Hospital Pharmacy - June 2017 - 401

401

Baker
Comments: Treatment of CIC may include fiber supplements, polyethylene glycol, lactulose, sodium picosulfate,
bisacodyl, linaclotide, lubiprostone, and/or biofeedback.
According to the ACG monograph, linaclotide is considered
effective in the treatment of CIC (high-quality evidence,
strong recommendation). Plecanatide is not mentioned in
this monograph.
Guideline: American Society of Colon and Rectal
Surgeons' clinical practice guideline for the evaluation and
management of constipation
Reference: American Society of Colon and Rectal
Surgeons7
Comments: Initial management of symptomatic constipation is dietary modification, which may include fiber and
fluid supplements. Osmotic laxatives are recommended for
the treatment of chorionic constipation. Stimulant laxatives
are recommended for short-term, second-line treatment of
chronic constipation. When dietary modifications as well as
osmotic and stimulant laxative therapy have failed, linaclotide and lubiprostone may be considered. Surgery may be
appropriate in certain refractory cases. Plecanatide is mentioned in this guideline as an investigational agent.
Studies. Drug: Plecanatide versus placebo
Reference: Miner PB, et al, 201317,18
Study Design: Randomized, double-blind, multicenter
study
Study Funding: Synergy Pharmaceuticals
Patients: 951 patients with CIC. Patients had to meet
modified Rome III criteria for CIC diagnosis and have
fewer than 3 complete spontaneous bowel movements
(CSBMs) per week. Exclusion criteria were loose or watery
stool in the absence of laxative use for more than 25% of
bowel movements during 3 months prior to screening or
during the 14-day pretreatment period; Rome III IBS-C
diagnosis; active peptic ulcer disease not adequately
treated; history of cathartic colon, laxative or enema abuse,
or ischemic colitis; fecal impaction within 3 months of
screening; disease or condition associated with constipation; structural abnormality of the GI tract or gastric bypass
surgery; pelvic floor dysfunction; pseudo-obstruction;
active infectious gastritis; diverticulitis; anal fissures or
disease/condition that can affect GI motility or defecation
or that is associated with abdominal pain; unexplained GI
bleeding, iron deficiency anemia, weight loss, or systemic
signs of infection or colitis; and major surgery within 60
days of screening. Of the 951 patients enrolled, 946 received
at least 1 dose of the study medication and had at least 1
postdose efficacy assessment. Plecanatide-treated patients
had a mean age of 47 years, and 86.5% were female; demographics of the placebo group were similar.
Intervention: Patients were randomized to receive placebo or plecanatide 0.3 mg, 1 mg, or 3 mg once daily for 12
treatment weeks.

Results
Primary End Point(s)
** Proportion of weekly responders, defined as those
having at least 3 CSBMs per week and an increase of
at least 1 CSBM per week from baseline, was 11.5%
with placebo (P = NS), 19% with plecanatide 0.3 mg
(P < .05), 17.2% with plecanatide 1 mg (P = NS), and
21.5% with plecanatide 3 mg (P < .01).
** Proportion of durable overall responders, defined as
patients who were weekly responders for at least 9 of
12 treatment weeks, including 3 of the last 4 treatment
weeks, was 10.7% with placebo (P = NS), 18.6% with
plecanatide 0.3 mg (P < .05), 16.8% with plecanatide
1 mg (P = NS), and 19% with plecanatide 3 mg (P <
.01). The number needed to treat (NNT) for durable
overall CSBM response over 12 weeks of therapy was
12.1 with plecanatide 3 mg.

Secondary End Point(s)
** Change in frequency of spontaneous bowel movements
(SBMs) and CSBMs per week from baseline occurred
within the first week and were maintained through week
12 with plecanatide 3 mg. Weekly CSBMs increased by
1 or more from baseline over 12 weeks in 36.8% of
patients with placebo (P = NS), 42.6% with plecanatide
0.3 mg (P = NS), 50% with plecanatide 1 mg (P < .01),
and 52.3% with plecanatide 3 mg (P < .001).
Comments: This phase 2b/3 dose-ranging study was
designed to assess the efficacy and safety of plecanatide in
the treatment of CIC. Electronic diaries were used to track
SBMs, CSBMs, and symptoms; missing diary data were
imputed using mean data as replacement. The study used a
modified intention-to-treat (mITT) population for analysis.
Limitations: Study results are only available as a published abstract.
Reference: Miner PB, et al, 2016 (Study-00)19,20
Study Design: Randomized, double-blind, multicenter
study
Study Funding: Synergy Pharmaceuticals
Patients: 1346 adults with CIC. Patients had to meet modified Rome III criteria for CIC diagnosis and had to have experienced symptoms for at least 3 months, with symptom onset
at least 6 months prior to diagnosis. Exclusion criteria were
loose or watery stool in the absence of laxative use for more
than 25% of bowel movements during 3 months prior to
screening or during the 14-day pretreatment period; active
peptic ulcer disease, diabetes, or hypertension not adequately
treated; history of cathartic colon, laxative or enema abuse, or
ischemic colitis; fecal impaction within 3 months of screening; disease or condition associated with constipation; structural abnormality of the GI tract or gastric bypass surgery;

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