Plecanatide Improves Symptoms of Irritable Bowel Syndrome with Constipation: Results of an Integrated Efficacy and Safety Analysis of Two Phase 3 Trials

Figures & data

Table 1 Baseline Demographic and Disease Characteristics

Characteristic	Plecanatide 3 mg (n=724)	Plecanatide 6 mg (n=723)	Placebo (n=729)
Age
Mean, y (SD)	43.5 (14.2)	43.1 (13.8)	43.9 (14.2)
≥65 y, n (%)	63 (8.7)	49 (6.8)	64 (8.8)
Female, n (%)	534 (73.8)	536 (74.1)	540 (74.1)
Mean BMI, kg/m^2 (SD)	28.2 (4.8)	28.1 (4.9)	28.0 (4.8)
Race/ethnicity, n (%)
White	527 (72.8)	515 (71.2)	536 (73.5)
Black	155 (21.4)	177 (24.5)	160 (21.9)
Asian	33 (4.6)	25 (3.5)	25 (3.4)
Other	9 (1.2)	6 (0.8)	8 (1.1)
Mean bowel movement frequency per week, n (SD)
SBMs	1.5 (1.1)	1.5 (1.1)	1.4 (1.1)
CSBMs	0.2 (0.5)	0.3 (0.5)	0.2 (0.5)
Mean stool consistency score (SD)	2.0 (0.9)*	1.9 (0.9)^†	2.0 (1.0)^‡
Mean straining score (SD)	6.7 (1.9)^§	6.7 (1.9)^¶	6.6 (1.9)^#
Abdominal symptoms
Mean abdominal pain score (SD)	6.3 (1.7)**	6.2 (1.8)^††	6.3 (1.7)^‡‡
Mean abdominal discomfort score (SD)	6.4 (1.6)**	6.4 (1.7)^††	6.4 (1.6)^‡‡
Mean abdominal fullness score (SD)	6.5 (1.7)**	6.4 (1.8)^††	6.5 (1.7)^††
Mean bloating score (SD)	6.5 (1.7)**	6.4 (1.8)^††	6.5 (1.8)^‡‡
Mean cramping score (SD)	6.0 (1.9)**	5.9 (2.0)^††	6.0 (2.0)^††
Mean patient global rating, n (SD)
Abdominal pain	−0.4 (0.7)^§§	−0.4 (0.7)^¶¶	−0.3 (0.7)^¶¶
IBS symptoms	−0.3 (0.8)^##	−0.3 (0.7)^§§	−0.3 (0.7)^§§
IBS disease severity	3.6 (0.7)***	3.5 (0.7)^##	3.6 (0.7)^##

Notes: *n=625. ^†n=615. ^‡n=627. ^§n=690. ^¶n=674. ^#n=676. **n=719. ^††n=716. ^‡‡n=717. ^§§n=689. ^¶¶n=688. ^##n=691. ***n=693. Stool consistency was determined using the 7-point Bristol Stool Form Scale (range, type 1 [“separate hard lumps, like nuts (hard to pass)”] to type 7 [“watery, no solid pieces, entirely liquid”]). Straining, abdominal pain, abdominal discomfort, abdominal fullness, bloating, and cramping were measured using an 11-point scale (range, 0 [“no or none”] to 10 [“worst possible”]). Patient global ratings were determined using a 5-point scale for abdominal pain and IBS symptoms (range, −2 [“significantly worse”] to 2 “[significantly relieved”]) and IBS disease severity (range, 1 [“none”] to 5 [“very severe”).

Abbreviations: BMI, body mass index; CSBM, complete spontaneous bowel movement; IBS, irritable bowel syndrome; SBM, spontaneous bowel movement.

Figure 1 Percentage of responders.

Notes: *P<0.001 vs placebo. ^†≥6 of 12 treatment weeks. Overall response was defined as abdominal pain response (≥30% decrease from baseline in the weekly average of worst abdominal pain severity) and stool frequency response (increase from baseline of ≥1 complete spontaneous bowel movement) during the same week for ≥6 of 12 treatment weeks (ie, composite). Sustained response was defined as overall response plus meeting weekly abdominal pain and stool frequency response composite criteria during ≥2 of last 4 treatment weeks.

Figure 2 LSM changes from baseline in (A) abdominal pain, (B) abdominal discomfort, (C) abdominal fullness, (D) bloating, and (E) cramping by week during the 12-week treatment period and 2-week posttreatment period.

Notes: *P≤0.001 vs placebo. ^†P≤0.01 vs placebo. ^‡P≤0.05 vs placebo.

Abbreviation: LSM, least-squares mean.

Table 2 Secondary Efficacy Outcomes Across 12 Weeks of Treatment

Outcome	Plecanatide 3 mg (n=724)	Plecanatide 6 mg (n=723)	Placebo (n=729)
Change from baseline in SBMs/week
LSM (SE)	1.5 (0.1)	1.6 (0.1)	0.8 (0.1)
Difference vs placebo (95% CI)	0.8 (0.5, 1.1)	0.8 (0.6, 1.1)
P value vs placebo	<0.0001	<0.0001
Change from baseline in CSBMs/week
LSM (SE)	1.2 (0.1)	1.4 (0.1)	0.7 (0.1)
Difference vs placebo (95% CI)	0.5 (0.3, 0.7)	0.7 (0.5, 0.9)
P value vs placebo	<0.001	<0.001
Change from baseline in straining*
LSM (SE)	−2.0 (0.1)	−2.1 (0.1)	−1.4 (0.1)
Difference vs placebo (95% CI)	−0.6 (−0.8, −0.4)	−0.7 (−0.9, −0.5)
P value vs placebo	<0.001	<0.001
Change from baseline in patient global rating—abdominal pain^†
LSM (SE)	1.1 (0)	1.2 (0)	0.9 (0)
Difference vs placebo (95% CI)	0.2 (0.1, 0.3)	0.3 (0.2, 0.4)
P value vs placebo	<0.0001	<0.0001
Change from baseline in patient global rating—IBS symptoms^‡
LSM (SE)	1.1 (0)	1.2 (0)	0.9 (0)
Difference vs placebo (95% CI)	0.2 (0.1, 0.3)	0.3 (0.2, 0.3)
P value vs placebo	<0.0001	<0.0001
Change from baseline in patient global rating—IBS disease severity^§
LSM (SE)	−1.0 (0)	−1.0 (0)	−0.8 (0)
Difference vs placebo (95% CI)	−0.2 (−0.2, −0.1)	−0.2 (−0.3, −0.1)
P value vs placebo	<0.0001	<0.0001

Notes: *Rated on an 11-point scale (range, 0 [“no or none”] to 10 [“worst possible”]). ^†Response to question of “How would you rate your abdominal pain overall over the past 7 days?” (5-point scale of 2 [“significantly relieved”], 1 [“moderately relieved”], 0 [“unchanged”], −1 [“moderately worse”], −2 [“significantly worse”]). ^‡Response to question of “How would you rate your IBS signs and symptoms overall over the past 7 days?” (5-point scale of 2 [“significantly relieved”], 1 [“moderately relieved”], 0 [“unchanged”], −1 [“moderately worse”], −2 [“significantly worse”]). ^§Response to question of “How would you rate the severity of your IBS symptoms at their worst over the past 7 days?” (5-point scale of 1 [“none”], 2 [“mild”], 3 [“moderate”], 4 [“severe”], 5 [“very severe”]). Bold font indicates statistical significance.

Abbreviations: CSBM, complete spontaneous bowel movement; IBS, irritable bowel syndrome; LSM, least-squares mean; SBM, spontaneous bowel movement.

Table 3 Adverse Events (Safety Population)

Patient with an AE, n (%)	Plecanatide 3 mg (n=726)	Plecanatide 6 mg (n=726)	Placebo (n=730)
≥1 AE	173 (23.8)	144 (19.8)	136 (18.6)
≥1 treatment-related AE*	48 (6.6)	47 (6.5)	24 (3.3)
≥1 SAE	6 (0.8)^†	5 (0.7)^‡	6 (0.8)^§
≥1 AE leading to discontinuation	18 (2.5)	16 (2.2)	3 (0.4)
Diarrhea leading to discontinuation	9 (1.2)	10 (1.4)	0
Patients with ≥1 AE possibly associated with treatment^¶	40 (5.5)	38 (5.2)	19 (2.6)
By AE intensity^#
Mild	96 (13.2)	78 (10.7)	85 (11.6)
Moderate	60 (8.3)	55 (7.6)	44 (6.0)
Severe	17 (2.3)	11 (1.5)	7 (1.0)
Most common AEs^#
Diarrhea	31 (4.3)	29 (4.0)	7 (1.0)
Headache	16 (2.2)	14 (1.9)	16 (2.2)
Nausea	12 (1.7)	8 (1.1)	7 (1.0)
Nasopharyngitis	11 (1.5)	6 (0.8)	9 (1.2)
Upper respiratory tract infection	9 (1.2)	3 (0.4)	6 (0.8)
Influenza	7 (1.0)	3 (0.4)	9 (1.2)
Urinary tract infection	7 (1.0)	11 (1.5)	5 (0.7)

Notes: *Probable, possible, or missing relationship with treatment. ^†One case of each of the following: acute cholecystitis, asthma, drowning, lymphadenitis, transaminases increased, viral infection. ^‡One case with hepatitis C and transaminases increased and 1 case of each of the following: affective disorder, costochondritis, liver function test abnormal, and suicidal ideation. ^§One case of myalgia, multiple sclerosis relapse, and suicidal ideation and 1 case of each of the following: alanine aminotransferase increased, bipolar disorder, hepatic enzyme increased, cartilage injury, and psychotic disorder. ^¶≥1.0% of patients in any group. ^#By maximum AE severity.

Abbreviations: AE, adverse event; SAE, serious adverse event.