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Study design:
Placebo-controlled, randomized, double-blind, multicenter, parallel-group study

Objectives:
The objectives of this double-blind comparative study were to verify the superiority of GOOFICE^® to placebo and examine the safety in patients with chronic constipation by administering GOOFICE^® 10 mg or placebo once daily for 14 days and defining the primary endpoint as the change in spontaneous bowel movement frequency from Week 2 of the observation period to Week 1 of the treatment period.

Subjects:
A total of 133 patients with chronic constipation (efficacy analysis set [FAS¹], 132 patients; safety analysis set, 132 patients).
With reference to the Rome III diagnostic criteria for functional constipation, the patients with chronic constipation as follows were included: Those who have had a mean spontaneous bowel movement frequency of less than 3 times/week for at least 6 months before informed consent, and who had at least one of the following three symptoms related to spontaneous bowel movement: [1] Straining in 25% or more of bowel movements, [2] lumpy or hard stools in 25% or more of bowel movements, and [3] sensation of incomplete evacuation in 25% or more of bowel movements.
Placebo group, 63 patients; and GOOFICE^® 10 mg group, 69 patients.

Method of administration:
After the 2-week observation period was set as the period of investigation of the bowel movement frequency before the start of administration of the investigational product, GOOFICE^® 10 mg or placebo was orally administered once daily before breakfast for 14 days. Subjects visited the study site at the specified time points and underwent observations, tests, etc. on an outpatient basis.

Endpoints:
<Efficacy endpoint>

1. Primary endpoint (confirmatory analysis item)
   Changes in spontaneous bowel movement frequency from Week 2 of the observation period to Week 1 of the treatment period
2. Secondary endpoints
   • Changes in spontaneous bowel movement frequency from Week 2 of the observation period to Week 2 of the treatment period
   • Changes in spontaneous bowel movement frequency from the observation period to the treatment period with the investigational product
   • Changes in complete spontaneous bowel movement frequency from Week 2 of the observation period to Weeks 1 and 2 of the treatment period
   • Changes in complete spontaneous bowel movement frequency from the observation period to the treatment period with the investigational product
   • Percentage of patients with the occurrence of spontaneous bowel movement within 24 and 48 hours from the start of administration of the investigational product
   • Percentages of responders in spontaneous bowel movement frequency and complete spontaneous bowel movement frequency at Weeks 1 and 2 of the treatment period
   • Time to occurrence of the first spontaneous bowel movement
   • Stool hardness based on Bristol Stool Form Scale
   • Weekly evaluation of severity of constipation at Weeks 1 and 2 of the treatment period
   • Status of use of rescue medication
   <Safety endpoints>
   • Adverse events
   • Laboratory test values
   • Vital signs

Analysis plan:
Changes in spontaneous bowel movement frequency from Week 2 of the observation period to Week 1 of the treatment period as the primary endpoint² were analyzed in the FAS, and the analysis of covariance (ANCOVA) was applied using the spontaneous bowel movement frequency at Week 2 of the observation period as a covariate.
Summary statistics were calculated for spontaneous bowel movement frequency and complete spontaneous bowel movement frequency.

P-values obtained from statistical methods not adjusted for multiplicity were considered nominal p-values.

[The data include the results of a part of the studies that are not approved, but they are presented here because they are the data for evaluation at the time of approval of long-term administration.]

Study design:
Open-label, multicenter study

Objectives:
The objective of this study was to evaluate the safety and efficacy of long-term (52 weeks) treatment with GOOFICE^® in patients with chronic constipation.

Subjects:
A total of 341 patients with chronic constipation (FAS, 340 patients and safety analysis set, 340 patients). With reference to the Rome III diagnostic criteria for functional constipation, the patients with chronic constipation as follows were included: Those who have had the mean spontaneous bowel movement frequency of less than 3 times/week for at least 6 months before informed consent, and who had at least one of the following three symptoms related to spontaneous bowel movement: [1] Straining in 25% or more of bowel movements, [2] lumpy or hard stools in 25% or more of bowel movements, and [3] sensation of incomplete evacuation in 25% or more of bowel movements.

Method of administration:
After the 2-week observation period was set as the period of investigation of the bowel movement frequency before the start of administration of the investigational product, GOOFICE^® was orally administered once daily before breakfast for 52 weeks. The initial dose was 10 mg once daily for 7 days. The dose was then adjusted to 5, 10, or 15 mg once daily according to symptoms. Subjects visited the study site at the specified time points and underwent observations, tests, etc. on an outpatient basis.

Endpoints:
<Efficacy endpoint>

• Changes in spontaneous bowel movement frequency from Week 2 of the observation period to each week of the treatment period
  
• Percentage of responders in spontaneous bowel movement frequency at each week of the treatment period
  
• Time to occurrence of the first spontaneous bowel movement
• Changes in complete spontaneous bowel movement frequency from Week 2 of the observation period to each week of the treatment period
• Percentage of responders in complete spontaneous bowel movement frequency at each week of the treatment period
• Time to occurrence of the first complete spontaneous bowel movement
• Changes in total bowel movement frequency² from Week 2 of the observation period to each week of the treatment period
• Stool hardness based on Bristol Stool Form Scale at each week of the treatment period
• Satisfaction with bowel movement
• Status of use of rescue medication
• QOL evaluation by JPAC-QOL

• Adverse events
• Laboratory test values
• Vital signs
  

Analysis plan:
The FAS was used as the analysis set, and summary statistics were calculated for spontaneous bowel movement frequency and complete spontaneous bowel movement frequency at each week of the treatment period.
Summary statistics were calculated for the changes from Week 2 of the observation period, and one-sample t-test was conducted at Weeks 4, 12, 24, 36, and 52 of the treatment period.

P-values obtained from statistical methods not adjusted for multiplicity were considered nominal p-values.

Spontaneous bowel movement
Bowel movements that occur without laxative/enema or manual disimpaction

Complete spontaneous bowel movement
Bowel movements that occur without laxative/enema or manual disimpaction without leaving the sensation of inadequate bowel movements

Responders
In the Japanese phase 2 study, Japanese phase 3 study, and Japanese long-term administration study, which are evaluation data for the approval of GOOFICE^®, the subjects whose spontaneous bowel movement or complete spontaneous bowel movement frequency per week improved by ≥1 from Week 2 of the observation period and was ≥3 times were defined as responders.

Bristol Stool Form Scale⁸
Bristol Stool Form Scale is a global standard for evaluating stool form. Types 1 and 2 on this scale are hard feces, and types 6 and 7 are soft feces. Subjects scored each bowel movement on the following 7-point scale.

Severity of constipation
Severity of constipation was recorded based on retrospective evaluation of the symptoms of constipation during the past one week. The symptoms of constipation were scored on the following 5-point scale.

0：Absent (no symptoms of constipation at all)
1：Mild (slight symptoms of constipation)
2：Moderate (constipation is present, but not severe)
3：Severe (severe constipation with difficulty in evacuation or slight feeling of evacuation in the toilet)
4：Very severe (persistent constipation, almost no bowel movement, or almost no feeling of evacuation in the toilet)

JPAC-QOL⁹
JPAC-QOL is the Japanese version of the Patient Assessment of Constipation Quality of Life (PAC-QOL). PAC-QOL is widely used as a disease-specific QOL evaluation scale for chronic constipation and translated into various languages. It is a questionnaire consisting of a total of 28 items including 4 domains related to constipation (physical discomfort score, psychosocial discomfort score, worries/concerns score, and satisfaction score) and their subscales, and it is used to evaluate symptoms during the past 2 weeks by the 5-point scale of "0: Not at all" to "4: Extremely." Lower scores indicate better QOL (Items 18 and 25 to 28 are reversed and tabulated in the analysis because lower scores indicate lower QOL).

Rome Diagnostic Criteria^10,11
The International Congress of Gastroenterology held in Rome in 1988 triggered a trend to unify the diagnostic criteria for irritable bowel syndrome (IBS), which had not been unified up to that time, and the Rome I Diagnostic Criteria were released in 1992. The Rome II Diagnostic Criteria were revised in 1999 to internationally unify the diagnostic criteria for IBS. Furthermore, in 2006, the Rome III Diagnostic Criteria, which were systematized for functional gastrointestinal disorders (FGIDs) including not only IBS but also functional constipation, were published. The diagnostic criteria for functional constipation based on the Rome III Diagnostic Criteria used as reference for patient enrollment in various clinical studies as evaluation data for GOOFICE^® at the time of approval are as follows:

<Rome III Diagnostic Criteria for functional constipation>
The patient has been aware of subjective symptoms for more than 6 months and has met the following criteria for the last 3 months.

1. Having 2 or more of the following symptoms.
   • Straining in 25% of bowel movements.
   • Sensation of anorectal obstruction/blockage in 25% of bowel movements.
   • Lumpy or hard stools in 25% of bowel movements.
   • Manual maneuvers to facilitate bowel movements are used for 25% of bowel movements (e.g., manual disimpaction, pelvic floor support).
   • Sensation of inadequate defecation in 25% of bowel movements.
   • Bowel movement frequency of less than 3 times per week.
2. Loose stool rarely occurs when laxatives are not used.
3. Not meeting the criteria for irritable bowel syndrome (IBS).
   

The Rome III Diagnostic Criteria were revised in 2016 to establish the Rome IV Diagnostic Criteria, but there was almost no change in the diagnostic criteria for functional constipation.