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

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)

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.

Study Overview

• Status: Completed
• Conditions: Chronic Constipation
• Intervention / Treatment: Drug: Placebo; Drug: ASP0456

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 383
• Phase: Phase 2

Contacts and Locations

Study Locations

• Japan
  • Aichi, Japan
    • Site: 35
  • Aichi, Japan
    • Site: 36
  • Chiba, Japan
    • Site: 27
  • Chiba, Japan
    • Site: 28
  • Chiba, Japan
    • Site: 29
  • Chiba, Japan
    • Site: 30
  • Fukuoka, Japan
    • Site: 48
  • Fukuoka, Japan
    • Site: 49
  • Fukuoka, Japan
    • Site: 50
  • Hokkaido, Japan
    • Site: 1
  • Hokkaido, Japan
    • Site: 2
  • Hyogo, Japan
    • Site: 45
  • Hyogo, Japan
    • Site: 46
  • Hyogo, Japan
    • Site: 47
  • Kanagawa, Japan
    • Site: 22
  • Kanagawa, Japan
    • Site: 23
  • Kanagawa, Japan
    • Site: 24
  • Kanagawa, Japan
    • Site: 25
  • Kanagawa, Japan
    • Site: 26
  • Kyoto, Japan
    • Site: 44
  • Osaka, Japan
    • Site: 37
  • Osaka, Japan
    • Site: 38
  • Osaka, Japan
    • Site: 39
  • Osaka, Japan
    • Site: 40
  • Osaka, Japan
    • Site: 41
  • Osaka, Japan
    • Site: 42
  • Osaka, Japan
    • Site: 43
  • Saitama, Japan
    • Site: 31
  • Saitama, Japan
    • Site: 32
  • Saitama, Japan
    • Site: 33
  • Saitama, Japan
    • Site: 34
  • Tokyo, Japan
    • Site: 5
  • Tokyo, Japan
    • Site: 10
  • Tokyo, Japan
    • Site: 11
  • Tokyo, Japan
    • Site: 12
  • Tokyo, Japan
    • Site: 13
  • Tokyo, Japan
    • Site: 14
  • Tokyo, Japan
    • Site: 15
  • Tokyo, Japan
    • Site: 16
  • Tokyo, Japan
    • Site: 17
  • Tokyo, Japan
    • Site: 18
  • Tokyo, Japan
    • Site: 19
  • Tokyo, Japan
    • Site: 20
  • Tokyo, Japan
    • Site: 21
  • Tokyo, Japan
    • Site: 3
  • Tokyo, Japan
    • Site: 4
  • Tokyo, Japan
    • Site: 6
  • Tokyo, Japan
    • Site: 7
  • Tokyo, Japan
    • Site: 8
  • Tokyo, Japan
    • Site: 9

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 79 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group; oral	Drug: Placebo; oral
Experimental: ASP0456 0.0625mg; oral	Drug: ASP0456; oral; Other Names: Linaclotide
Experimental: ASP0456 0.125mg; oral	Drug: ASP0456; oral; Other Names: Linaclotide
Experimental: ASP0456 0.25mg; oral	Drug: ASP0456; oral; Other Names: Linaclotide
Experimental: ASP0456 0.5mg; oral	Drug: ASP0456; oral; Other Names: Linaclotide

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc

Publications and helpful links

General Publications

• Fukudo S, Miwa H, Nakajima A, Kinoshita Y, Kosako M, Nakagawa A, Akiho H, Kuroishi K, Johnston JM, Currie M, Ohkusa T. Dose-finding study of linaclotide in Japanese patients with chronic constipation: A phase II randomized, double-blind, and placebo-controlled study. Neurogastroenterol Motil. 2018 Dec;30(12):e13442. doi: 10.1111/nmo.13442. Epub 2018 Aug 7.

Helpful Links

• Link to results on the Astellas Clinical Study Results website

Study record dates

Study Major Dates

• Study Start (Actual): April 13, 2015
• Primary Completion (Actual): October 31, 2015
• Study Completion (Actual): October 31, 2015

Study Registration Dates

• First Submitted: April 7, 2015
• First Submitted That Met QC Criteria: April 21, 2015
• First Posted (Estimate): April 24, 2015

Study Record Updates

• Last Update Posted (Actual): December 12, 2018
• Last Update Submitted That Met QC Criteria: December 10, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: linaclotide; ASP0456; chronic constipation
• Additional Relevant MeSH Terms: Signs and Symptoms, Digestive; Constipation; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Enzyme Activators; Linaclotide
• Other Study ID Numbers: 0456-CL-1021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to anonymized individual participant level data collected during the trial, in addition to study-related supporting documentation, is planned for trials conducted with approved product indications and formulations, as well as compounds terminated during development. Conditions and exceptions are described under the Sponsor Specific Details for Astellas on www.clinicalstudydatarequest.com.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR