Trial Outcomes & Findings for 12-Week Study of Plecanatide for CIC (The National CIC3 Study) (NCT NCT02122471)

Last Updated: 2019-05-28

Results Overview

The primary efficacy endpoint was measured by the number of durable overall CSBM responders over the 12-week Treatment Period. A durable overall CSBM responder was defined as a weekly CSBM responder for at least 9 of the 12 treatment weeks, including at least 3 of the last 4 weeks. A CSBM weekly responder was defined as a patient who has ≥ 3 Complete Spontaneous Bowel Movements (CSBMs) per week and an increase from baseline of ≥1 CSBM for that week. A CSBM was a bowel movement that occurred in the absence of laxative use within 24 hours and was associated with the feeling of complete evacuation.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1410 participants

Primary outcome timeframe

12-Week Treatment Period

Results posted on

2019-05-28

Participant Flow

The data are correct and approved in the NDA. 1410 randomized subj.including 95 (index and non-index) duplicate subj. The index subj (22) were duplicate appeared the first time in the study and the same subject appeared in other studies or sites were non-index duplicate (73) who were excluded in the ITT population (1337).

Participant milestones

Participant milestones
Measure	Placebo Matching placebo tablets QD for 12 weeks	Plecanatide 3 mg Plecanatide tablets 3 mg QD for 12 weeks	Plecanatide 6 mg Plecanatide tablets 6 mg QD for 12 weeks
Overall Study STARTED	445	443	449
Overall Study COMPLETED	406	392	405
Overall Study NOT COMPLETED	39	51	44

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

12-Week Study of Plecanatide for CIC (The National CIC3 Study)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=445 Participants Matching placebo tablets QD for 12 weeks	Plecanatide 3 mg n=443 Participants Plecanatide tablets 3 mg QD for 12 weeks	Plecanatide 6 mg n=449 Participants Plecanatide tablets 6 mg QD for 12 weeks	Total n=1337 Participants Total of all reporting groups
Age, Continuous	44.6 years STANDARD_DEVIATION 14.59 • n=5 Participants	45.5 years STANDARD_DEVIATION 14.38 • n=7 Participants	45.3 years STANDARD_DEVIATION 14.47 • n=5 Participants	45.1 years STANDARD_DEVIATION 14.47 • n=4 Participants
Sex: Female, Male Female	350 Participants n=5 Participants	345 Participants n=7 Participants	353 Participants n=5 Participants	1048 Participants n=4 Participants
Sex: Female, Male Male	95 Participants n=5 Participants	98 Participants n=7 Participants	96 Participants n=5 Participants	289 Participants n=4 Participants

PRIMARY outcome

Timeframe: 12-Week Treatment Period

Population: The modified ITT population (1310 subjects) for primary outcome was ITT population minus 27 subjects eliminated from two OAI sites. The ITT population (1337) as described in the Participate Flow consisted of the randomized subjects (1410) excluding 73 non-index subjects. "Index" subjects were duplicate subjects appeared once in the ITT population.

Outcome measures

Outcome measures
Measure	Placebo n=440 Participants Matching placebo tablets QD for 12 weeks	Plecanatide 3 mg n=430 Participants Plecanatide tablets 3 mg QD for 12 weeks	Plecanatide 6 mg n=440 Participants Plecanatide tablets 6 mg QD for 12 weeks
Number of Durable Overall CSBM Responders, Mean Replacement Approach	57 Participants	88 Participants	88 Participants

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: A total of 1288 patients included in ITT-E population for secondary outcome which consisted of the randomized subjects (1410) excluding 95 duplicate subjects as described in the Participate Flow and 27 subjects eliminated from two OAI sites.

The change from baseline in the number of Complete Spontaneous Bowel Movements (CSBMs) over the 12-week Treatment Period was analyzed. Baseline was the mean number of CSBMs recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. A CSBM was a bowel movement that occurred in the absence of laxative use within 24 hours and was associated with the feeling of complete evacuation.

Outcome measures

Outcome measures
Measure	Placebo n=432 Participants Matching placebo tablets QD for 12 weeks	Plecanatide 3 mg n=422 Participants Plecanatide tablets 3 mg QD for 12 weeks	Plecanatide 6 mg n=434 Participants Plecanatide tablets 6 mg QD for 12 weeks
Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach Baseline	1.41 CSBMs per week Standard Error 0.138	2.34 CSBMs per week Standard Error 0.139	2.19 CSBMs per week Standard Error 0.138
Change From Baseline in CSBMs (CSBMs/Week) Over the 12-week Treatment Period , Mean Replacement Approach 12 weeks	1.69 CSBMs per week Standard Error 0.159	2.66 CSBMs per week Standard Error 0.162	2.50 CSBMs per week Standard Error 0.159

SECONDARY outcome

Timeframe: Baseline and 12 weeks

The change from baseline in the number of Spontaneous Bowel Movement (SBM) over the 12-week Treatment Period was analyzed. Baseline was the mean number of SBMs recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. The weekly SBM totals were derived from the daily diary entries reported during the Treatment Period.

Outcome measures

Outcome measures
Measure	Placebo n=432 Participants Matching placebo tablets QD for 12 weeks	Plecanatide 3 mg n=422 Participants Plecanatide tablets 3 mg QD for 12 weeks	Plecanatide 6 mg n=434 Participants Plecanatide tablets 6 mg QD for 12 weeks
Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach Baseline	1.55 SBMs per week Standard Deviation 1.591	1.79 SBMs per week Standard Deviation 2.084	1.63 SBMs per week Standard Deviation 1.673
Change From Baseline in SBMs (SBMs/Week) Over the 12-week Treatment Period, Mean Replacement Approach 12 weeks	1.81 SBMs per week Standard Deviation 2.879	3.25 SBMs per week Standard Deviation 3.938	3.10 SBMs per week Standard Deviation 4.164

SECONDARY outcome

Timeframe: Baseline and 12 weeks

The change from baseline in the stool consistency score (i.e. BSFS) over the 12-week Treatment Period was analyzed. Baseline was the mean BSFS score recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. The weekly mean BSFS score per patient was derived from the BSFS entries reported during the Treatment Period in the Daily Symptom Diary. The stool consistency of each bowel movement (BM) was assessed by patients using the 7-point Bristol Stool Form Scale \[BSFS\] from 1 to 7. 1. = separate hard lumps like nuts (difficult to pass) 2. = sausage shaped but lumpy 3. = like a sausage but with cracks on its surface 4. = like a sausage or snake, smooth and soft 5. = soft blobs with clear-cut edges (passed easily) 6. = fluffy pieces with ragged edges, a mushy stool 7. = watery, no solid pieces (entirely liquid)

Outcome measures

Outcome measures
Measure	Placebo n=432 Participants Matching placebo tablets QD for 12 weeks	Plecanatide 3 mg n=422 Participants Plecanatide tablets 3 mg QD for 12 weeks	Plecanatide 6 mg n=434 Participants Plecanatide tablets 6 mg QD for 12 weeks
Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach Baseline	2.35 score on a scale Standard Deviation 1.090	2.16 score on a scale Standard Deviation 1.036	2.27 score on a scale Standard Deviation 1.113
Change From Baseline in Average Weekly SBM Stool Consistency Over the 12-week Treatment Period, Mean Replacement Approach 12 weeks	1.02 score on a scale Standard Deviation 1.346	1.71 score on a scale Standard Deviation 1.475	1.59 score on a scale Standard Deviation 1.497

SECONDARY outcome

Timeframe: Baseline and 12 weeks

The change from baseline in the straining score over the 12-week Treatment Period was analyzed. Baseline was the mean of non-missing straining scores recorded during the 2-week baseline diary assessment period prior to the first dose of study drug. The weekly average straining score was derived from the straining scores reported during the Treatment Period in the Daily Symptom Diary. The severity of straining during bowel movements was assessed on a 5-point Likert scale where 0 = none, 1 = mild, 2 = moderate, 3 = severe, and 4 = very severe.

Outcome measures

Outcome measures
Measure	Placebo n=432 Participants Matching placebo tablets QD for 12 weeks	Plecanatide 3 mg n=422 Participants Plecanatide tablets 3 mg QD for 12 weeks	Plecanatide 6 mg n=434 Participants Plecanatide tablets 6 mg QD for 12 weeks
Change From Baseline in Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach Baseline	2.42 score on a scale Standard Deviation 0.855	2.46 score on a scale Standard Deviation 0.859	2.47 score on a scale Standard Deviation 0.888
Change From Baseline in Average Weekly Straining Score Over the 12-week Treatment Period, Mean Replacement Approach 12 weeks	-0.79 score on a scale Standard Deviation 1.132	-1.09 score on a scale Standard Deviation 1.092	-1.04 score on a scale Standard Deviation 1.084

Adverse Events

Placebo

Serious events: 8 serious events

Other events: 15 other events

Deaths: 0 deaths

Plecanatide 3 mg

Serious events: 8 serious events

Other events: 25 other events

Deaths: 0 deaths

Plecanatide 6 mg

Serious events: 4 serious events

Other events: 31 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=466 participants at risk Matching placebo tablets QD for 12 weeks	Plecanatide 3 mg n=467 participants at risk Plecanatide tablets 3 mg QD for 12 weeks	Plecanatide 6 mg n=469 participants at risk Plecanatide tablets 6 mg QD for 12 weeks
Gastrointestinal disorders Diarrhoea	1.3% 6/466 • Number of events 6 The data are correct and approved in the NDA. The ITT-S population (1402) was more than the ITT population (1337) in the Participant Flow because all duplicate subjects (index and non-index) who received at lease one dose of study drug were included in the ITT-S population. A total of 1410 randomized subjects, of which eight subjects were not treated with the study drug after being enrolled and resulted in 1402 subjects.	3.2% 15/467 • Number of events 15 The data are correct and approved in the NDA. The ITT-S population (1402) was more than the ITT population (1337) in the Participant Flow because all duplicate subjects (index and non-index) who received at lease one dose of study drug were included in the ITT-S population. A total of 1410 randomized subjects, of which eight subjects were not treated with the study drug after being enrolled and resulted in 1402 subjects.	4.5% 21/469 • Number of events 25 The data are correct and approved in the NDA. The ITT-S population (1402) was more than the ITT population (1337) in the Participant Flow because all duplicate subjects (index and non-index) who received at lease one dose of study drug were included in the ITT-S population. A total of 1410 randomized subjects, of which eight subjects were not treated with the study drug after being enrolled and resulted in 1402 subjects.
Nervous system disorders Headache	1.9% 9/466 • Number of events 10 The data are correct and approved in the NDA. The ITT-S population (1402) was more than the ITT population (1337) in the Participant Flow because all duplicate subjects (index and non-index) who received at lease one dose of study drug were included in the ITT-S population. A total of 1410 randomized subjects, of which eight subjects were not treated with the study drug after being enrolled and resulted in 1402 subjects.	2.1% 10/467 • Number of events 10 The data are correct and approved in the NDA. The ITT-S population (1402) was more than the ITT population (1337) in the Participant Flow because all duplicate subjects (index and non-index) who received at lease one dose of study drug were included in the ITT-S population. A total of 1410 randomized subjects, of which eight subjects were not treated with the study drug after being enrolled and resulted in 1402 subjects.	2.1% 10/469 • Number of events 10 The data are correct and approved in the NDA. The ITT-S population (1402) was more than the ITT population (1337) in the Participant Flow because all duplicate subjects (index and non-index) who received at lease one dose of study drug were included in the ITT-S population. A total of 1410 randomized subjects, of which eight subjects were not treated with the study drug after being enrolled and resulted in 1402 subjects.

Additional Information

Dr. Patrick H. Griffin

Synergy Pharmaceuticals Inc.

Phone: 212-297-0020

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place