Diverticulitis
Conditions
Brief summary
The purpose of this study is to determine whether Asacol® 2.4 g/day (400 mg Mesalamine) is safe and effective in the treatment of diverticulitis.
Detailed description
This study is designed to evaluate the safety and efficacy of Asacol® 2.4 g/day in generally healthy, adult patients who have had an attack of acute diverticulitis. The study will evaluate the safety and efficacy of a 12 week treatment with Asacol® followed a 9 month non-treatment observation period in approximately 180 patients with acute diverticulitis.
Interventions
DRUGMesalamine
6 - 400 mg tablets once daily
DRUGProbiotic
Once capsule daily Bifidobacterium infantis 35624 added at Visit 2 (Day 10 + 4 days)
DRUGPlacebo
6 placebo tablets for first 10 (+4) days followed by once daily placebo tablets.
OTHERDietary Advice
Dietary advice
DRUGAntibiotic for Diverticulitis
Physician recommended antibiotic for Diverticulitis taken for 10-14 days. Antibiotic not specified for study.
Sponsors
Warner Chilcott
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
35 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* A clinical diagnosis of acute diverticulitis * Female patients must be postmenopausal (at least 1 year without spontaneous menses) or surgically sterile or have a negative urine pregnancy test and practice acceptable contraception (e.g., abstinence; oral, intramuscular, or implanted hormonal contraception \[at least 3 months prior to enrollment\]; 2-barrier methods \[e.g., condom, diaphragm, or spermicide\]; intrauterine device or verbal report of partner with history of non-reversed vasectomy) * Willing and able to participate in the study and provide a signed informed consent
Exclusion criteria
* Presence of diverticular complications (e.g., fistula, abscess, obstruction, stenosis); * Active or recent history (within 6 months) of a peptic ulcer; * Prior history of irritable bowel syndrome (IBS), as determined by the Investigator; * History of major abdominal surgery (as determined by the Investigator); * History of GI surgery within 3 months of diagnosis of acute diverticulitis; * History of immunocompromising disease, human immunodeficiency virus (HIV) infection, or acquired immunodeficiency syndrome (AIDS); * If female patient, active or recent history of endometriosis or dysmenorrhea; * Received a dose of a product that contains, or is metabolized to, mesalamine by any route within 4 weeks before the screening visit;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global Symptom Score (GSS) at Week 12, Primary Efficacy Population | 12 Weeks | GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Responders at Week 52 - ITT Population | 52 Weeks | Responder - patient whose GSS scores for all symptoms were either 0 or 1 GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse). |
| Change in GSS From Baseline to Week 12 - ITT Population | Baseline to Week 12 | GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse). |
| Change in GSS From Baseline to Week 52 - ITT Population | Baseline to Week 52 | GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse). |
| Percentage of Responders at Week 12 - ITT Population | 12 Weeks | Responder - patient whose GSS scores for all symptoms were either 0 or 1 GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse). |
| Recurrent Diverticulitis, Percentage, ITT Population, Week 12 | 12 Weeks | At least one report of recurrent diverticulitis since the last visit (prior to the Week 12 visit). |
| Recurrent Diverticulitis, Percentage, ITT Population, Week 52 | 52 Weeks | At least one report of recurrent diverticulitis since the last visit (prior to the Week 52 visit). |
| Withdrawal Due to Surgery for Diverticulitis, Percentage, ITT Population, Week 12 | 12 Weeks | — |
Countries
United States
Participant flow
Recruitment details
First patient screened 6 Dec 2007
Pre-assignment details
Randomization 1:1:1 ratio with subsequent stratification based on number of prior episodes (1 attack vs. more than 1 attack).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo tablets (matching mesalamine, 6 tablets daily) | 41 |
| Mesalamine 400 mg mesalamine (6 tablets daily) | 40 |
| Mesalamine & Probiotic 400 mg mesalamine (6 tablets daily) plus Align (1 capsule daily) | 36 |
| Total | 117 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Non-Treatment Phase (9 Months) | Lost to Follow-up | 1 | 2 | 0 |
| Non-Treatment Phase (9 Months) | Relapse | 2 | 1 | 1 |
| Non-Treatment Phase (9 Months) | Withdrawal by Subject | 4 | 2 | 2 |
| Treatment Period (12 Weeks) | Adverse Event | 3 | 5 | 1 |
| Treatment Period (12 Weeks) | Lost to Follow-up | 1 | 0 | 2 |
| Treatment Period (12 Weeks) | Physician Decision | 3 | 0 | 0 |
| Treatment Period (12 Weeks) | Protocol Violation | 0 | 0 | 2 |
| Treatment Period (12 Weeks) | Recurrent diverticulitis,surgery require | 1 | 2 | 0 |
| Treatment Period (12 Weeks) | Withdrawal by Subject | 4 | 1 | 4 |
Baseline characteristics
| Characteristic | Placebo | Mesalamine | Mesalamine & Probiotic | Total |
|---|---|---|---|---|
| Age, Customized < 65 years | 31 Participants | 28 Participants | 25 Participants | 84 Participants |
| Age, Customized >= 65 years | 10 Participants | 12 Participants | 11 Participants | 33 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 2 Participants | 4 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants | 38 Participants | 32 Participants | 107 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian (Oriental) | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized Caucasian | 39 Participants | 39 Participants | 33 Participants | 111 Participants |
| Race/Ethnicity, Customized Multi-racial | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment United States | 41 participants | 40 participants | 36 participants | 117 participants |
| Sex: Female, Male Female | 19 Participants | 23 Participants | 19 Participants | 61 Participants |
| Sex: Female, Male Male | 22 Participants | 17 Participants | 17 Participants | 56 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 41 | 37 / 40 | 26 / 36 |
| serious Total, serious adverse events | 6 / 41 | 5 / 40 | 0 / 36 |
Outcome results
Primary
Global Symptom Score (GSS) at Week 12, Primary Efficacy Population
GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse).
Time frame: 12 Weeks
Population: Primary Efficacy Population - Subset of ITT population including only patients with GSS value at Week 12 and baseline GSS of at least 12.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Global Symptom Score (GSS) at Week 12, Primary Efficacy Population | 7.3 Scores on a Scale | Standard Error 1.3 |
| Mesalamine | Global Symptom Score (GSS) at Week 12, Primary Efficacy Population | 4.4 Scores on a Scale | Standard Error 1.07 |
| Mesalamine & Probiotic | Global Symptom Score (GSS) at Week 12, Primary Efficacy Population | 5.9 Scores on a Scale | Standard Error 1.16 |
Comparison: It was assumed that the placebo treatment group and mesalamine treatment group would have an average composite score of 8.4 and 5.88 at Week 12, respectively. The common standard deviation was set to 4.5 based on the 2 standard deviation rule. Based on these assumptions, 60 patients per treatment group required to detect 30% treatment difference at 1-sided, 0.1 level of significance, with 80% power.p-value: 0.3781ANCOVA
Comparison: It was assumed that the placebo treatment group and mesalamine treatment group would have an average composite score of 8.4 and 5.88 at Week 12, respectively. The common standard deviation was set to 4.5 based on the 2 standard deviation rule. Based on these assumptions, 60 patients per treatment group required to detect 30% treatment difference at 1-sided, 0.1 level of significance, with 80% power.p-value: 0.6285ANCOVA
Comparison: It was assumed that the placebo treatment group and mesalamine treatment group would have an average composite score of 8.4 and 5.88 at Week 12, respectively. The common standard deviation was set to 4.5 based on the 2 standard deviation rule. Based on these assumptions, 60 patients per treatment group required to detect 30% treatment difference at 1-sided, 0.1 level of significance, with 80% power.p-value: 0.4365ANCOVA
Secondary
Change in GSS From Baseline to Week 12 - ITT Population
GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse).
Time frame: Baseline to Week 12
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in GSS From Baseline to Week 12 - ITT Population | -16.14 Scores on a Scale | Standard Error 2.082 |
| Mesalamine | Change in GSS From Baseline to Week 12 - ITT Population | -17.63 Scores on a Scale | Standard Error 1.825 |
| Mesalamine & Probiotic | Change in GSS From Baseline to Week 12 - ITT Population | -16.11 Scores on a Scale | Standard Error 2.11 |
p-value: 0.3082ANOVA
p-value: 0.5113ANOVA
p-value: 0.6988ANOVA
Secondary
Change in GSS From Baseline to Week 52 - ITT Population
GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse).
Time frame: Baseline to Week 52
Population: ITT Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in GSS From Baseline to Week 52 - ITT Population | -16.82 Scores on a Scale | Standard Error 2.527 |
| Mesalamine | Change in GSS From Baseline to Week 52 - ITT Population | -17.30 Scores on a Scale | Standard Error 2.04 |
| Mesalamine & Probiotic | Change in GSS From Baseline to Week 52 - ITT Population | -16.00 Scores on a Scale | Standard Error 1.931 |
p-value: 0.4448ANOVA
p-value: 0.6029ANOVA
p-value: 0.6615ANOVA
Secondary
Percentage of Responders at Week 12 - ITT Population
Responder - patient whose GSS scores for all symptoms were either 0 or 1 GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse).
Time frame: 12 Weeks
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Responders at Week 12 - ITT Population | 41.4 Percentage of Participants |
| Mesalamine | Percentage of Responders at Week 12 - ITT Population | 62.5 Percentage of Participants |
| Mesalamine & Probiotic | Percentage of Responders at Week 12 - ITT Population | 48.1 Percentage of Participants |
p-value: 0.0576Cochran-Mantel-Haenszel
p-value: 0.3248Cochran-Mantel-Haenszel
p-value: 0.8596Cochran-Mantel-Haenszel
Secondary
Percentage of Responders at Week 52 - ITT Population
Responder - patient whose GSS scores for all symptoms were either 0 or 1 GSS - Abdominal Pain & Symptom Rating, scale 0-none (better) to 6-severe (worse) for each of the following categories: abdominal pain, abdominal tenderness, nausea/vomiting, bloating, constipation, diarrhea, mucus in stool, feeling urge to evacuate but no bowel movement, painful straining with bowel movement, pain/difficulty urinating. Total minimum score 0 (better), total maximum score 60 (worse).
Time frame: 52 Weeks
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Responders at Week 52 - ITT Population | 50.0 Percentage of Participants |
| Mesalamine | Percentage of Responders at Week 52 - ITT Population | 66.7 Percentage of Participants |
| Mesalamine & Probiotic | Percentage of Responders at Week 52 - ITT Population | 29.2 Percentage of Participants |
p-value: 0.1266Cochran-Mantel-Haenszel
p-value: 0.9288Cochran-Mantel-Haenszel
p-value: 0.9962Cochran-Mantel-Haenszel
Secondary
Recurrent Diverticulitis, Percentage, ITT Population, Week 12
At least one report of recurrent diverticulitis since the last visit (prior to the Week 12 visit).
Time frame: 12 Weeks
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Recurrent Diverticulitis, Percentage, ITT Population, Week 12 | 20.0 Percentage of Participants |
| Mesalamine | Recurrent Diverticulitis, Percentage, ITT Population, Week 12 | 12.5 Percentage of Participants |
| Mesalamine & Probiotic | Recurrent Diverticulitis, Percentage, ITT Population, Week 12 | 11.8 Percentage of Participants |
p-value: 0.1907Cochran-Mantel-Haenszel
p-value: 0.173Cochran-Mantel-Haenszel
p-value: 0.4613Cochran-Mantel-Haenszel
Secondary
Recurrent Diverticulitis, Percentage, ITT Population, Week 52
At least one report of recurrent diverticulitis since the last visit (prior to the Week 52 visit).
Time frame: 52 Weeks
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Recurrent Diverticulitis, Percentage, ITT Population, Week 52 | 31.0 Percentage of Participants |
| Mesalamine | Recurrent Diverticulitis, Percentage, ITT Population, Week 52 | 28.1 Percentage of Participants |
| Mesalamine & Probiotic | Recurrent Diverticulitis, Percentage, ITT Population, Week 52 | 37.0 Percentage of Participants |
p-value: 0.3983Cochran-Mantel-Haenszel
p-value: 0.6721Cochran-Mantel-Haenszel
p-value: 0.7703Cochran-Mantel-Haenszel
Secondary
Withdrawal Due to Surgery for Diverticulitis, Percentage, ITT Population, Week 12
Time frame: 12 Weeks
Population: ITT Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Withdrawal Due to Surgery for Diverticulitis, Percentage, ITT Population, Week 12 | 2.4 Percentage of Participants |
| Mesalamine | Withdrawal Due to Surgery for Diverticulitis, Percentage, ITT Population, Week 12 | 5.0 Percentage of Participants |
| Mesalamine & Probiotic | Withdrawal Due to Surgery for Diverticulitis, Percentage, ITT Population, Week 12 | 0.0 Percentage of Participants |
p-value: 0.7165Cochran-Mantel-Haenszel
p-value: 0.1708Cochran-Mantel-Haenszel
p-value: 0.1039Cochran-Mantel-Haenszel