A Study to Evaluate Dose Responses of Efficacy and Safety of ASP0456 in Patient With Chronic Constipation

Study Overview
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Brief Summary
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The objective of this study is to investigate dose-responses of efficacy and safety of ASP0456 in patients with chronic constipation (diagnosed by Rome III criteria of functional constipation (FC), not including constipation due to organic diseases) compared to placebo and to find the appropriate dose for P3 study.

Detailed Description
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To determine optimum dose of ASP0456 for the patients with chronic constipation (not including constipation due to organic diseases) in Japan based on its efficacy and safety, multicentered, placebo-controlled, double-blind, parallel group comparative study will be conducted. After two-week observation period, the patient who meets the primary registration criteria will be randomized to the one from five groups and will start treatment period. The patients will take once daily orally before the breakfast for two weeks.

Official Title
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Phase II Study of ASP0456 - A Double-blind, Placebo-controlled, Parallel-group, Comparative Study in Patients With Chronic Constipation (Not Including Constipation Due to Organic Diseases)

Conditions
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Chronic Constipation

Intervention / Treatment
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* Drug: ASP0456
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient who had SBM* (Spontaneous bowel movement) less than 3 times per week, more than six months prior to the provisional registration *Defecation without procedure of laxative, suppository, enema, or stool extraction on the day or preceding day of the defecation Patient who was affected with one or more following symptoms before more than six months of provisional registration: Straining during at least 25% of defecations Lumpy or hard stools in at least 25% of defecations Sensation of incomplete evacuation for at least 25% of defecations Loose stools are rarely present without the use of laxatives more than six months prior to the provisional registration. Patients who had pancolonoscopy or contrast enema (or sigmoidoscopy) after the onset of chronic constipation symptom and had no organic changes Exclusion Criteria: Patient who has met IBS-C diagnostic criteria from Rome III more than six months prior to provisional registration. Meaning that patient who had recurrent abdominal pain or discomfort at least 3 days/month in last 3 months associated with two or more of the following, and patient who was affected with following IBS symptoms more than six months prior to the provisional registration: Improvement with defecation Onset associated with a change in frequency of stool Onset associated with a change in form (appearance) of stool Patient with history of surgical resection of stomach, gallbladder, small intestine, or large intestine (excluding resection of appendicitis and benign polyp) Patient with history or current evidence of inflammatory bowel disease (Crohn's disease or ulcerative colitis) Patient with history or current evidence of ischemic colitis Patient currently affected by infectious enteritis Patient currently affected by hyperthyroidism or hypothyroidism Patient with apparent mechanical obstruction (i.e. patient with ileus caused by hernia) Patient with mega colon or mega rectum Patient currently affected by constipation due to anorectal dysfunction Patient currently affected by drug induced constipation. Patient with constipation due to other organic disease Patient currently affected by active peptic ulcer In the case of a female, the one currently affected by endometriosis or uterine adenomyosis Patient with high depression or anxiety considered to influence drug evaluation Patient with history of abuse of drug or alcohol within a year before consent acquisition, or with current abuse Patient who used or underwent or will use or undergo drug/therapy/test prohibited to combine 3 days before the start of bowel habit observation period (Day -17) or thereafter (however, patient who used or underwent restricted drug/therapy according to Protocol may be enrolled provisionally) Patient with history or current evidence of malignant tumor Patient currently affected by serious cardiovascular disease, respiratory disease, kidney disease, hepatic disease, gastrointestinal disease (excluding CC), hemorrhagic disease, or neural/mental disease Patient with history of drug allergy

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 79 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP0456 0.0625mg<br>oral | Drug: ASP0456<br>* oral<br>* Other names: Linaclotide;|
| Experimental: ASP0456 0.125mg<br>oral | Drug: ASP0456<br>* oral<br>* Other names: Linaclotide;|
| Experimental: ASP0456 0.25mg<br>oral | Drug: ASP0456<br>* oral<br>* Other names: Linaclotide;|
| Experimental: ASP0456 0.5mg<br>oral | Drug: ASP0456<br>* oral<br>* Other names: Linaclotide;|
| Placebo Comparator: Placebo group<br>oral | Drug: Placebo<br>* oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in weekly average of SBM frequency | SBM: Spontaneous Bowel Movement. SBM means the defecation without procedure of laxative, suppository, enema, or stool extraction on the day or preceding day of the defecation. SBM frequency is calculated as follows: (the week total number of SBM )/ (the total number of days on which the frequency of SBM is evaluable) x7 | From baseline to week 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weekly responder rate for SBM | The weekly average value of SBM frequency is more than 3 and over 1 more than the weekly mean value of SBM frequency in the bowel habit observation period | up to 2 weeks | 
| Weekly responder rate for CSBM | The weekly average value of CSBM frequency is more than 3 and over 1 more than the weekly mean value of CSBM frequency in the bowel habit observation period | up to 2 weeks | 
| Percentage of subjects with SBM within 24 hours after the start of initial treatment |  | up to 24 hours | 
| Change in weekly average of CSBM frequency |  | From baseline to week 1 | 
| Proportion of subjects with CSBM within 24 hours after the start of initial treatment |  | up to 24 hours | 
| Weekly responder rate of the global assessment of relief of chronic constipation. | The weekly responder of the evaluation items shall be the subject satisfying the following at the time of evaluation in each week: Score of Global assessment of relief of chronic constipation symptoms (7 scores: 1-7) is 1 or 2 | up to 2 weeks | 
| Weekly responder rate of the abdominal bowel habits improvement in chronic constipation. | Score of abdominal bowel habits improvement effect (7 scores: 1-7) is 1 or 2 | up to 2 weeks | 
| Weekly responder rate of abdominal symptom relief of chronic constipation. | Score of abdominal symptom improvement effect (7 scores: 1-7) is 1 or 2 | up to 2 weeks | 
| Score of the global assessment of relief of chronic constipation | Scores will be measured using a seven-point ordinal score | up to 2 weeks | 
| Changes in IBS-QOL-J scores (entire scores or scores on the sub-scales) | IBS-QOL-J: Irritable bowel syndrome quality of life Japanese version | Week 0, and 2 | 
| Changes in weekly average of SBM frequency | SBM: Spontaneous Bowel Movement | From baseline to every week until 2 weeks | 
| Changes in weekly average of CSBM frequency | CSBM: Complete Spontaneous Bowel Movement | From baseline to every week until 2 weeks | 
| Changes in weekly average of stool form | Stool form will be measured using seven-point Bristol Stool Form Scale | From baseline to every week until 2 weeks | 
| Changes in weekly average of abdominal bloating severity scores | Abdominal bloating severity will be measured using a five-point ordinal score | From baseline to every week until 2 weeks | 
| Changes in weekly average of abdominal pain/discomfort severity scores | Abdominal pain/discomfort severity will be measured using a five-point ordinal score | From baseline to every week until 2 weeks | 
| Changes in weekly average of straining severity scores | Straining severity will be measured using a five-point ordinal score | From baseline to every week until 2 weeks | 
| Score of the abdominal bowel habits improvement in chronic constipation | Scores will be measured using a seven-point ordinal score | up to 2 weeks | 
| Score of the abdominal symptom relief of chronic constipation | Scores will be measured using a seven-point ordinal score | up to 2 weeks | 
| Safety assessed by development of incidence of adverse events, vital signs, clinical laboratory tests and body weight |  | up to 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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linaclotide, ASP0456, chronic constipation