Synopsis
Name of the sponsor
Takeda Pharmaceutical company Limited
Name of the finished product
Dasen® tablet (10 mg tablet)
Name of active ingredient
Serrapeptase
Title of the study
Serrapeptase (Dasen® tablet) Post-marketing Clinical Study
- Investigation on Chronic Bronchitis -
Study centers:
38 study centers
Related publications
None
Study period
(Date of obtaining first subject’s
informed consent - Date of completing
the study treatment in the last subject)
First subject enrolled: March 2, 2000
Phase of development:
Phase IV
Objective of the study
To investigate the efficacy of serrapeptase (Dasen® tablet) at a daily
Last subject completed: September 12, 2008
dosage of 30 mg by a double-blind, placebo controlled, parallel group,
comparative study using improvement in “difficulty in expectorating”
as the primary endpoint in patients with chronic bronchitis patients.
Method of the study
Multicenter, double-blind, placebo controlled, parallel group,
comparative
Number of subjects
< At planning >
(planned and analyzed)
Number of registered subjects: 150 subjects per group, total of 300
subjects.
Number of subjects evaluable for the primary endpoint: 138 subjects
per group, total of 276 subjects.
< At analysis >
Efficacy analysis subjects: serrapeptase group 148 subjects, Placebo
group 150 subjects.
Safety analysis subjects: serrapeptase group 152 subjects, Placebo
group 151 subjects
Main entrance criteria
<Subjects population>
Chronic bronchitis (including bronchitis complicated with
bronchiectasis, pulmonary emphysema, or old pulmonary tuberculosis)
patients
<Inclusion criteria>
1) Patients whose severity of “difficulty in expectorating” is 2 (slightly
difficult to expectorate) or severer for no less than 2 weeks before the
1
initiation of the observation period
2) Patients who exhibit no changes in severity of “difficulty in
expectorating” during the observation period (1 week)
3) Sex and outpatient/inpatient status are unquestioned
4) Patients aged 20 years or older
5) Patients with the ability to agree to participate in this study who are
able to read and understand the informed consent
<Exclusion criteria>
1) Patients who use anti-inflammatory enzyme preparations or
expectorants
2) Patients who use steroids
3) Patients with a history of hypersensitivity against serrapeptase
4) Patients with abnormality in blood coagulation system
5) Patients with severe hepatic dysfunction or renal impairment
6) Patients with a history of drug hypersensitivity
7) Patients who are under treatment for malignant tumor
8) Other patients who are judged inadequate as subject by the
post-marketing study investigator or sub-investigator for the conduct
of this study
Test product, dose and mode of
<Test product>
administration, and batch number
Serrapeptase (Dasen® tablet) 10 mg tablet
<Dose and mode of administration>
3 times daily orally after meals
<Batch number>
Z9162021, Z9162031, Z9162041, Z9162053
Comparator Product, dose and mode
<Comparator product>
of administration, and batch number
Placebo tablet (containing no active ingredient)
<Dose and mode of administration>
3 times daily orally after meals
<Batch number>
Z9161021, Z9161031, Z9161041, Z9161061
Duration of Treatment
2 weeks
Endpoint
<Primary endpoint>
“difficulty in expectorating”
<Secondary endpoint>
“frequency of sputum” and “frequency of coughing” and “global
improvement”
2
<Safety endpoints>
Adverse events (subjective and objective symptoms) and clinical
laboratory test results
Statistical Methods
<Efficacy analysis>
(1) Analysis method of primary endpoint
1) Primary analysis
For the ordinal evaluation scale based on drop in severity from the time
of the start of treatment with the study drug at the final treatment of the
FAS, 2-sample Wilcoxon test was applied (level of significance:
both sides 5%)
(2) Analysis method of secondary endpoints
1) With regard to the improvement of the rate for drop in severity in
“frequency of sputum” and “frequency of coughing” after 1 week, 2
weeks and at the end of treatment with the study drug compared to the
start of treatment with the study drug, primary analysis for the primary
endpoints were performed.
2) The same analysis was performed for “global improvement” that
included the change in severity of “viscosity of sputum”, “rale
(auscultation)” in addition to “difficulty in expectorating”, “frequency
of sputum” and “frequency of coughing”.
<Safety analysis>
The following analyses were performed on adverse events and
laboratory tests of the “safety analysis set”.
(1) Adverse Events (TEAE: Treatment emergent Adverse Events)
For any new onset or worsening of subjective and objective symptoms
that occurred during treatment with the study drug, a summary Table
was generated by system organ class (SOC) and preferred term (PT)
for each treatment group.
(2) Clinical laboratory tests results
In the event that the general hematology tests and blood biochemistry
tests were performed before and after treatment with the study drug,
the summary statistics were calculated by treatment group for changes
in values compared to the ones before treatment.
Summary of Results
A total of 311 subjects (serrapeptase group, 156 subjects; placebo
group, 155 subjects) administered the study drugs under randomized
double-blinded condition. Of these subjects, 4 each in both groups
violated GCP significantly. With the exclusion of these subjects, a sum
3
analysis was performed for 152 in the serrapeptase group and 151 in
the placebo group.
For efficacy, the drop in grade of severity from the start of treatment
with the study drug in the primary endpoint “difficulty in
expectorating” at the end of treatment with the study drug and the rate
of improvement (no less than 60% in both the serrapeptase group and
placebo group) at the end of treatment showed no significant difference
between the two groups.
For the secondary endpoints “frequency of sputum” and “frequency of
coughing” as well as the “global improvement”, no significant
difference was found between both groups, the same as the results in
the primary endpoint.
For safety, there was no clinically significant concern.
Date of Report
January 5, 2011
4