Trial Outcomes & Findings for 12-Week Study of Plecanatide for CIC (The CIC3 Study) (NCT NCT01982240)

NCT ID: NCT01982240

Last Updated: 2019-12-26

Results Overview

A durable overall CSBM responder was defined as a weekly CSBM responder for at least 9 of the 12 treatment weeks, included 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: 1394 participants
• Primary outcome timeframe: 12-week Treatment Period
• Results posted on: 2019-12-26

Participant Flow

The data are correct and approved in the NDA. 1394 randomized subj.including 69 (index and non-index) duplicate subj. The index subj (21) were duplicate appeared the first time in the study and the same subject appeared in other studies or sites were non-index duplicate (48) who were excluded in the ITT population (1346).

Participant milestones

Measure	Placebo Matching placebo tablets QD for 12 weeks Placebo: Matching placebo tablets QD for 12 weeks	Plecanatide 3.0 mg Plecanatide tablets 3.0 mg QD for 12 weeks Plecanatide: Plecanatide tablets QD for 12 weeks	Plecanatide 6 mg Plecanatide tablets 6.0 mg QD for 12 weeks
Overall Study STARTED	452	453	441
Overall Study COMPLETED	385	384	371
Overall Study NOT COMPLETED	67	69	70

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Placebo n=452 Participants Matching placebo tablets QD for 12 weeks	Plecanatide 3.0 mg n=453 Participants Plecanatide tablets 3.0 mg QD for 12 weeks	Plecanatide 6.0 mg n=441 Participants Plecanatide tablets 6.0 mg QD for 12 weeks	Total n=1346 Participants Total of all reporting groups
Age, Continuous	46.4 years n=5 Participants	45.0 years n=7 Participants	45.1 years n=5 Participants	45.5 years n=4 Participants
Sex: Female, Male Female	357 Participants n=5 Participants	368 Participants n=7 Participants	362 Participants n=5 Participants	1087 Participants n=4 Participants
Sex: Female, Male Male	95 Participants n=5 Participants	85 Participants n=7 Participants	79 Participants n=5 Participants	259 Participants n=4 Participants

PRIMARY outcome

Timeframe: 12-week Treatment Period

Population: The ITT (Intent-to-treat) population was used for analysis.

A durable overall CSBM responder was defined as a weekly CSBM responder for at least 9 of the 12 treatment weeks, included 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.

Outcome measures

Measure	Placebo n=452 Participants Matching placebo tablets QD for 12 weeks Placebo: Matching placebo tablets QD for 12 weeks	Plecanatide 3.0 mg n=453 Participants Plecanatide tablets 3.0 mg QD for 12 weeks Plecanatide: Plecanatide tablets QD for 12 weeks	Plecanatide 6.0 mg n=441 Participants Plecanatide tablets 6.0 mg QD for 12 weeks
Number of Durable Overall CSBM Responders , Mean Replacement Approach	46 Participants	95 Participants	86 Participants

SECONDARY outcome

Timeframe: 12-Week Treatment Period

Population: The ITT (Intent-to-treat) population was used for analysis.

A Complete Spontaneous Bowel Movement (CSBM) was a Bowel Movement (BM) that occurred in the absence of laxative use within 24 hours of the BM and the patient reported a feeling of complete evacuation. A weekly responder had 3 or more CSBMs and an increase of at least one CSBM from baseline in the same week.

Outcome measures

Measure	Placebo n=452 Participants Matching placebo tablets QD for 12 weeks Placebo: Matching placebo tablets QD for 12 weeks	Plecanatide 3.0 mg n=453 Participants Plecanatide tablets 3.0 mg QD for 12 weeks Plecanatide: Plecanatide tablets QD for 12 weeks	Plecanatide 6.0 mg n=441 Participants Plecanatide tablets 6.0 mg QD for 12 weeks
Change From Baseline in CSBMs (CSBMS/Week) Over 12-week Treatment Period, Mean Replacement Approach Baseline	0.39 CSBMs per week Standard Deviation 0.570	0.32 CSBMs per week Standard Deviation 0.514	0.32 CSBMs per week Standard Deviation 0.509
Change From Baseline in CSBMs (CSBMS/Week) Over 12-week Treatment Period, Mean Replacement Approach Week 12 change from baseline	1.45 CSBMs per week Standard Deviation 2.310	2.68 CSBMs per week Standard Deviation 3.891	2.39 CSBMs per week Standard Deviation 3.296

SECONDARY outcome

Timeframe: 12-Week Treatment Period

Population: The ITT (Intent-to-treat) population was used for analysis.

The change from baseline in the number of Spontaneous Bowel Movement (SBM) over the 12-week Treatment Period was assessed. 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 in the BM and Symptom Diary.

Outcome measures

Measure	Placebo n=452 Participants Matching placebo tablets QD for 12 weeks Placebo: Matching placebo tablets QD for 12 weeks	Plecanatide 3.0 mg n=453 Participants Plecanatide tablets 3.0 mg QD for 12 weeks Plecanatide: Plecanatide tablets QD for 12 weeks	Plecanatide 6.0 mg n=441 Participants Plecanatide tablets 6.0 mg QD for 12 weeks
Change From Baseline in SBM (SBMs/Week) Over 12-week Treatment Period, Mean Replacement Approach Baseline	2.18 SBMs per week Standard Deviation 2.032	1.97 SBMs per week Standard Deviation 1.772	1.82 SBMs per week Standard Deviation 1.824
Change From Baseline in SBM (SBMs/Week) Over 12-week Treatment Period, Mean Replacement Approach Week 12 change from baseline	1.37 SBMs per week Standard Deviation 2.881	3.30 SBMs per week Standard Deviation 4.628	3.24 SBMs per week Standard Deviation 4.518

SECONDARY outcome

Timeframe: 12-Week Treatment Period

Population: The ITT (Intent-to-treat) population was used for analysis.

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

Measure	Placebo n=452 Participants Matching placebo tablets QD for 12 weeks Placebo: Matching placebo tablets QD for 12 weeks	Plecanatide 3.0 mg n=453 Participants Plecanatide tablets 3.0 mg QD for 12 weeks Plecanatide: Plecanatide tablets QD for 12 weeks	Plecanatide 6.0 mg n=441 Participants Plecanatide tablets 6.0 mg QD for 12 weeks
Change From Baseline in Stool Consistency Score Over the 12-week Treatment Period, Mean Replacement Approach Baseline	2.56 score on a scale Standard Deviation 1.114	2.52 score on a scale Standard Deviation 1.046	2.59 score on a scale Standard Deviation 1.171
Change From Baseline in Stool Consistency Score Over the 12-week Treatment Period, Mean Replacement Approach Week 12 change from baseline	0.83 score on a scale Standard Deviation 1.246	1.56 score on a scale Standard Deviation 1.504	1.47 score on a scale Standard Deviation 1.584

SECONDARY outcome

Timeframe: 12-Week Treatment Period

Population: The ITT (Intent-to-treat) population was used for analysis.

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

Measure	Placebo n=453 Participants Matching placebo tablets QD for 12 weeks Placebo: Matching placebo tablets QD for 12 weeks	Plecanatide 3.0 mg n=452 Participants Plecanatide tablets 3.0 mg QD for 12 weeks Plecanatide: Plecanatide tablets QD for 12 weeks	Plecanatide 6.0 mg n=441 Participants Plecanatide tablets 6.0 mg QD for 12 weeks
Change From Baseline in Straining Score Over 12-Week Treatment Period, Mean Replacement Approach Baseline	2.31 score on a scale Standard Deviation 0.835	2.30 score on a scale Standard Deviation 0.842	2.28 score on a scale Standard Deviation 0.894
Change From Baseline in Straining Score Over 12-Week Treatment Period, Mean Replacement Approach Week 12 change from baseline	-0.70 score on a scale Standard Deviation 0.967	-0.95 score on a scale Standard Deviation 1.027	-1.00 score on a scale Standard Deviation 1.155

Adverse Events

Placebo

Serious events: 4 serious events

Other events: 8 other events

Deaths: 0 deaths

Plecanatide 3.0 mg

Serious events: 6 serious events

Other events: 38 other events

Deaths: 0 deaths

Plecanatide 6.0 mg

Serious events: 5 serious events

Other events: 37 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo n=458 participants at risk Matching placebo tablets QD for 12 weeks	Plecanatide 3.0 mg n=474 participants at risk Plecanatide tablets 3.0 mg QD for 12 weeks	Plecanatide 6.0 mg n=457 participants at risk Plecanatide tablets 3.0 mg QD for 12 weeks
Gastrointestinal disorders Intestinal obstruction	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.21% 1/474 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.22% 1/457 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Hepatobiliary disorders Cholelithiasis	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.21% 1/474 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/457 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Infections and infestations Diverticulitis	0.22% 1/458 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/474 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/457 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Infections and infestations Mastitis	0.22% 1/458 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/474 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/457 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Infections and infestations Pneumonia	0.22% 1/458 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/474 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/457 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Investigations Aspartate aminotransferase increased	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.21% 1/474 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/457 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Nervous system disorders Cerebral infarction	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.21% 1/474 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/457 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Pregnancy, puerperium and perinatal conditions Pregnancy	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.42% 2/474 • Number of events 2 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/457 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Vascular disorders Peripheral arterial occlusive disease	0.22% 1/458 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/474 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/457 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Infections and infestations Gastroenteritis	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/474 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.22% 1/457 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Infections and infestations Staphylococcal infection	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/474 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.22% 1/457 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Injury, poisoning and procedural complications Ankle fracture	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/474 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.22% 1/457 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Nervous system disorders Headache	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/474 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.22% 1/457 • Number of events 1 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.

Other adverse events

Measure	Placebo n=458 participants at risk Matching placebo tablets QD for 12 weeks	Plecanatide 3.0 mg n=474 participants at risk Plecanatide tablets 3.0 mg QD for 12 weeks	Plecanatide 6.0 mg n=457 participants at risk Plecanatide tablets 3.0 mg QD for 12 weeks
Gastrointestinal disorders Diarrhoea	1.3% 6/458 • Number of events 6 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	5.9% 28/474 • Number of events 28 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	5.7% 26/457 • Number of events 28 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Infections and infestations Sinusitis	0.44% 2/458 • Number of events 2 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	2.1% 10/474 • Number of events 11 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/457 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.
Infections and infestations Nasopharyngitis	0.00% 0/458 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	0.00% 0/474 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.	2.4% 11/457 • Number of events 12 The Intent-to-treat Safety (ITT-S) population (1389) was the enrolled population (1394) who received at least one dose of study drug.

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