diet and no use of rescue medication within 14 days of randomization • Female patients: postmenopausal or surgically sterile or abstinent or receiving contraception, if sexually active

Abbreviations: IBS-D, irritable bowel syndrome with diarrhea; QoL, quality of life.

Figure 3 Forest plots of efficacy outcomes.

Note: Eluxadoline vs placebo at 12 and 26 weeks.
Abbreviations: IBS, irritable bowel syndrome; IV, inverse variance; OR, odds ratio; QoL, quality of life; SE, standard error; SMD, standardized mean difference.

Figure 4 Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages across all included studies.

Table 2 Meta-analysis of efficacy outcomes and main adverse events

Outcome	Studies	Participants	Effect estimate (95% CI)	Heterogeneity: I^2 (%)
Efficacy outcomes
Bristol Stool Scale consistency score
12 weeksa	3	1524	SMD: −0.29 (−0.45, −0.13)	56
26 weeksa	2	1057	SMD: −0.42 (−0.64, −0.20)	67
Daily Pain Score
12 weeksa	3	1529	SMD: −0.17 (−0.27, −0.07)	0
26 weeksa	2	1060	SMD: −0.16 (−0.28, −0.04)	0
IBS-QoL Total Score
12 weeksa	3	1581	SMD: 0.21 (0.11, 0.31)	10
26 weeksa	2	1128	SMD: 0.16 (0.04, 0.27)	31
Global Symptom Score
12 weeksa	2	1287	SMD: −0.15 (−0.27, −0.04)	0
26 weeksa	2	1060	SMD: −0.14 (−0.27, −0.02)	0
Adequate Relief of IBS Symptoms
12 weeksb	3	913	OR: 1.99 (1.61, 2.45)	2
26 weeksb	2	1060	OR: 1.78 (1.35, 2.35)	0
Adverse events
All adverse eventsc	2	1991	OR: 1.02 (0.79, 1.32)	32
Constipationc	2	1991	OR: 3.49 (2.20, 5.55)	0
Vomitingc	2	1991	OR: 3.42 (1.79, 6.54)	0
Abdominal painc	2	1991	OR: 1.78 (1.17, 2.70)	0
Nauseac	2	1937	OR: 1.42 (0.97, 2.07)	0

Notes:

a SMD (inverse variance random effects).

b OR (inverse variance random effects).

c OR (Mantel–Haenszel random effects).

Abbreviations: IBS, irritable bowel syndrome; OR, odds ratio; QoL, quality of life; SMD, standardized mean difference.

Figure 5 Forest plots of adverse events.

Note: Eluxadoline 100 mg vs placebo.
Abbreviations: M-H, Mantel–Haenszel; OR, odds ratio.

Table 3 Frequency of adverse events for IBS-2001, IBS-3001, and IBS-3002

Adverse events	Pooled analysis of IBS-3001 and IBS-3002				IBS-2001
	Eluxadoline			Placebo (n = 808)	Eluxadoline				Placebo (n = 159)
	75 mg (n = 807)	100 mg (n = 859)	Combined groups (n = 1,666)		5 mg (n = 105)	25 mg (n = 170)	100 mg (n = 165)	200 mg (n = 172)
All adverse events	486 (60.2)a	500 (58.2)	986 (59.2)	450 (55.7)	46 (43.8)	86 (50.6)	73 (44.2)	90 (52.3)	78 (49.1)
Serious adverse events	34 (4.2)	41 (4.8)	75 (4.5)	24 (3.0)
Cardiac events	12 (1.5)	17 (2.0)	75 (4.5)	8 (1.0)
Pancreatitis	2 (0.2)	3 (0.3)	5 (0.3)	0 (0.0)
Spasm of the sphincter of Oddi	1 (0.1)	7 (0.8)	8 (0.5)	0 (0.0)
Constipation	60 (7.4)	74 (8.6)	134 (8.0)	20 (2.5)	2 (1.9)	5 (2.9)	10 (6.1)	6 (3.5)	4 (2.5)
Nausea	65 (8.1)	64 (7.5)	129 (7.7)	41 (5.1)	6 (5.7)	11 (6.5)	9 (5.5)	18 (10.5)	7 (4.4)
Abdominal pain	47 (5.8)	62 (7.2)	109 (6.5)	33 (4.1)	3 (2.9)	6 (3.5)	4 (2.4)	13 (7.6)	3 (1.9)
Vomiting	32 (4.0)	36 (4.2)	68 (4.1)	11 (1.4)	1 (1.0)	7 (4.1)	7 (4.2)	12 (7.0)	1 (0.6)
Abdominal distension	21 (2.6)	22 (2.6)	43 (2.6)	13 (1.6)	0 (0.0)	0 (0.0)	6 (3.6)	1 (0.6)	2 (1.3)
Gastroenteritis	36 (4.5)	19 (2.2)	55 (3.3)	27 (3.3)
Flatulence	21 (2.6)	27 (3.1)	48 (2.9)	13 (1.6)
Upper respiratory tract infection	27 (3.3)	47 (5.5)	74 (4.4)	32 (4.0)
Bronchitis	26 (3.2)	27 (3.1)	53 (3.2)	18 (2.2)	4 (3.8)	4 (2.4)	3 (1.8)	1 (0.6)	3 (1.9)
Sinusitis	27 (3.3)	24 (2.8)	51 (3.1)	26 (3.2)	5 (4.8)	4 (2.4)	3 (1.8)	1 (0.6)	9 (5.7)
Nasopharyngitis	33 (4.1)	23 (2,7)	56 (3.4)	27 (3.3)	4 (3.8)	8 (4.7)	7 (4.2)	6 (3.5)	6 (3.8)
Dizziness	21 (2.6)	28 (3.3)	49 (2.9)	17 (2.1)
Anxiety	10 (1.2)	19 (2.2)	29 (1.7)	14 (1.7)
Increased level of alanine aminotransferase	17 (2.1)	26 (3.0)	43 (2.6)	12 (1.5)

Note:

a Number of patients (%).

Abbreviation: IBS, irritable bowel syndrome.

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