Conditions: Bacterial Enteritis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 43
Healthy volunteers: no

Brief summary:
To assess safety, efficacy and pharmacokinetics of multiple dosesin patients with Bacterial Enteritis caused by Clostridium difficile infection(CDI) or Enteric infection.

Detailed description:

Arms:
arm 1: OPS-2071 50 mg/day：25 mg tablet administered orally twice daily arm 2: OPS-2071 100 mg/day：50 mg tablet administered orally twice daily arm 3: OPS-2071 200 mg/day：100 mg tablet administered orally twice daily arm 4: OPS-2071 400 mg/day：100 mg two tablets administered orally twice daily

Interventions: intervention 1: OPS-2071 tablet
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
An Open-label, Multicenter Clinical Trial to Assess the Safety and 
Efficacy of Three Different Doses of OPS-2071 
in Patients With Bacterial Enteritis 
(Phase 2a Trial) 
 
 
 
 
NCT Number: NCT02473393 
PRT NO.: 341-13-002 
Version Date: 15 July 2016 (Version 3.0) 


Protocol No. 341-13-002 
Confidential - Otsuka Proprietary Information 
 
Version 3.0, 15 Jul 2016 
 
 
 
An Open-label, Multicenter Clinical Trial to Assess the Safety and 
Efficacy of Three Different Doses of OPS-2071  
in Patients With Bacterial Enteritis 
(Phase 2a Trial) 
 
 
Clinical Protocol 
Protocol No.:  341-13-002 
 
 
Confidential 
 
 
 
 
 
 
 
Otsuka Pharmaceutical Co., Ltd. 
2-9 Kanda-Tsukasamachi, Chiyoda-ku, Tokyo 101-8535, Japan 
 
Version 3.0: 15 Jul 2016 
 
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Statement of Confidentiality 
The trial protocol is to be treated as confidential information and is to be made available 
only to persons involved in the trial.  The content of the protocol is not to be disclosed to 
any third party without the prior written consent of Otsuka Pharmaceutical Co., Ltd., 
except in the case of its being explained to a candidate trial subject.  Disclosure of the 
results of the trial to academic societies or journals, etc, in part or in whole, will require 
the prior written approval of Otsuka Pharmaceutical Co., Ltd. 
 
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Trial Protocol Synopsis 
Name of Test Product 
OPS-2071 
Trial Title 
An open-label, multicenter clinical trial to assess the safety 
and efficacy of three different doses of OPS-2071 in patients 
with bacterial enteritis 
Trial Objectives 
Primary objectives: 
• To assess the safety and efficacy of oral multiple doses 
of OPS-2071 in patients with bacterial enteritis 
associated with Clostridium difficile infection (CDI) or 
enteric infection (caused by Salmonella, Campylobacter, 
or pathogenic Escherichia coli [E. coli]) 
• To assess the pharmacokinetics of multiple doses of 
OPS-2071 in patients with bacterial enteritis associated 
with CDI or enteric infection 
Secondary objectives: 
• To assess the recurrence rate of CDI in patients with 
bacterial enteritis associated with CDI after multiple 
doses of OPS-2071 
• To assess the time to resolution of diarrhea in patients 
with bacterial enteritis associated with CDI or enteric 
infection after multiple doses of OPS-2071 
• To assess the improvement of clinical symptoms in 
patients with bacterial enteritis associated with CDI or 
enteric infection after multiple doses of OPS-2071 
• To assess the sensitivity to OPS-2071 of the causative 
pathogen strain isolated from patients with bacterial 
enteritis associated with CDI or enteric infection 
Phase of Development 
Phase:  2a 
Type of trial:  Dose-ranging trial 
Trial Design 
Multi-center, randomized, open-label trial 
Target Disease 
Bacterial enteritis 
Target Number of Patients A total of 60 patients with 20 patients (10 patients each in 
CDI and enteric infection groups) in each dosing group.  
Enroll 10 patients in each dosing group of the CDI group to 
assess microbiological outcome.  For the enteric infection 
group, enroll at least five patients in each dosing group to 
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assess microbiological outcome with the sum of Salmonella, 
Campylobacter, and pathogenic E. coli.  If a sufficient 
number of patients are not available for microbiological 
assessment after enrollment of 10 patients in each group, 
enroll more patients. 
Inclusion Criteria 
Patients who meet all of the following criteria will be 
selected. 
1. The patient is an Asian male or female of minimum legal 
age to provide consent (ie, 21 years for Singapore, 19 
years for Korea, and 20 years for Japan at time of 
informed consent). 
2. The patient provides written, informed consent before the 
clinical trial is initiated. 
3. The patient has distinctive symptoms and findings of 
bacterial enteritis (regardless of inpatient or outpatient.) 
4. The patient has bacterial enteritis with one or more of the 
following causative pathogens either proven or 
presumed: 
Clostridium difficile (C. difficile), Salmonella, 
Campylobacter, pathogenic E. coli, and other bacteria 
estimated to cause bacterial enteritis (except for typhoid 
bacillus, Salmonella paratyphi A, enterohemorrhagic E. 
coli, Shigella, and Vibrio cholerae [V. cholerae]) 
5. The patient and his/her partner are willing to take 
contraceptive measures from initiation of investigational 
medicinal products (IMPs) to 4 weeks after 
administration of IMPs. 
CDI group: 
6. The patient satisfies both the following: 
 Liquid or unformed stools ≥ 3 times/day within 24 
hours before the start of IMP administration 
 A positive clinical laboratory result in one of the 
following methods to confirm CDI within 48 hours 
before the start of IMP administration: 
• Toxin A/B assay (positive for either or both 
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toxins A and B) 
• Polymerase chain reaction (PCR) (detection of 
toxin genes) 
• Colonoscopy (findings of pseudomembranous 
colitis) 
Enteric infection group: 
7. The patient satisfies all the following: 
 Liquid or unformed stools ≥ 3 times/day within 24 
hours before the start of IMP administration 
 Any of the following clinical findings of enteric 
infection within 24 hours before the start of IMP 
administration 
• Either symptom of abdominal pain, nausea, or 
vomiting 
 Negative toxin A/B assay or PCR within 48 hours 
before the start of IMP administration 
Exclusion Criteria 
Patients who fall under any of the following exclusion 
criteria will be excluded from participation in the trial. 
1. Intractable vomiting, inability to take oral medication, 
patients with feeding tubes 
2. The patient has severe or progressive underlying disease 
or complication, making it difficult to ensure safety in 
the study or proper efficacy assessment. 
3. Complication of chronic bowel diseases such as Crohn’s 
disease, ulcerative colitis, irritable bowel syndrome, or 
colorectal cancer 
4. History of stem cell transplantation, organ 
transplantation, or bone marrow transplantation (within 6 
months before the screening examination) 
5. History of total colectomy 
6. Suspected viral enteritis 
7. History of allergic conditions caused by quinolone 
antibacterials 
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8. The patient has a current diagnosis or history of 
convulsive disorders, such as convulsion and epilepsy. 
9. The patient has a severe hepatic dysfunction (eg, AST 
[GOT] or ALT [GPT] ≥ 3 times of the upper limit of 
normal at the study center, etc) 
10. The patient has a severe cardiac dysfunction (eg, cardiac 
arrest, ischemic disease) 
11. The patient has cardiac arrhythmia or congenital or 
sporadic long QTc syndrome.  Or the patient is treated 
with a drug reported to prolong QTc interval (eg, 
amiodarone, sotalol, disopyramide, quinidine, 
procainamide, terfenadine, astemizole, cisapride, 
pimozide) 
12. The patient has a moderate or severe renal dysfunction 
(eg, serum creatinine level ≥ 2 mg/dL or necessity of 
renal dialysis, etc) 
13. The patient was treated with UDP-
glucuronosyltransferase 1A1 (UGT1A1) inhibitors 
(atazanavir) within 2 days before the start of IMP 
administration. 
14. Women with confirmed or suspected pregnancy or 
breast-feeding women 
15. The patient was treated with another IMPs within 3 
months before the screening examination 
16. Patients judged to be ineligible by the investigator for 
any other reasons 
CDI group: 
17. The patient was treated with drugs and therapies to treat 
CDI within 24 hours before the start of IMP 
administration. 
18. The patient with severe and complex CDI who has any of 
the following at the screening examination. 
• Complicated disease:  ileus, mental status changes, 
organ dysfunction (kidney and respiratory organs), 
septic shock, peritonitis, toxic megacolon, marked 
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dehydration 
• Admission to intensive care unit due to CDI 
Enteric infection group: 
19. The patient was treated with other antibacterial agent by 
oral administration or injection within 7 days before the 
start of IMP administration. 
20. Typhoid bacillus, Salmonella paratyphi A, 
enterohemorrhagic E. coli, Shigella, or V. cholerae was 
isolated/identified. 
21. The patient has marked dehydration at the screening 
examination. 
Discontinuation Criteria 
1. If the patient wishes to withdraw 
2. If it is found after the start of the trial that the patient did 
not meet all the inclusion criteria or fell under any of the 
exclusion criteria 
3. If a drug or therapy from either item 1 or item 7 in the 
list of prohibited concomitant drugs and therapies is used 
or judged to be required 
4. If an AE making continuation of trial participation 
difficult occurs 
5. If the female patient is found to be pregnant 
6. If symptoms of the primary disease exacerbate, and the 
investigator or subinvestigator judges that it is not 
appropriate to continue the trial participation 
7. If it becomes impossible to comply with the protocol for 
any another reason or if the investigator or 
subinvestigator judges that it is necessary to discontinue 
the trial participation for any another reason 
Investigational Medicinal 
Products, Dose and 
Regimen, and Treatment 
Period 
Investigational medicinal products: 
OPS-2071 25 mg tablets, 50 mg tablets, 100 mg tablets 
Dose and regimen: 
Any of the daily three dosages of 50, 100, 200, or 400 mg of 
OPS-2071 is administered twice a day in the morning and 
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evening to the CDI group for 10 days and to the enteric 
infection group for 7 days.  Take IMP after meal where 
possible with at least 10 hours of interval between dosings.  
Ensure to have evening meal before dosing on the previous 
day of blood collection for PK and to have breakfast before 
dosing on the day to perform blood collection for PK.  
Whether or not the symptoms improve during the treatment 
period, use all IMPs prescribed for the predetermined period. 
 
Follow the algorithm shown below to decide on dosage. 
Start with the 100 mg group.  The safety and efficacy during 
the treatment period will be assessed separately for the CDI 
group and the enteric infection group by the Data Review 
Committee (DRC). 
1. If there are no safety concerns and IMP is considered 
effective in the 100 mg group: 
The next step is to randomize 10 patients each who were 
not in the 100 mg group to the 200 mg or 50 mg group.  
The two groups will be treated in parallel.  Treatment 
will be started in the CDI and enteric infection groups, 
respectively. 
2. If there are no safety concerns and IMP is considered not 
effective in the 100 mg group: 
The next step is to allocate 10 patients who were not in 
the 100 mg group to the 200 mg group.  Treatment will 
be started in the CDI and enteric infection groups, 
respectively.  The DRC assesses the safety of the 200 mg 
group during the treatment period.  If the 200 mg has no 
safety concerns, 10 patients who were not in the 100 mg 
or 200 mg group will be allocated to the 400 mg group as 
the next step.  Treatment will be started in the CDI and 
enteric infection groups, respectively. 
Prohibited Concomitant 
Drugs and Therapies and 
Restricted Concomitant 
Prohibited concomitant drugs and therapies: 
The use of following drugs and therapies will be prohibited 
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Drugs 
during the period from the start day of IMP administration to 
the end day of the trial for items 1 and 7, from screening to 
the end day of the trial for the following items 2 through 6, 
and from the start day of IMP administration to the end day 
of IMP administration for item 8. 
1) For enteric infection group only: antibiotic 
agents/synthetic antibacterial agents (oral, 
injection, suppository) 
2) For enteric infection group only: non-steroidal anti-
inflammatory/analgesic drugs (oral, injection, 
suppository)* 
3) For enteric infection group only: corticosteroid 
preparation (oral, injection, suppository) 
4) For enteric infection group only: 
immunosuppressant medications (oral, injection, 
suppository) 
5) For enteric infection group only: biological 
preparation (TNF inhibitor) 
6) Antidiarrheal drugs, drugs to inhibit bowel motility 
7) Other drugs and therapies to treat CDI and enteric 
infection (eg, fecal microbiota transplantation) 
8) UGT1A1 inhibitors (atazanavir) 
*:  Use for purposes other than treating enteric infection is 
allowed.  (Concomitant use is allowed for treating 
common cold during the trial period.) 
Restricted concomitant drugs: 
Among of drugs listed below, concomitant use of drugs 
listed in item 1) are prohibited in principle from the start day 
of the IMP administration until the day of examination at the 
end of treatment if the drugs are used for a purpose other 
than treatment of CDI.  However, in cases that drugs are 
used to treat an underlying disease at the time of screening 
and cannot be discontinued even after the start day of the 
IMP administration due to the necessity for continuous drug 
treatment, such concomitant use is allowed.  Drugs listed in 
items 2) through 5) are allowed to be administered 
concomitantly as long as the drugs are used at the time of 
screening and the dose regimen is not changed during the 
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period from screening until the day of examination at the end 
of treatment.   
Drugs listed in item 6) are allowed to be administered 
concomitantly under the following conditions: the drugs  are 
used at the time of screening, and the dose regimen is not 
changed in the period from screening to the end day of trial 
for CDI groups, or the period from screening to the end day 
of IMP administration for enteric infection group.  If the 
foods described in item 6) are taken, instruct the patient not 
to change the daily amount of consumption during the period 
from screening until the end day of the trial. 
1) For CDI group only: antibiotic agents/synthetic 
antibacterial agents (oral, injection, suppository) 
2) For CDI group only: non-steroidal anti-
inflammatory/analgesic drugs (oral, injection, 
suppository)* 
3) For CDI group only: corticosteroid preparation 
(oral, injection, suppository) 
4) For CDI group only: immunosuppressant 
medications (oral, injection, suppository) 
5) or CDI group only: biological preparation  (TNF 
inhibitor) 
6) Probiotics 
*:  Use for purposes other than treating CDI is allowed.  
(Concomitant use is allowed for treating common cold 
during the trial period.) 
Endpoints 
Safety endpoints: 
• Adverse events, clinical laboratory tests, vital signs 
(body temperature, blood pressure, and pulse rate), 12-
lead electrocardiogram (ECG) 
Efficacy endpoints: 
• Microbiological outcome (microbiological outcome, 
toxin A/B assay) 
• Clinical response 
• Recurrence of CDI (CDI group only) 
• Time to resolution of diarrhea 
• Improvement of clinical symptoms 
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• Drug sensitivity of isolated strain 
Pharmacokinetics endpoints: 
• Plasma pharmacokinetics:  plasma concentration, 
pharmacokinetic parameters (maximum [peak] plasma 
concentration of the drug [Cmax], time to maximum 
[peak] plasma concentration [tmax], Cmax normalized by 
dose [Cmax/D]) of OPS-2071 
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Criteria for Evaluation 
Microbiological outcome: 
Microbiological outcome will be judged according to the 
following assessment criteria for the bacterial strain isolated 
as the causative pathogen based on the data from the 
microbiological examination.  For infection due to multiple 
causative pathogens, microbiological outcome will be 
assessed for each individual pathogen. 
Time of Observation 
Assessment of 
Microbiological 
Outcome 
Baseline 
Day 4 
End of 
Treatment 
+ 
– 
– 
Excellent 
+ 
+ 
– 
Good 
− 
+ 
Not applicable 
+ 
+ 
+ 
Poor 
− 
+ 
– 
+ 
Not applicable 
Others 
Unknown/ 
indeterminate 
+:  culture positive; − :  culture negative 
Not applicable:  Bacterial culture test was not performed.  The 
causative pathogen was not isolated or identified. 
 
Assessment of 
Microbiological 
Outcome 
Definition 
Excellent 
Pathogen is absent from bacterial culture 
obtained at Day 4 and at the end of treatment. 
Good 
Pathogen is still present in bacterial culture 
obtained at Day 4, and absent from bacterial 
culture at the end of treatment. 
Poor 
Pathogen is still present in bacterial culture 
obtained at the end of treatment 
Unknown/ 
indeterminate 
Applicable to none of the above, but falls 
under the cases below for example. 
• 
Cultures are not available because of 
withdrawal from the study or other 
reasons. 
• 
Culture was obtained after the use of 
prohibited concomitant drugs/therapies. 
• 
Any other circumstance, which makes it 
impossible to define the microbiological 
response. 
 
Clinical response: 
Assess clinical response at the time of observation (Day 4 
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and end of treatment) according to the following assessment 
criteria. 
 
Clinical 
Response 
Assessment 
Definition 
Clinical cure 
Meeting all the following criteria within 24 hours 
before observation 
• 
No liquid or unformed stool 
• 
No abdominal symptoms and no other 
symptoms (fever, nausea, vomiting) 
• 
No need of medication or therapy to treat CDI 
or enteric infection 
Clinical 
improvement 
Fulfilling at least one of the following criteria within 
24 hours before observation 
• 
Liquid or unformed stools ≤ 2 times/day 
• 
No abdominal symptoms and no other 
symptoms (fever, nausea, vomiting) 
• 
No need of medication or therapy to treat CDI 
or enteric infection 
Clinical failure 
Fulfilling none of the above-mentioned clinical 
improvement criteria. 
Patients who received medication or therapy to treat 
CDI or enteric infection prior to the time of 
observation are to be assessed as “clinical failure”. 
 
Recurrence of CDI (CDI group only): 
For patients who achieved “clinical cure” at the end of 
treatment, assess the recurrence of CDI at follow-up 2 (FU2) 
or withdrawal according to the following assessment criteria. 
Assessment of 
Recurrence of 
CDI 
Definition 
Sustained cure 
No recurrence 
Recurrence 
Meeting all the following criteria 
• 
New episode of diarrhea is occurred in the 
period from the end of treatment to FU2 or 
withdrawal (liquid or unformed stools ≥ 3 
times/day within 24 hours) 
• 
Medication or therapy is required to treat 
CDI in the period from the end of treatment 
to FU2 or withdrawal 
• 
A positive toxin A/B assay at FU2 or 
withdrawal (positive for either or both toxins) 
 
 
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Time to resolution of diarrhea: 
The time from the start of dosing until the first formed stool 
(except in cases where liquid or unformed stools recurs) will 
be evaluated as time to resolution of diarrhea. 
Scheduled Duration of the 
Trial 
01 Jul 2015 through 31 Mar 2017 
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Table of Contents 
Trial Protocol Synopsis ................................................................................. 3 
Table of Contents ......................................................................................... 15 
List of Abbreviations and Definition of Terms ......................................... 18 
1 
Introduction ........................................................................................ 21 
1.1 
Background of Trial Plan ..................................................................................21 
1.2 
Study Results and Trial Rationale .....................................................................21 
2 
Trial Objectives ................................................................................... 30 
3 
Trial Plan ............................................................................................. 31 
3.1 
Trial Design .......................................................................................................31 
3.2 
Rationale for Trial Design .................................................................................34 
3.3 
Endpoints ...........................................................................................................35 
3.4 
Target Number of Patients ................................................................................38 
4 
Investigational Medicinal Products .................................................. 39 
4.1 
Test Product and Comparator ............................................................................39 
4.2 
Packaging and Labeling ....................................................................................39 
5 
Trial Population .................................................................................. 40 
5.1 
Target Disease ...................................................................................................40 
5.2 
Inclusion Criteria ...............................................................................................40 
5.3 
Exclusion Criteria ..............................................................................................41 
6 
Trial Design ......................................................................................... 43 
6.1 
Dose, Regimen, and Treatment Period ..............................................................43 
6.2 
Prior and Concomitant Treatment .....................................................................44 
6.3 
Method of Minimizing or Avoiding Bias ..........................................................47 
7 
Trial Procedures ................................................................................. 48 
7.1 
Schedule and Procedures ...................................................................................48 
7.2 
Method of Evaluation ........................................................................................56 
7.3 
Measures to Be Taken for Patients Visiting or Planning to Visit Other 
Hospitals or Departments ..................................................................................62 
8 
Adverse Events .................................................................................... 63 
8.1 
Definitions .........................................................................................................63 
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8.2 
Response to Occurrence of Adverse Events......................................................64 
8.3 
Assessment of Adverse Events..........................................................................66 
8.4 
Follow-up Investigation of Adverse Events ......................................................68 
8.5 
Pregnancy ..........................................................................................................69 
9 
Withdrawal of Individual Patients From the Trial ......................... 72 
9.1 
Screen Failure ....................................................................................................72 
9.2 
Criteria and Procedures for Withdrawal of Individual Patients ........................72 
9.3 
Follow-up Investigation of Patients Who Do not Visit the Trial Site ...............73 
10 
Collection of Case Report Form Data and Specification of 
Source Data ......................................................................................... 74 
10.1 
Collection of Case Report Form Data ...............................................................74 
10.2 
Source Documents .............................................................................................74 
10.3 
Case Report Form Items to Be Treated as Source Data ....................................75 
10.4 
Data to Be Collected by the Sponsor.................................................................75 
11 
Statistical Analysis .............................................................................. 76 
11.1 
Statistical Analysis Sets.....................................................................................76 
11.2 
Handling of Data ...............................................................................................76 
11.3 
Analysis Items and Method ...............................................................................77 
11.4 
Procedures for Reporting Deviations From the Original Statistical 
Analysis Plan .....................................................................................................82 
11.5 
Rationale for Target Number of Patients ..........................................................82 
12 
Quality Control and Quality Assurance for the Trial .................... 84 
13 
General Items of Caution Pertaining to the Trial ........................... 85 
13.1 
Ethics and Good Clinical Practice Compliance ................................................85 
13.2 
Institutional Review Board ................................................................................85 
13.3 
Patient Consent ..................................................................................................85 
13.4 
Management of Investigational Medicinal Products .........................................87 
13.5 
Direct Access to Source Documents and Monitoring .......................................87 
13.6 
Deviations From and Changes or Amendments to the Trial Protocol ..............88 
13.7 
Archiving of Records ........................................................................................89 
13.8 
Termination or Interruption of Part or All of the Trial ......................................89 
13.9 
Protection of Patients’ Personal Information ....................................................90 
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13.10 
Compensation for Injury to Health ....................................................................90 
13.11 
Agreement on Publication .................................................................................90 
14 
Trial Administrative Structure ......................................................... 91 
15 
Scheduled Duration of the Trial ........................................................ 92 
16 
References ............................................................................................ 93 
 
Appendix 
Patient diary 
Annex 
Trial Organization and Emergency Contact 
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List of Abbreviations and Definition of Terms 
List of Abbreviations 
Abbreviation 
Expansion 
AAD 
Antibiotic-associated diarrhea 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AZM 
Azithromycin 
BMI 
Body mass index 
CDAD 
Clostridium difficile-associated diarrhea 
CDI 
Clostridium difficile infection 
CPFX 
Ciprofloxacin 
CPPS 
Clinical per protocol set 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P-450 
DNA 
Deoxyribonucleic acid 
DRC 
Data Review Committee 
EDC 
Electronic data capture 
FAS 
Full analysis set 
FDX 
Fidaxomicin 
FU 
Follow-up 
GCP 
Good Clinical Practice 
hCG 
Human chorionic gonadotropin 
ICH 
International Conference on Harmonisation 
IMP 
Investigational medicinal product 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response Services 
IUD 
Intrauterine device 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry  
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum inhibitory concentration 
MIC90 
Minimum inhibitory concentration required to inhibit the growth of 
90% of bacterial strains tested 
MPC 
Mutant prevention concentration 
MPPS 
Microbiological per protocol set 
MTZ 
Metronidazole 
PMDA 
Pharmaceuticals and Medical Devises Agency 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetics 
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Abbreviation 
Expansion 
PKS 
Pharmacokinetics set 
PP 
Per protocol 
QTc 
Corrected QT interval 
QTcB 
QT interval corrected using the Bazette’s formula 
QTcF 
QT interval as corrected by Fridericia’s formula 
RFX 
Rifaximin 
SAE 
Serious adverse event 
SS 
Safety set 
TEAE 
Treatment-emergent adverse event 
UGT 
Uridine diphosphate glucuronosyltransferase 
URTI 
Upper respiratory tract infection 
VCM 
Vancomycin 
VRE 
Vancomycin-resistant enterococci 
WHO 
World Health Organization 
 
Definitions of Terms 
Term 
Definition 
Screen failure 
A screen failure is a patient from whom written informed 
consent was obtained, but to whom the investigational medicinal 
product was not assigned. 
Trial start date for 
individual patient 
The day of obtaining the patient’s written informed consent 
Trial completion date 
for individual patient 
CDI group:  The completion day of follow-up 2 (FU2) or 
withdrawal examination for individual patients 
Enteric infection group:  The completion day of follow-up 1 
(FU1) or withdrawal examination for individual patients 
Trial withdrawal date 
for individual patient 
The day when withdrawal is considered necessary by the 
investigator or subinvestigator for individual patient or the day 
of withdrawal examination 
Trial period for 
individual patient 
Period from the day of obtaining the patient’s informed consent 
to the day of trial completion.  It does not include the follow-up 
period after the trial completion date for individual patient. 
 
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List of Pharmacokinetic Parameters 
Abbreviation and Term (Unit) 
Expansion or Definition 
AUC0-t 
μg·h/L 
Area under the concentration-time curve calculated 
to the last observable concentration at time t 
AUC0-∞ 
μg·h/L 
Area under the concentration-time curve from time 
zero to infinity 
Cmax 
μg/L 
Maximum (peak) plasma concentration of the drug 
Cmax/D 
μg/L/mg 
Cmax normalized by dose 
fef,xh 
% 
Fraction of the drug excreted into the feces to x 
hours 
feu,xh 
% 
Fraction of the systemically available drug excreted 
into the urine to x hours 
tmax 
h 
Time to maximum (peak) plasma concentration 
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1 
Introduction 
1.1 
Background of Trial Plan 
According to the World Health Organization (WHO) report, diarrheal disease is in the 
top-10 list of leading causes of death in the world, with 1.5 million people dying from 
diarrheal disease in 2012. 1  Diarrhea is the major symptom of enteric infections caused 
by bacteria such as Salmonella, Campylobacter, Vibrio, Shigella, and Escherichia coli (E. 
coli).  In addition, a number of antibiotic-resistant pathogens have been reported in recent 
years,2 and quinolone-resistant Campylobacter in particular has become widespread.3,4 
All of the commercially available antibiotics have the potential to cause diarrhea during 
treatment of infectious diseases.5  Use of antibiotics sometimes disrupts intestinal flora, 
followed by microbial substitution, which leads to an increase in pathogenic bacteria and 
eventually induces diarrhea (antibiotic-associated diarrhea:  AAD).  Since Clostridium 
difficile (C. difficile) is resistant to most of the currently available antibiotics, and AAD 
caused by C. difficile is specifically known as C. difficile infection (CDI).6  Use of 
existing quinolone drugs has been known to increase the risk of CDI,7 and the number of 
CDI cases has been increasing in recent years.8  Metronidazole (MTZ) and vancomycin 
(VCM) are the preferred first-line therapeutic agents for CDI; however, treatment failure 
with the use of MTZ and recurrence with the use of VCM in 15% to 30% of cases have 
been reported.9  An additional concern regarding the use of VCM is the emergence of 
VCM-resistant enterococci (VRE).8 
In order to solve these problems, Otsuka Pharmaceutical Co. Ltd. discovered OPS-2071, 
which shows a broad spectrum of activity against intestinal infectious bacteria, including 
C. difficile and Campylobacter, and is expected to cause few adverse effects because of 
its low systemic absorption following oral administration.10  OPS-2071 is a new chemical 
entity with a quinolone structure for enteric infections, including CDI. 
1.2 
Study Results and Trial Rationale 
1.2.1 
Nonclinical Study Results 
1.2.1.1 
Efficacy Pharmacology 
1) Efficacy Pharmacology 
In vitro studies showed OPS-2071 to have broad and potent antibacterial activity against 
clinically isolated bacteria that caused enteric infections.  The antibacterial activity of 
OPS-2071 was equivalent or superior to that of existing drugs.  Moreover, OPS-2071 
showed potent activity against C. difficile [minimum inhibitory concentration required to 
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inhibit the growth of 90% of bacterial strains tested (MIC90):  0.5 μg/mL] and 
Campylobacter jejuni (C. jejuni) (MIC90:  0.25 μg/mL), both of which are known to be 
resistant to existing quinolone drugs.  The antibacterial activity of OPS-2071 against 
C. difficile was comparable to that of rifaximin (RFX) and fidaxomicin (FDX) and 
superior to that of other antibiotics, including VCM.  The antibacterial activity of OPS-
2071 against C. jejuni was comparable to that of azithromycin (AZM) and superior to 
that of other antibiotics. 
No spontaneous resistance to OPS-2071 was observed.  The frequency of spontaneous 
resistance to OPS-2071 was lower than that for RFX and FDX, which are under 
development or have already been approved as therapeutic agents for C. difficile infection.  
The mutant prevention concentrations (MPC:  concentration that shows no emergence of 
resistant bacteria) of OPS-2071 were similar to or lower than those of existing quinolones 
and VCM, and considerably lower than those of RFX and FDX.  The risk of emergence 
of bacteria resistant to OPS-2071 is therefore presumed to be similar to or lower than for 
existing quinolones and VCM and considerably lower than for RFX and FDX. 
The therapeutic efficacy of OPS-2071 was examined using two animal models, a mouse 
typhoid model and a hamster C. difficile-associated diarrhea (CDAD) model, and potency 
was observed to be well correlated with that observed in vitro.  The efficacy of OPS-2071 
was similar to that of ciprofloxacin (CPFX) in the mouse typhoid model and superior to 
that of VCM, FDX, and metronidazole (MTZ) in the hamster CDAD model.  These 
results indicate that OPS-2071 has the potential to be a potent antibiotic for the treatment 
of a variety of infectious intestinal diseases, including typhoid fever and CDI. 
2) Safety Pharmacology 
OPS-2071 at single oral doses of up to 2000 mg/kg showed no effects on general signs 
and behavior in rats or on respiratory and cardiovascular parameters in conscious dogs.  
OPS-2071 inhibited human ether-a-go-go related gene current in Chinese hamster ovary 
cells at 100 µmol/L with a 30% inhibitory concentration of 132 µmol/L.  OPS-2071 did 
not induce prolongation of QT interval, corrected QT interval (QTc), monophasic action 
potential duration at 90% repolarization, effective refractory period, or terminal 
repolarization period even at an intravenous dose of 3 mg/kg in anesthetized dogs, 
suggesting a low potential for proarrhythmic effects.  OPS-2071 showed no inhibitory 
effects on γ-aminobutyric acid receptor binding in either the absence or presence of 
flurbiprofen or biphenylacetate, nonsteroidal anti-inflammatory analgetics, suggesting a 
low potential for convulsion. 
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3) Nonclinical Absorption, Distribution, Metabolism, and Excretion 
Absorption 
Following single oral administration in mice, hamsters, rats and monkeys, the plasma 
exposure of OPS-2071 increased with dose increase.  The oral bioavailability of OPS-
2071 at 1 mg/kg was 2.9% in male rats and 5.0% in male monkeys.  No apparent 
sex differences were observed in the plasma concentration profile of OPS-2071 in rats.  
Plasma exposure of OPS-2071 was lower for oral administration in a fed state than for a 
fasted state in rats.  In monkeys, absorption of OPS-2071 was delayed following 
administration in a fed state versus a fasted state.  OPS-2071 showed higher membrane 
permeability in vitro than in metoprolol, a high permeability marker. 
Distribution: 
Following oral administration of 14C-OPS-2071 at 3 mg/kg to male and female rats, 
concentrations of radioactivity in the stomach, small intestine, large intestine, kidney, and 
liver were considerably higher than that in the plasma at 1 hour postdose (time to 
maximum concentration [tmax] was 1 hour in all of these tissues except the large 
intestine).  Radioactivity was hardly detected in the central nervous system.  Following 
oral administration of 14C-OPS-2071 at 3 mg/kg to male pigmented rats, OPS-2071 and 
its metabolites were scarcely bound to melanin.  The in vitro protein binding of 14C-
OPS-2071 was lower than 79.3% in human, mouse, hamster, rat, rabbit, dog, and monkey 
serum. 
Metabolism 
Following repeated oral administration of OPS-2071 at 2000 mg/kg/day, a glucuronide of 
OPS-2071 was detected in rat and monkey plasma, and a hydrate of OPS-2071 was 
detected in monkey plasma.  In reaction with human uridine diphosphate (UDP) 
glucuronosyltransferase (UGT)-expressing microsomes, a glucuronide of OPS-2071 was 
predominantly produced by UDP-glucuronosyltransferase 1A1 (UGT1A1)-mediated 
reaction and slightly produced by UGT1A9-mediated reaction.  OPS-2071 had no 
inhibitory effect on CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, CYP2E1, and CYP3A4 at up to 100 µmol/L.  OPS-2071 at up to 5 µmol/L 
caused no induction of CYP1A2, CYP2B6, and CYP3A4. 
Excretion 
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Following single oral administration of OPS-2071 at 2 mg/kg to hamsters, OPS-2071 in 
the cecal contents reached a Cmax of 42.95 µg/g at 4 hours postdose and then decreased 
with a terminal-phase elimination half-life (t1/2,z) of 8.3 hours, and the cumulative fecal 
excretion of OPS-2071 within 72 hours postdose accounted for 67.0% of the 
administered dose.  Following oral administration of 14C-OPS-2071 at 3 mg/kg, the 
urinary and fecal excretion of radioactivity within 168 hours postdose accounted for 
1.416% to 2.297% and 95.35% to 96.14% of the administered dose in rats and 21.51% 
and 80.59% in monkeys, respectively. 
4) Toxicology 
In 4-week repeated-dose oral toxicity studies in rats and monkeys, no deaths or severe 
clinical signs were observed in either males or females at doses of up to 2000 mg/kg/day.  
In genotoxicity studies, OPS-2071 showed mutagenicity in vitro in a bacterial reverse 
mutation test in one strain (TA102) of Salmonella Typhimurium.  However, no 
mutagenicity was found in four other standard strains.  In a mammalian cell chromosome 
aberration test, OPS-2071 showed clastogenicity at 15 μg/mL and higher, but no 
genotoxicity was seen in an erythrocyte micronucleus test or in a liver unscheduled DNA 
synthesis test in male rats intraperitoneally administered OPS-2071 at up to 2000 mg/kg; 
thereby, the genotoxic potential seen in vitro is considered to have no relevance in 
clinical use.  In reproductive and developmental toxicity studies, the no observed adverse 
effect level (NOAEL) with fertility and early embryonic development in male and female 
rats was considered to be 2000 mg/kg/day.  In an embryo-fetal development study in rats, 
NOAEL was considered to be lower than 200 mg/kg/day for general toxicity in dams and 
2000 mg/kg/day for reproduction in dams and for embryo-fetal development.  In an 
embryo-fetal development study in mice, NOAEL was considered to be 2000 mg/kg/day.  
In an in vitro phototoxicity testing, OPS-2071 was considered to show phototoxic 
potential.  However, no phototoxicity was noted in an in vivo skin phototoxicity study 
using mice intraperitoneally administered OPS-2071 at doses of up to 2000 mg/kg. 
1.2.2 
Effects in Humans 
The safety and pharmacokinetics of OPS-2071 in healthy volunteers have been assessed 
in three phase 1 trials in Singapore, Korea, and Japan.  The Singapore trial (Trial 341-12-
001) addressed a single dose, multiple doses, and the effect of food.  The Korean trial 
(Trial 341-KOA-1301i) addressed a single and multiple doses.  The Japanese trial 
addressed a single dose (Trial 341-13-001).  Multiple dosing was conducted by twice 
daily administration for 7 days. 
1) Pharmacokinetics: 
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Following single administrations of OPS-2071 at doses of 30, 60, 120, 240, 300, 600, 900, 
and 1200 mg in a fasting state, median tmax was 1.0 to 4.0 hours postdose.  Following 
multiple dose administration at doses of 60, 120, 300, and 600 mg after a light meal, 
median tmax was 2.0 to 3.5 hours in the Singapore trial, and following multiple dose 
administration before meals, median tmax was 2.5 to 3.5 hours in the Korean trial.  OPS-
2071 Cmax, AUC from time zero to the last quantifiable concentration (AUC0-t) and AUC 
from time zero extrapolated to infinity (AUC0-∞) values increased dose-dependently but 
in a less than dose proportional manner following single- and multiple-dose 
administration.  The mean apparent terminal phase half-life (t1/2) of OPS-2071 was 
variable at 10 to 21 hours for the single dose treatments across the 30 to 1200 mg dose in 
the Singapore trial and approximately at 12 to 50 hours in the Korean and Japanese trials 
across the same dose range. 
Following administration of OPS-2071 at a single dose of 600 mg after consumption of a 
meal, Cmax was 2.21, AUC0-t and AUC0-∞ were 2.04-fold higher compared with the 
values following administration in a fasted state.  In multiple dosing of OPS-2071, 
steady-state conditions were achieved by Day 2 of administration of OPS-2071. 
The mean percent of OPS-2071 excreted in urine (feu,72h) was approximately 2.4% or 
less of the administered dose following single and multiple dose administration.  The 
mean amount excreted in the feces as a percentage of dose administered (fef,72h) ranged 
from approximately 30.0% to 55.0% of the administered dose following single dose 
administration. 
2) Pharmacodynamics: 
In the Singapore and Korean trials, OPS-2071 at doses of 60, 120, 300, and 600 mg was 
repeatedly administered for assessing the effect on intestinal bacterial flora.  Some 
intestinal bacteria decreased because of the repeated administration of OPS-2071.  
However, regardless of the dose of OPS-2071, the intestinal bacterial flora returned to the 
baseline status by the time of follow-up after the end of treatment.  There was no 
apparent effect on intestinal bacterial flora. 
3) Safety: 
In the three trials, no subject was withdrawn due to an adverse event (AE) related to 
OPS-2071.  In the Singapore trial, one subject was withdrawn from the trial due to three 
AEs of syncope, hemorrhage intracranial, and atrial fibrillation, all of which were 
unrelated to OPS-2071 (syncope and hemorrhage intracranial were also serious adverse 
events [SAEs]).  In the Korean and Japanese trials, no subjects experienced any SAEs. 
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Singapore trial (Trial 341-12-001) 
Following a single administration of OPS-2071 or placebo in a fasting state, five of 20 
subjects (25%) experienced seven treatment-emergent adverse events (TEAEs) (OPS-
2071:  seven events in five subjects).  There were two TEAEs of Grade 4 severity 
[Common Terminology Criteria for Adverse Events (CTCAE) severity grading], reported 
for one subject (30 mg); these were events of syncope and hemorrhage intracranial, 
assessed by the investigator as not related to the investigational medicinal product (IMP), 
but considered to be SAEs necessitating withdrawal.  Subjects also experienced upper 
respiratory tract infections (URTIs; 2/20 [10%]), cough (1/20 [5%]), rhinorrhea (1/20 
[5%]) and atrial fibrillation (1/20 [5%]). 
Following administration of OPS-2071 at 600 mg in both fed and fasted states, one 
subject (1/12 [8.33%]) experienced two TEAEs, which were mild gastroenteritis and 
URTI. 
Following multiple administration of OPS-2071 in a fed state, nine subjects (9/32 
[28.13%]) experienced 15 TEAEs.  Treatment-related TEAEs were five events of alanine 
aminotransferase (ALT) increased (5/32 [15.63%]), and one event (1/32 [3.13%]) each of 
ventricular extrasystoles, aspartate aminotransferase (AST) increased, electrocardiogram 
QT prolonged (described in the CRF as “QTcB > 450 ms”; however, central 
measurements revealed that QTcB and QTcF were < 450 ms), gamma-
glutamyltransferase increased and headache. 
Korean trial (Trial 341-KOA-1301i) 
Following a single administration of OPS-2071 or placebo in a fasting state, 10 of 64 
subjects (15.6%) experienced 14 TEAEs (OPS-2071:  12 events in eight subjects; 
placebo:  two events in two subjects).  TEAEs reported were two events (2/64 [3.1%]) 
each of URTI and epistaxis, and one event (1/64 [1.6%]) each of vision blurred, 
abdominal pain, abdominal pain upper, diarrhoea, oral pustule, dizziness, headache, 
pleuritic pain, rhinorrhoea, and dry skin. 
Following multiple administration of OPS-2071 or placebo before morning meal and 
before evening meal, 10 of 32 subjects (31.3%) experienced 22 TEAEs (OPS-2071:  18 
events in seven subjects; placebo:  four events in three subjects).  TEAEs reported were 
three events (3/32 [9.4%]) of diarrhoea, two events (2/32 [6.3%]) each of headache and 
somnolence, and one event (1/32 [3.1%]) each of dry eye, visual acuity reduced, 
abdominal distension, abdominal pain, abdominal pain upper, nausea, sensation of 
foreign body, epistaxis, oropharyngeal pain, pharyngeal haemorrhage, pleuritic pain, dry 
skin, pruritus, rash, and rash erythematous. 
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Japanese trial (Trial 341-13-001) 
After single oral administration of OPS-2071 or placebo in a fasting state, a total of 25 
TEAEs were reported for 22 (34.38%) of the 64 subjects (OPS-2071:  18 events in 16 
subjects; placebo:  seven events in six subjects).  The highest incidence of TEAEs 
occurred in the System Organ Class of gastrointestinal disorders (13 events in 11 of the 
64 subjects [17.19%], comprising 11 events of diarrhoea (10/64 [15.63%]) and two 
events of abdominal pain (1/64 [1.56%]).  The other TEAEs comprised three events of 
headache (3/64 [4.69%]), two events (2/64 [3.13%]) each of pharyngitis and blood 
creatine phosphokinase increased, two events (1/64 [1.56%]) of ALT increased, and one 
event (1/64 [1.56%]) each of subcutaneous hematoma, AST increased, blood bilirubin 
increased, back pain, and proteinuria. 
1.2.3 
Trial Rationale 
OPS-2071 is a novel anti-enteric infection agent with a quinolone structure that has been 
shown to have potent antibacterial activity against various bacteria known to cause 
general enteric infections, including CDI.  This study is designed as a multi-center, open-
label phase 2a trial to assess the safety and efficacy (microbiological outcome and 
clinical response) of three different doses of OPS-2071 in patients with bacterial enteritis. 
For the trial population of this study, patients with bacterial enteritis will be divided into 
two groups, a CDI group for patients with bacterial enteritis associated with C. difficile 
infection and an enteric infection group for patients with bacterial enteritis for which the 
causative pathogen is Salmonella, Campylobacter, and pathogenic E. coli.  The safety 
and efficacy will be assessed in each group.  Since this is the first trial in patients, in 
order to ensure patient safety, Salmonella, Campylobacter, and pathogenic E. coli, which 
are relatively less likely to cause severe infection, have been selected as the causative 
pathogens for enteric infection.  However, among these three types of bacteria, typhoidal 
Salmonella, enterohemorrhagic E. coli (EHEC), and Vibrio cholerae (V. cholerae) are 
excluded because they are more likely to cause severe infection.  Shigella is also 
excluded for the same reason. 
The dosage of OPS-2071 in this trial is estimated based on the results of non-clinical 
pharmacological test.  In hamster CDAD model, the therapeutic effect of OPS-2071, 
VCM, and FDX was confirmed.  The result demonstrated that OPS-2071 showed 
significant therapeutic effect at 0.04 to 1 mg/kg and VCM and FDX showed significant 
therapeutic effect at 1 to 5 mg/kg.  Thus, OPS-2071 showed therapeutic effect equal to or 
greater than that of VCM or FDX at 1/25 to 1/5 lower concentrations.  It is estimated that 
the clinical dose of OPS-2071 is 16 to 100 mg, and that dose range OPS-2071 is expected 
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to show therapeutic effect equal to or greater than VCM at 500 mg (clinical dose) and 
FDX at 400 mg (clinical dose).  Within the range of 16 to 100 mg/day, a dose of 100 
mg/day is expected to show the most satisfactory effectiveness and at present 100 mg is 
considered likely to be the recommended human dose, and therefore the starting dose is 
set at 100 mg/day.  Concerning the treatment period, 10 days is selected for the CDI 
group in reference to American College of Gastroenterology (ACG) 2013 guideline,11 
and information of FDX, VCM, and MTZ.  In the enteric infection group, the trial adopts 
a 7-day treatment period, regardless of the causative pathogen or the efficacy during the 
trial for an exploratory assessment on how OPS-2071 affects clinical response and 
microbiological outcome. 
In the trial design, 100 mg/day, considered to be the clinically recommended dose, is set 
for the starting dose.  If there are no safety concerns and efficacy is confirmed in the 100 
mg group, safety and efficacy will be assessed in the 200 mg group.  By further 
confirming the safety and efficacy of OPS-2071 in the 50 mg group, the low dose cohort, 
at the same time, exploratory information on the recommended dose will be obtained.  If 
efficacy at 100 mg/day is not confirmed and there are no safety concerns, the safety and 
efficacy of OPS-2071 will be assessed at 200 mg/day and then at 400 mg/day in a 
sequential ascending manner.  Thus, the trial has a dose increase/decrease design.  A Data 
Review Committee (DRC) will be established as a third-party organization for assessing 
the safety and efficacy of each dose escalation based on a consistent perspective of 
specialists. 
The target number of enrollment is 10 patients in each dosage of the CDI group, and 10 
patients in each dosage of the enteric infection group.  To obtain information on 
microbiological outcome required for planning trial design on and after the next phase, 
each dosage secures at least 10 patients in the CDI group to assess the microbiological 
outcome and at least five patients in the enteric infection group to assess microbiological 
outcome with the sum of Salmonella, Campylobacter, and pathogenic E. coli.  If a 
sufficient number of patients are not available for microbiological assessment after 
enrollment of 10 patients in each group, enroll more patients. 
This trial is performed as a global trial in Japan, Korea, and Singapore.  A phase 1 study 
was performed in Asian healthy male adults in Japan, Korea, and Singapore.  The single-
dose study demonstrated tolerability up to 1200 mg.  In the 7-day multiple dose study 
(twice daily after meal), it was confirmed that there were no safety concerns up to 1200 
mg/day as with the single dose.  Individual variability was relatively high in all these 
countries, and distinctive difference among the studies was not noted in the exposure.  
There appears no remarkable difference in the safety and pharmacokinetics of Asian 
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subjects among three countries.  Further, we consider there is no remarkable difference in 
the distribution of pathogens, risk factors of the development of symptoms, and patient 
background among three countries. 
Preceding the planning of a phase 2a trial, a consultation before the beginning of the 
phase 2a trial was held with Pharmaceuticals and Medical Devices Agency (PMDA) on 
11 Jun 2014.  The face-to-face advice/post-termination consultation was subsequently 
performed on 10 Dec 2014. 
 
Based on the above, we have judged that performing this trial as a global trial in patients 
with bacterial enteritis is scientifically and ethically appropriate. 
 
Please refer to the investigational brochure for the detail of data described in this study 
protocol and other study results. 
 
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2 
Trial Objectives 
The objectives of this trial are: 
Primary objectives: 
• To assess the safety and efficacy of oral multiple doses of OPS-2071 in patients with 
bacterial enteritis associated with CDI or enteric infection (caused by Salmonella, 
Campylobacter, or pathogenic E. coli) 
• To assess the pharmacokinetics of multiple doses of OPS-2071 in patients with 
bacterial enteritis associated with CDI or enteric infection. 
Secondary objectives: 
• To assess the recurrence rate of CDI in patients with bacterial enteritis associated 
with CDI after multiple doses of OPS-2071. 
• To assess the time to resolution of diarrhea in patients with bacterial enteritis 
associated with CDI or enteric infection after multiple doses of OPS-2071. 
• To assess the improvement of clinical symptoms in patients with bacterial enteritis 
associated with CDI or enteric infection after multiple doses of OPS-2071. 
• To assess the sensitivity to OPS-2071 of the causative pathogen strain isolated from 
patients with bacterial enteritis associated with CDI or enteric infection. 
 
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3 
Trial Plan 
3.1 
Trial Design 
This is a multi-center, open-label trial to assess the safety and efficacy (microbiological 
outcome and clinical response) of three different doses of OPS-2071 in patients with 
bacterial enteritis. 
Patients with bacterial enteritis will be divided into two groups, a CDI group for patients 
with bacterial enteritis associated with C. difficile infection and an enteric infection group 
for patients with bacterial enteritis for which the causative pathogen is Salmonella, 
Campylobacter, or pathogenic E. coli. 
Outline of the trial design is shown in Figure 3.1-1. 
The target number of enrollment is 10 patients in each dosage of the CDI group, and 10 
patients in each dosage of enteric infection group.  Enroll 10 patients in each dosing 
group of the CDI group to assess microbiological outcome.  For the enteric infection 
group, enroll at least five patients in each dosing group to assess microbiological outcome 
with the sum of Salmonella, Campylobacter, and pathogenic E. coli.  If a sufficient 
number of patients are not available for microbiological assessment after enrollment of 
10 patients in each group, enroll more patients. 
Of daily dosages of 50, 100, 200, or 400 mg of OPS-2071, three dosages of 100, 50, and 
200 mg, or 100, 200, and 400 mg are administered.  The DRC will assess the 
appropriateness of dose escalation. 
Any of the daily three dosages of 50, 100, 200, or 400 mg of OPS-2071 is administered 
twice a day in the morning and evening to the CDI group for 10 days and to the enteric 
infection group for 7 days.  Whether or not the symptoms improve during the treatment 
period, use all IMPs prescribed for the predetermined period. 
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Figure 3.1-1 
Outline of Trial Design 
 
Criteria for dose escalation 
Start with the 100 mg group.  Enroll patients until the target population is achieved in 
each dosing group with CDI and enteric infection.  The DRC will assess the safety and 
efficacy during the treatment period at 100 mg separately for the CDI and enteric 
infection groups. 
1. If there are no safety concerns and IMP is considered effective in the 100 mg group: 
The next step is to randomize 10 patients each who were not in the 100 mg group to 
the 200 mg or 50 mg group.  The two groups will be treated in parallel.  Treatment 
will be started in the CDI and enteric infection groups, respectively. 
2. If there are no safety concerns and IMP is considered not effective in the 100 mg 
group: 
The next step is to allocate 10 patients not in the 100 mg group to the 200 mg group.  
Treatment will be started in the CDI and enteric infection groups, respectively.  The 
DRC assesses the safety of the 200 mg group during the treatment period.  When 
there are no safety concerns in the 200 mg group, the next step is to allocate 10 
patients not in the 100 mg or 200 mg group to the 400 mg group.  Treatment will be 
started in the CDI and enteric infection groups, respectively. 
200 mg group
200 mg/day
（10 patients）
50 mg group
50 mg/day
（10 patients）
400 mg group
400 mg/day
（10 patients）
200 mg group
200 mg/day
（10 patients）
Data Review Committee
Data Review Committee
100 mg group
100 mg/day
（10 patients）
2. If there are no safety concerns 
and IMP is considered not effective in 
the 100 mg group
1. If there are no safety concerns 
and IMP is considered 
effective in the 100 mg group
Randomization
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3.1.1 
Outline of Trial Schedule 
The investigator or subinvestigator will obtain written informed consent from patients, 
register the patients to Interactive Voice Response Services (IVRS) or Interactive Web 
Response Services (IWRS) to obtain patient numbers, perform screening examination 
within 2 days before administering IMPs, and assess patient eligibility based on the result 
of screening examination.  Patients assessed as eligible will be allocated to dosing groups 
via IVRS or IWRS. 
Patients in the CDI group will be treated with 50, 100, 200, or 400 mg as the daily 
dosages of OPS-2071 twice daily for 10 days, and patients in the enteric infection group 
for 7 days.  For both the CDI and enteric infection groups, observation will be performed 
on Day 4 of dosing, and the day after the final dosing (Day 11 for the CDI group; Day 8 
for the enteric infection group).  Further, follow-up observation will be conducted on Day 
24 and Day 38 for the CDI group and on Day 14 for the enteric infection group. 
The trial period of each patient will start on the day of informed consent to the day when 
scheduled examinations are completed (on Day 38 for the CDI group and on Day 14 for 
the enteric infection group or at the end of withdrawal examination).  This trial will make 
no distinction between inpatients and outpatients.  Trial schedule is shown in Figure 3.1-2. 
 
Figure 3.1-2 
Trial Schedule 
*Performed only in CDI group 
 
CDI group
-1
.
4 .
11
.
.
Enteric infection group
-1
.
4 .
8
.
.
-2
-2
1
1
10
7
24
14
Day
Day
38
-
Follow-up 1
Follow-up 2 *
Treatment period
Acquisition of informed consent/Screening
IMP allocation/start of administration
Observation
End of IMP administration
Observation at the end of administration
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3.2 
Rationale for Trial Design 
1) Design for dose increase/decrease 
On the basis of the result of a non-clinical pharmacological study using a hamster CDAD 
model, 16 to 100 mg of OPS-2071 is expected to have therapeutic effect.  Within the 
range of 16 to 100 mg/day, a dose of 100 mg/day is expected to show the most 
satisfactory effectiveness and at present 100 mg is considered likely to be the 
recommended human dose, and therefore the starting dose is set at 100 mg/day.  (See 
Section “6.1 Dose, Regimen, and Treatment Period” for rationale of dose setting.) 
If there are no safety concerns and efficacy is confirmed in the 100 mg group, safety and 
efficacy will be assessed in the 200 mg group.  By confirming the safety and efficacy of 
OPS-2071 in the 50 mg group in parallel, the low dose cohort, at the same time, 
exploratory information on the recommended dose will be obtained.  If efficacy at 100 
mg/day is not confirmed and there are no safety concerns, the safety and efficacy of OPS-
2071 will be assessed at 200 mg/day and then at 400 mg/day in a sequential ascending 
manner.  Thus, the trial has a dose increase/decrease design. 
2) Data Review Committee  
This is an open-label trial, and in order to ensure objectivity in efficacy assessment, a 
DRC will be established as a third-party organization to assess the safety and efficacy at 
each dose based on a consistent perspective of specialists.  The DRC will separately 
specify their procedures to be followed. 
3) Treatment Period 
For mild and moderate CDI, American College of Gastroenterology (ACG) 2013 
guideline recommends a 10-day administration of VCM or MTZ.  A 10-day comparison 
study between 400 mg/day fidaxomicin (hereafter, FDX) and 500 mg/day VCM 
confirmed that FDX has a clinical therapeutic effect for CDI comparable to VCM, and 
FDX is approved to treat CDI with the regimen of twice daily for 10 days.  In reference 
to these, we selected 10 days for the treatment period. 
The treatment period for enteric infection is usually 3 to 7 days, although it differs 
according to the causative pathogen, improvement of clinical symptoms, and type of 
antimicrobial drug.  For an exploratory assessment on how OPS-2071 affects clinical 
response and microbiological outcome, the trial adopts a 7-day treatment period, 
regardless of the causative pathogen or the efficacy during the trial so as to confirm the 
safety and usefulness of OPS-2071. 
In the result of the 7-day multiple dose study on OPS-2071 in healthy male adults, some 
intestinal bacteria decreased because of the repeated administration of OPS-2071.  
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However, regardless of the dose of OPS-2071, the intestinal bacterial flora returned to the 
baseline status by the time of follow-up after the end of treatment.  There was no 
apparent effect on intestinal bacterial flora. 
4) Follow-up 2 (CDI group) 
The problem in the treatment for CDI is its high recurrence rate.  CDI responds to the 
treatment with MTZ or VCM but recurs in approximately 15% to 30% cases.  CDI 
repeatedly recurs, which may result in hospitalization and treatment for a long period.  In 
this trial, for exploratory confirmation of the effect of OPS-2071 to prevent recurrence, 
presence/absence of recurrence will be confirmed 28 days after the end of treatment 
(FU2:  Day 38) or at withdrawal in patients who achieved “clinical cure” at the end of 
treatment in the CDI group. 
3.3 
Endpoints 
3.3.1 
Safety Endpoints 
Adverse events, clinical laboratory tests, vital signs (body temperature, blood pressure, 
and pulse rate), 12-lead ECG 
3.3.2 
Efficacy Endpoints 
3.3.2.1 
Microbiological Outcome 
Microbiological outcome will be judged according to the assessment criteria shown in 
Table 3.3-1 and Table 3.3-2 for the bacterial strain isolated as the causative pathogen 
based on the data from the microbiological examination.  For infection due to multiple 
causative pathogens, microbiological outcome will be assessed for each individual 
pathogen. 
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Table 3.3-1 
Assessment Table for Microbiological Outcome 
Time of Observation 
Assessment of 
Microbiological 
Outcome 
Baseline 
Day 4 
End of Treatment 
+ 
– 
– 
Excellent 
+ 
+ 
– 
Good 
− 
+ 
Not applicable 
+ 
+ 
+ 
Poor 
− 
+ 
– 
+ 
Not applicable 
Others 
Unknown/ 
indeterminate 
+:  culture positive, −:  culture negative 
Not applicable:  Bacterial culture test was not performed.  The causative pathogen was not isolated 
or identified. 
 
Table 3.3-2 
Assessment Criteria for Microbiological Outcome 
Assessment of 
Microbiological 
Outcome 
Definition 
Excellent 
Pathogen is absent from bacterial culture obtained at Day 4 and at the end of 
treatment. 
Good 
Pathogen is still present in bacterial culture obtained at Day 4, and absent from 
bacterial culture at the end of treatment. 
Poor 
Pathogen is still present in bacterial culture obtained at the end of treatment. 
Unknown/indeterminate 
Applicable to none of the above but falls under the cases below for example. 
• 
Cultures are not available because of withdrawal from the study or other 
reasons. 
• 
Culture was obtained after the use of prohibited concomitant 
drugs/therapies. 
• 
Any other circumstance, which makes it impossible to define the 
microbiological response. 
 
3.3.2.2 
Toxin A/B Assay (Clostridium Difficile Infection Group Only) 
Assess positive or negative for toxin A/B. 
3.3.2.3 
Clinical Response 
The investigator or subinvestigator will refer to the information from patients (eg, patient 
diary), and assess clinical response at the time of observation (Day 4 and end of 
treatment) according to the assessment criteria shown in Table 3.3-3. 
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Table 3.3-3 
Assessment Criteria for Clinical Response 
Clinical 
Response 
Assessment 
Definition 
Clinical cure 
Meeting all the following criteria within 24 hours before observation 
• 
No liquid or unformed stool 
• 
No abdominal symptoms and no other symptoms (fever, nausea, vomiting) 
• 
No need of medication or therapy to treat CDI or enteric infection 
Clinical 
improvement 
Fulfilling at least one of the following criteria within 24 hours before observation 
• 
Liquid or unformed stools ≤ 2 times/day 
• 
No abdominal symptoms and no other symptoms (fever, nausea, vomiting) 
• 
No need of medication or therapy to treat CDI or enteric infection 
Clinical failure 
Fulfilling none of the above-mentioned clinical improvement criteria. 
Patients who received medication or therapy to treat CDI or enteric infection prior to 
the time of observation are to be assessed as “clinical failure”. 
 
3.3.2.4 
Recurrence of Clostridium Difficile Infection (Clostridium 
Difficile Infection Group Only) 
The investigator or subinvestigator will assess the recurrence of CDI at FU2 or 
withdrawal according to the assessment criteria shown in Table 3.3-4 for patients who 
achieved “clinical cure” at the end of treatment. 
Table 3.3-4 
Assessment Criteria for Recurrence of Clostridium Difficile 
Infection 
Assessment of 
Recurrence of 
CDI 
Definition 
Sustained cure 
No recurrence 
Recurrence 
Meeting all the following criteria 
• 
New episode of diarrhea is occurred in the period from the end of treatment to 
FU2 or withdrawal (liquid or unformed stools ≥ 3 times/day within 24 hours) 
• 
Medication or therapy is required to treat CDI in the period from the end of 
treatment to FU2 or withdrawal 
• 
A positive toxin A/B assay at FU2 or withdrawal (positive for either or both 
toxins) 
 
3.3.2.5 
Time to Resolution of Diarrhea 
The time from the start of dosing until the first formed stool (except in cases where liquid 
or unformed stools recurs) will be evaluated as time to resolution of diarrhea. 
3.3.2.6 
Improvement of Clinical Symptoms 
Assess the improvement of clinical symptoms, ie, daily stool count, fecal properties, 
bloody stool, fever, abdominal pain, nausea, and vomiting. 
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3.3.2.7 
Drug Sensitivity of Isolated Strain 
Determine the minimum inhibitory concentration (MIC) of OPS-2071 for the 
isolated/identified C. difficile or the strain identified as the causative pathogen of enteric 
infection. 
3.3.3 
Pharmacokinetics Endpoints 
3.3.3.1 
Plasma Pharmacokinetics 
• Plasma concentration of OPS-2071, Cmax, tmax, Cmax/D 
 
3.4 
Target Number of Patients 
A total of 60 patients with 20 patients (10 patients each in CDI and enteric infection 
groups) in each dosing group 
Enroll 10 patients in each dosing group of the CDI group to assess microbiological 
outcome.  For the enteric infection group, enroll at least five patients in each dosing 
group to assess microbiological outcome with the sum of Salmonella, Campylobacter, 
and pathogenic E. coli.  If a sufficient number of patients are not available for 
microbiological assessment after enrollment of 10 patients in each group, enroll more 
patients. 
Patients available for microbiological assessment are those assessed as either “excellent,” 
“good,” or “poor” according to Table 3.3-2, which means that patients assessed as 
“Unknown/indeterminate” will not be included in microbiological assessment. 
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4 
Investigational Medicinal Products 
4.1 
Test Product and Comparator 
4.1.1 
Test Product 
Code Name 
OPS-2071 
Generic Name 
None 
Molecular Formula 
C20H15FN4O3 
Content 
and 
Formulation 
A pale yellow film coated tablet containing 25, 50, or 100 mg as OPS-2071 
Storage Conditions 
To be stored in room temperature 
 
4.2 
Packaging and Labeling 
4.2.1 
Packaging 
Blister pack sheets each containing ten 25, 50, or 100 mg IMP tablets are packaged in a 
box. 
4.2.2 
Contents of Label 
The labels of the package box show the following information requested by regulatory 
authorities in individual countries:  specification that the drug is for use in a clinical trial, 
code name, protocol number, lot number, expiration date, name and address of the 
sponsor, and other information as precautions etc. 
 
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5 
Trial Population 
5.1 
Target Disease 
Bacterial enteritis 
5.2 
Inclusion Criteria 
Patients who meet all of the following criteria will be selected. 
1. The patient is an Asian male or female of minimum legal age to provide consent (ie, 
21 years for Singapore, 19 years for Korea, and 20 years for Japan at time of 
informed consent). 
2. The patient provides written informed consent before the clinical trial is initiated. 
3. The patient has distinctive symptoms and findings of bacterial enteritis (regardless of 
inpatient or outpatient). 
4. The patient has bacterial enteritis with one or more of the following causative 
pathogens either proven or presumed: 
C. difficile, Salmonella, Campylobacter, pathogenic E. coli, and other bacteria 
estimated to cause bacterial enteritis (except for typhoid bacillus, Salmonella 
paratyphi A, enterohemorrhagic E. coli, Shigella, and V. cholerae) 
5. The patient and his/her partner are willing to take contraceptive measures from 
initiation of IMPs to 4 weeks after administration of IMPs. 
CDI group: 
6. The patient satisfies both the following: 
 Liquid or unformed stools ≥ 3 times/day within 24 hours before the start of IMP 
administration 
 A positive clinical laboratory result in one of the following methods to confirm 
CDI within 48 hours before the start of IMP administration: 
• 
Toxin A/B assay (positive for either or both toxins A and B) 
• 
PCR (detection of toxin genes) 
• 
Colonoscopy (findings of pseudomembranous colitis) 
Enteric infection group: 
7. The patient satisfies all the following: 
 Liquid or unformed stools ≥ 3 times/day within 24 hours before the start of IMP 
administration 
 Any of the following clinical findings of enteric infection within 24 hours before 
the start of IMP administration. 
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• 
Either symptom of abdominal pain, nausea, or vomiting 
 Negative toxin A/B assay or PCR within 48 hours before the start of IMP 
administration. 
5.3 
Exclusion Criteria 
Patients who fall under any of the following exclusion criteria will be excluded from 
participation in the trial. 
1. Intractable vomiting, inability to take oral medication, patients with feeding tubes 
2. The patient has severe or progressive underlying disease or complication, making it 
difficult to ensure safety in the study or proper efficacy assessment. 
3. Complication of chronic bowel diseases such as Crohn’s disease, ulcerative colitis, 
irritable bowel syndrome, or colorectal cancer 
4. History of stem cell transplantation, organ transplantation, or bone marrow 
transplantation (within 6 months before the screening examination) 
5. History of total colectomy 
6. Suspected viral enteritis 
7. History of allergic conditions caused by quinolone antibacterials 
8. The patient has a current diagnosis or history of convulsive disorders, such as 
convulsion and epilepsy 
9. The patient has a severe hepatic dysfunction (eg, AST [GOT] or ALT [GPT] ≥ 3 
times of the upper limit of normal at the study center, etc) 
10. The patient has a severe cardiac dysfunction (eg, cardiac arrest, ischemic disease) 
11. The patient has cardiac arrhythmia or congenital or sporadic long QTc syndrome.  Or 
the patient is treated with a drug reported to prolong QTc interval (eg, amiodarone, 
sotalol, disopyramide, quinidine, procainamide, terfenadine, astemizole, cisapride, 
pimozide) 
12. The patient has a moderate or severe renal dysfunction (eg, serum creatinine level ≥ 2 
mg/dL or necessity of renal dialysis, etc) 
13. The patient was treated with UGT1A1 inhibitors (atazanavir) within 2 days before the 
start of IMP administration. 
14. Women with confirmed or suspected pregnancy or breast-feeding women 
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15. The patient was treated with another IMPs within 3 months before the screening 
examination 
16. Patients judged to be ineligible by the investigator for any other reasons 
CDI group: 
17. The patient was treated with drugs and therapies to treat CDI within 24 hours before 
the start of IMP administration 
18. The patient with severe and complex CDI who has any of the following at the 
screening examination. 
• Complicated disease:  ileus, mental status changes, organ dysfunction (kidney and 
respiratory organs), septic shock, peritonitis, toxic megacolon, marked 
dehydration 
• Admission to intensive care unit due to CDI 
Enteric infection group: 
19. The patient was treated with other antibacterial agent by oral administration or 
injection within 7 days before the start of IMP administration. 
20. Typhoid bacillus, Salmonella paratyphi A, enterohemorrhagic E. coli, Shigella, or V. 
cholerae was isolated/identified. 
21. The patient has marked dehydration at the screening examination. 
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6 
Trial Design 
6.1 
Dose, Regimen, and Treatment Period 
Start with the 100 mg group, and the safety and efficacy during the treatment period will 
be assessed by the DRC.  If the 100 mg has no safety concerns and the efficacy is 
assessed “effective,” 10 patients each who were not in the 100 mg group will be 
randomized to the 200 mg or 50 mg group, and the two groups will be treated in parallel.  
If the 100 mg has no safety concerns and the efficacy is assessed “not effective,” 10 
patients who were not in the 100 mg group will be allocated to the 200 mg group as the 
next step.  After the assessment by the DRC based on the safety of the 200 mg group 
during the treatment period, start dosing for the 400 mg group.  Treatment will be started 
in the CDI and enteric infection groups, respectively. 
Table 6.1-1 shows the dosage and formulations selected for each dosing group. 
• Daily dosage:  OPS-2071 50 mg, 100 mg, 200 mg, 400 mg 
• Number/route of administration:  twice daily, morning and evening/oral 
administration 
• Take IMP after meal where possible with at least 10 hours of interval between 
dosings.  Ensure to have evening meal before dosing on the previous day of blood 
collection for PK and to have breakfast before dosing on the day to perform blood 
collection for PK. 
• Treatment period:  10 days for CDI group and 7 days for enteric infection group 
Note:  Whether or not the symptoms improve during the treatment period, use 
all IMPs prescribed for the predetermined period. 
 
Table 6.1-1 
Dosage and Formulations for Each Dosing Group 
Dosing Group 
Dosage of OPS-2071 
Formulation 
50 mg group 
50 mg/day 
25 mg tablet × 1, twice daily 
100 mg group 
100 mg/day 
50 mg tablet × 1, twice daily 
200 mg group 
200 mg/day 
100 mg tablet × 1, twice daily 
400 mg group 
400 mg/day 
100 mg tablet × 2, twice daily 
 
[Rationale for dose and regimen] 
It has been confirmed that there are no safety concerns up to 1200 mg in the phase 1 
single dose study in healthy male adults and up to 1200 mg per day in the 7-day multiple 
dose study (twice daily after meals).  The barrier function of membranes may be 
deteriorated because of infection in patients with enteritis, which may increase the 
absorption of the drug.  OPS-2071, with favorable membrane permeability, is unlikely to 
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increase absorption in patients with enteritis relative to healthy adults. 
In a non-clinical pharmacological study, therapeutic effect of OPS-2071, VCM, and FDX 
was assessed using the hamster CDAD model.  Significant therapeutic effect was 
demonstrated by OPS-2071 at 0.04 to 1 mg/kg, and VCM and FDX at 1 to 5 mg/kg, 
showing that OPS-2071 has therapeutic effect comparable with or higher than FDX and 
VCM at doses 1/5 to 1/25 times lower than FDX and VCM.  According to the calculation 
of clinical dose, 16 to 100 mg of OPS-2071 is expected to have therapeutic effect 
comparable to or higher than VCM (clinical dose 500 mg) and FDX (clinical dose 
400 mg). 
Based on the above, 100 mg/day, the clinically recommended dose at present from which 
the efficacy can be certainly expected among clinical dose ranging 16 to 100 mg/day is 
selected for the starting dose.  If there are no safety concerns and the efficacy is 
confirmed in the 100 mg group, the safety and efficacy of OPS-2071 will be assessed at 
50 mg/day, the low dose cohort, and at 200 mg/day, 2-fold higher than the clinically 
recommended dose.  If the efficacy at 100 mg/day is not confirmed and there are no 
safety concerns, the safety and efficacy of OPS-2071 will be assessed at up to 
400 mg/day in a sequential ascending manner.  Thus, the trial has a dose 
increase/decrease design. 
This trial is designed for twice-daily administration of OPS-2071, the same as in the 
phase 1 multiple-dose trial, with an interval of at least 10 hours between dosings. 
It is demonstrated that OPS-2071 Cmax is higher by 2.21 times and AUC0–t by 2.04 times 
in administration after taking high fat meal relative to fasting.  Administration after meal 
is desirable for the assessment of safety and PK at higher exposure.  On the other hand, 
patients with severe symptoms of bacterial enteritis may not be able to take meals.  Thus, 
the IMP should be administered after a meal where possible.  However, for PK 
assessment in a steady state, the IMP must be administered after dinner on the day before 
blood sampling and after breakfast on the day of blood sampling to avoid any influence 
on PK assessment. 
 
6.2 
Prior and Concomitant Treatment 
If a drug other than an IMP has been used during the period from the acquisition of 
consent to the end of the trial, the name of the drug, purpose of use, mode of 
administration, daily dose, route of administration, and dates of start and end of 
administration will be recorded in the source documents and case report form (CRF).  For 
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a non-drug therapy, the name of therapy, purpose, and dates of start and end of that 
therapy treatment will be recorded in the source documents and CRF.  For CDI group, if 
a drug or therapy from either item 7 in the list of prohibited concomitant drugs and 
therapies or item 1 in the list of restricted concomitant drugs and foods has been used 
during the period from 7 days before the start of IMP administration to the start day of 
the IMP administration, such will also be recorded in the source documents and CRF. 
To avoid emergent risks such as the need for treatment of an AE, if it is necessary to treat 
a patient with a prohibited concomitant drug or therapy, the patient will be withdrawn 
from this trial according to Section 9.2, Criteria and Procedures for Withdrawal of 
Individual Patients. 
6.2.1 
Prohibited Concomitant Drugs and Therapies 
The use of following drugs and therapies will be prohibited during the period from the 
start day of IMP administration to the end day of the trial for items 1 and 7, from 
screening to the end day of the trial for the following items 2 through 6, and from the 
start day of IMP administration to the end day of IMP administration for item 8. 
1) For enteric infection group only: antibiotic agents/synthetic antibacterial agents 
(oral, injection, suppository) 
2) For enteric infection group only: non-steroidal anti-inflammatory/analgesic 
drugs (oral, injection, suppository)* 
3) For enteric infection group only: corticosteroid preparation (oral, injection, 
suppository) 
4) For enteric infection group only: immunosuppressant medications (oral, 
injection, suppository) 
5) For enteric infection group only: biological preparation (TNF inhibitor) 
6) Antidiarrheal drugs, drugs to inhibit bowel motility 
7) Other drugs and therapies to treat CDI and enteric infection (eg, fecal 
microbiota transplantation) 
8) UGT1A1 inhibitors (atazanavir) 
*:  Use for purposes other than treating enteric infection is allowed.  (Concomitant 
use is allowed for treating common cold during the trial period.) 
6.2.2 
Restricted Concomitant Drugs and Foods 
Restricted concomitant drugs and foods among of drugs listed below, concomitant use of 
drugs listed in 1) in principle are prohibited from the start day of the IMP administration 
to the day of examination at the end of treatment if the drug is used for a purpose other 
than treatment of CDI.   
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However, in cases that drugs are used to treat an underlying disease at the time of 
screening and cannot be discontinued even after the start day of the IMP administration 
due to the necessity for continuous drug treatment, such concomitant use is allowed.  
Drugs listed in items 2) through 5) are allowed to be administered concomitantly as long 
as the drugs are used at the time of screening and the dose regimen is not changed during 
the period from screening until the day of examination at the end of treatment.   
Drugs listed in item 6) are allowed to administer concomitantly under the following 
condition: the drugs are used at the time of screening, and the dose regimen is not 
changed in the period from screening to the end day of trial for CDI groups, or the period 
from screening to the end day of IMP administration for enteric infection group.  If the 
food described in item 6) is taken, instruct the patient not to change the daily amount of 
consumption in the period from screening to the end day of the trial. 
1) For CDI group only: antibiotic agents/synthetic antibacterial agents (oral, 
injection, suppository)  
2) For CDI group only: non-steroidal anti-inflammatory/analgesic drugs (oral, 
injection, suppository)* 
3) For CDI group only: corticosteroid preparation (oral, injection, suppository) 
4) For CDI group only: immunosuppressant medications (oral, injection, 
suppository) 
5) For CDI group only: Biological preparation  (TNF inhibitor) 
6) Probiotics 
*: Use for purposes other than treating CDI is allowed. (Concomitant use is 
allowed for treating common cold during the trial period.) 
 
[Rationale for establishing the prohibited and restricted concomitant drugs and therapies] 
The above defined prohibited and restricted concomitant drugs and therapies were set 
considering the possible impact on the proper assessment of the efficacy and safety of 
IMPs.  Topical use is allowed for 1) to 4) of the prohibited concomitant drugs. 
Since OPS-2071 is metabolized by UGT1A1 and UGT1A9, concomitant use of No. 8) in 
the list of prohibited concomitant drugs may increase the plasma concentration of OPS-
2071.  To secure safety, concomitant use of inhibitors that may increase plasma 
concentrations of OPS-2071 is prohibited. 
 
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6.3 
Method of Minimizing or Avoiding Bias 
If efficacy is confirmed in the 100 mg group and there are no safety concerns, in the next 
step patients in each group (the CDI group and the enteric infection group) will be 
randomized to the 200 mg and 50 mg groups by stratified allocation using country (Japan, 
Korea, or Singapore) as the stratifying variable. 
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7 
Trial Procedures 
7.1 
Schedule and Procedures 
The investigator or subinvestigator will perform observations, examinations, and 
evaluations in accordance with Table 7-1, Schedule of Observations, Examinations, and 
Evaluations. 
Table 7-1 
Schedule of Observations, Examinations, and Evaluations 
 
a  To be performed at the trial site to confirm the eligibility, separately from the test for efficacy and 
safety assessment.  Colonoscopy will be performed when necessary only in the CDI group. 
b  Pregnancy test will be performed only in women with childbearing potential 
Screening
End of
administration
FU1
FU2
Withdrawal
CDI group
-
1
4
10
11
24
38
-
Enteric infection group
-
1
4
7
8
14
-
-
CDI group
Enteric infection group
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X d
X
X c
X
X
X
X
X
X
X
X
X
X d
X
X
X
X
X d
X
X
X
X
X
X e
Pharmacokinetics assessment
Plasma drug concentration
Efficacy assessment of enteric infection group
Bacterial culture test
Drug sensitivity of isolated strain
Clinical response
Confirmation of patient's clinical symptom
Patient diary
Toxin A/B test
Drug sensitivity of isolated strain
Clinical response
Recurrence of CDI
Confirmation of patient's clinical symptom
Patient diary
Vital signs
(blood pressure, pulse rate, body temperature)
12-lead ECG
Adverse events
Concurrent drugs and combination therapies
Efficacy assessment of CDI group
Bacterial culture test
Assignment
Administration
Confirmation of compliance
Safety assessment
Physical examination
Clinical laboratory test
(hematological test, biochemical test, urinalysis)
Patient background
Height/Body weight
Toxin A/B screening, PCR test, or colonoscopy a
Clinical laboratory test
(hematological test, biochemical test, urinalysis) a
Pregnant test b
IMP
+1
±3
±3
+2
Acquisition of informed consent
Inclusion/Exclusion criteria
Administration period
Observation
day
Allowance
range
-2
0
+1
0
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c  To be performed only in the case of withdrawal after the end of administration. 
d  To be performed only in the case of withdrawal during administration period. 
e  Inpatient:  1 (± 15 minutes), 2 (± 15 minutes), and 4 hours (± 30 minutes) after morning 
administration. 
 
Outpatient:  once within 12 hours after morning administration but before evening administration 
 
7.1.1 
Acquisition of Informed Consent 
The investigator or subinvestigator will obtain written consent directly from patients 
before any screening examinations can take place.  After obtaining informed consent, the 
investigator, subinvestigator, or a trial associate will register each patient in either the 
IVRS or the IWRS to assign a patient number.  The patient number (three-digit trial site 
number + S + five-digit sequential serial number at the trial site) and the date of written 
informed consent will be recorded on the source documents and CRF.  The investigator 
or subinvestigator will confirm the content of enrollment, and perform screening 
examination. 
7.1.2 
Screening Examination:  Allowance − 2 Days 
The investigator or subinvestigator will perform the following screening examinations, 
and select patients who meet the inclusion criteria and do not fall under any of the 
exclusion criteria. 
Virus quick test, toxin A/B assay, PCR, colonoscopy, and clinical laboratory tests 
(hematology test, biochemistry test, and urinalysis) will be performed by the method 
specified by the trial site.  Eligibility will be assessed based on the test result at the trial 
site.  The latest data from colonoscopy performed within 48 hours before administration 
of IMP can be used for screening, even if they are obtained before informed consent. 
For bacterial culture test, toxin A/B assay, PCR, and drug sensitivity test on isolated 
strains at screening, stool specimens will be collected within 48 hours before the 
administration of IMP (The latest data performed within 48 hours for CDI group or 24 
hours for Enteric infection group before administration of IMP can be used for screening, 
even if they are obtained before informed consent).  Stool specimens and specimens for 
clinical laboratory tests collected at the screening examination will also be tested by the 
laboratory for microbiological examination (hereafter, microbiological laboratory), and 
the central laboratory for clinical laboratory tests (hereafter, central laboratory). 
• Height, body weight 
• Confirmation of patients’ clinical symptoms (daily stool count, stool symptoms, 
bloody stool, fever, abdominal pain, nausea, and vomiting) 
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• Virus quick test (if considered necessary by the investigator or subinvestigator)* 
• Toxin A/B assay* 
• PCR or colonoscopy:  CDI group only* 
• Collection of stool specimens (the following items will be tested by the 
microbiological laboratory) 
• Bacterial culture test 
• Toxin A/B assay:  CDI group only 
• Drug sensitivity test on isolated strains 
• Physical examination 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis)* 
• hCG pregnancy test 
The pregnancy test will be performed for female patients at the trial site.  A 
pregnancy test will not be required for patients who have undergone bilateral 
oophorectomy or hysterectomy, or have not experienced menses for at least 12 
consecutive months for whatever other medical reasons. 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• 12-lead ECG 
• Confirmation of concomitant drugs and therapies 
*Use the test result at the trial site to assess eligibility at the time of screening. 
7.1.3 
Patient Information 
At the time of obtaining informed consent or at the screening examination, the 
investigator or subinvestigator will check and record the following patient information in 
the source documents and CRF. 
• Disease group (CDI group, enteric infection group) 
• Date of informed consent acquisition 
• Patient number 
• Patient background (sex, date of birth, country where the trial will be conducted, 
race) 
• Inpatient/outpatient (at the time of informed consent) 
• Medical history and concomitant disease 
• Clinical condition of patients (daily stool count, fecal properties, bloody stool, 
fever, abdominal pain, nausea, and vomiting) 
• Diagnostic procedures of CDI (toxin A/B test, PCR, colonoscopy):  CDI group 
only 
• History of CDI:  CDI group only 
• Number of CDI episodes and date of the latest diagnosis of CDI if there is a 
history of CDI 
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7.1.4 
Allocation of Patients to Dosing Groups 
The investigator or subinvestigator will verify that the patient meets the inclusion criteria 
and does not fall under any of the exclusion criteria based on the results of the screening 
examination, and register the information of patients in either the IVRS or the IWRS.  
The investigator or subinvestigator will obtain the allocated dosage information of IMPs 
from IVRS or IWRS and administer the allocated dose of IMPs to patients.  The 
investigator or subinvestigator will record the information on the following dose group to 
the source documents and CRF. 
• Dosage groups (50 mg group, 100 mg group, 200 mg group, and 400 mg group)  
 
7.1.5 
Examination and Evaluation for Clostridium Difficile Infection 
Group 
Collect stool specimens to be used for bacterial culture test, toxin A/B assay, and drug 
sensitivity test on isolated strains within 24 hours before each test. 
7.1.5.1 
Day 1 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
7.1.5.2 
Day 4:  Allowance + 1 Day 
• Collection of stool specimens (the following items will be tested by the 
microbiological laboratory) 
• Bacterial culture test 
• Toxin A/B assay 
• Confirmation of IMP compliance 
• Confirmation of patients’ clinical symptoms on Days 1 to 3 (daily stool count, 
stool symptoms, bloody stool, fever, abdominal pain, nausea, and vomiting) 
• Assessment of clinical response 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis) 
• Blood sampling for measuring plasma concentration 
• Inpatient:  1 (± 15 minutes), 2 (± 15 minutes), and 4 hours (± 30 minutes) after 
morning administration 
• Outpatient:  once within 12 hours after morning administration but before 
evening administration. 
• 12-lead ECG 
• Vital signs (blood pressure, pulse rate, and body temperature) 
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• Physical examination 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
7.1.5.3 
Day 11 (End of Treatment):  Allowance + 1 Day 
• Collection of stool specimens (the following items will be tested by the 
microbiological laboratory) 
• Bacterial culture test 
• Toxin A/B assay 
• Drug sensitivity test on isolated strains 
• Confirmation of IMP compliance 
• Confirmation of patients’ clinical symptoms on Days 4 to 10 (daily stool count, 
stool symptoms, bloody stool, fever, abdominal pain, nausea, and vomiting) 
• Assessment of clinical response 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis) 
• 12-lead ECG 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Physical examination 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
7.1.5.4 
Day 24 (at Follow-up 1):  Allowance ± 3 Days 
• Confirmation of patients’ clinical symptoms on Days 11 to 23 (daily stool count, 
stool symptoms, bloody stool, fever, abdominal pain, nausea, and vomiting) 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis) 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Physical examination 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
7.1.5.5 
Day 38 (at Follow-up 2):  Allowance ± 3 Days 
• Collection of stool specimens (the following items will be tested by the 
microbiological laboratory) 
• Bacterial culture test 
• Toxin A/B assay 
• Drug sensitivity test on isolated strains 
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• Confirmation of patients’ clinical symptoms on Days 24 to 37 (daily stool count, 
stool symptoms, bloody stool, fever, abdominal pain, nausea, and vomiting) 
• Assessment of recurrence of CDI 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis) 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Physical examination 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
7.1.6 
Examination and Evaluation for Enteric Infection Group 
Collect stool specimens for bacterial culture test and drug sensitivity test on isolated 
strains within 24 hours before each test. 
7.1.6.1 
Day 1 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
7.1.6.2 
Day 4:  Allowance + 1 Day 
• Collection of stool specimens (the following items will be tested by the 
microbiological laboratory) 
• Bacterial culture test 
• Confirmation of IMP compliance 
• Confirmation of patients’ clinical symptoms on Days 1 to 3 (daily stool count, 
stool symptoms, bloody stool, fever, abdominal pain, nausea, and vomiting) 
• Assessment of clinical response 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis) 
• Blood sampling for measuring plasma concentration 
• Inpatient:  1 (± 15 minutes), 2 (± 15 minutes), and 4 hours (± 30 minutes) after 
morning administration 
• Outpatient:  once within 12 hours after morning administration but before 
evening administration. 
• 12-lead ECG 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Physical examination 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
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7.1.6.3 
Day 8 (End of Treatment):  Allowance + 1 Day 
• Collection of stool specimens (the following items will be tested by the 
microbiological laboratory) 
• Bacterial culture test 
• Drug sensitivity test on isolated strains 
• Confirmation of IMP compliance 
• Confirmation of patients’ clinical symptoms on Days 4 to 7 (daily stool count, 
stool symptoms, bloody stool, fever, abdominal pain, nausea, and vomiting) 
• Assessment of clinical response 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis) 
• 12-lead ECG 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Physical examination 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
7.1.6.4 
Day 14 (at Follow-up 1):  Allowance ± 3 Days 
• Confirmation of patients’ clinical symptoms on Days 8 to 13 (daily stool count, 
stool symptoms, bloody stool, fever, abdominal pain, nausea, and vomiting) 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis) 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Physical examination 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
7.1.7 
Time of Withdrawal and Withdrawal Examination:  Allowance ± 2 
Days 
The investigator or subinvestigator will perform the following examination, observation, 
and assessments for patients who withdrew from the trial within 2 days after the day 
when withdrawal is considered necessary.  If the patient refuses to undergo any 
examinations at the time of withdrawal, or if the investigator or subinvestigator judges 
that any examinations at the time of withdrawal cannot be performed due to an 
emergency or other circumstances (eg, SAE or recurrence of CDI), of the examination 
items specified for the time of withdrawal, only those items that can be performed will be 
performed.  Results of tests and assessment, the date of measurements and assessment, 
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and the date of blood/urine/stool sampling will be recorded in the source records and 
CRF. 
7.1.7.1 
Clostridium Difficile Infection Group 
• Collection of stool specimens (the following items will be tested by the 
microbiological laboratory) 
• Bacterial culture test 
• Toxin A/B assay 
• Confirmation of IMP compliance until withdrawal 
• Confirmation of patients’ clinical symptoms until withdrawal (daily stool count, 
stool symptoms, bloody stool, fever, abdominal pain, nausea, and vomiting) 
• Assessment of clinical response:  to be performed only in case of withdrawal 
during the IMP administration period 
• Assessment of recurrence of CDI:  to be performed only in case of withdrawal 
after completing the IMP administration 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis) 
• 12-lead ECG:  to be performed only in case of withdrawal during the IMP 
administration period 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Physical examination 
• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
7.1.7.2 
Enteric Infection Group 
• Collection of stool specimens (the following items will be tested by the 
microbiological laboratory) 
• Bacterial culture test:  to be performed only in case of withdrawal during the 
IMP administration period 
• Confirmation of IMP compliance until withdrawal 
• Confirmation of patients’ clinical symptoms until withdrawal (daily stool count, 
stool symptoms, bloody stool, fever, abdominal pain, nausea, and vomiting) 
• Assessment of clinical response:  to be performed only in case of withdrawal 
during the IMP administration period 
• Clinical laboratory tests (hematology test, biochemistry test, and urinalysis) 
• 12-lead ECG:  to be performed only in case of withdrawal during the IMP 
administration period 
• Vital signs (blood pressure, pulse rate, and body temperature) 
• Physical examination 
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• Confirmation of adverse events 
• Confirmation of concomitant drugs and therapies 
 
7.1.8 
Information at Conclusion (Discontinuation) of the Trial 
The investigator or subinvestigator will register the necessary items in IVRS or IWRS at 
the time of conclusion (discontinuation) of the trial for each patient. 
7.1.9 
Follow-up Investigation 
If an AE has not resolved by FU1, FU2, or withdrawal, additional examinations of the 
AE will be performed in accordance with Section 8.4, Follow-up Investigation of 
Adverse Events. 
7.2 
Method of Evaluation 
7.2.1 
Safety Evaluation 
7.2.1.1 
Height, Body Weight 
Measure height and body weight according to the procedures stipulated by the trial site, 
and record the date of measurements and results in the source documents and CRF. 
7.2.1.2 
Physical Examination 
The investigator or subinvestigator will examine the patients, record the physical findings 
in source documents, and evaluate any clinically significant events as AEs, and record the 
AEs in CRF.  In case if abnormal findings are not judged as AEs, enter the reason in 
source documents. 
7.2.1.3 
Clinical Laboratory Tests (Hematology Test, Biochemistry Test, 
and Urinalysis) 
At screening, the following clinical laboratory test items will be measured at each trial 
site according to the procedures stipulated by each trial site.  Record the date and result of 
examination in source documents, not in CRF. 
The sample collected at the screening examination will be dispensed in two containers 
and tested by the trial site and central laboratory. 
The central laboratory will determine the following clinical laboratory test items at all the 
prescheduled time points (including screening examination).  Use the container provided 
by the central laboratory when sampling.  The investigator or subinvestigator will record 
the sampling date in the source documents and CRF, and review the report on clinical 
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laboratory tests performed by the central laboratory, date, and sign the report.  In case if 
abnormal values are not judged as AEs, enter the reason in source documents. 
Follow the separately stipulated procedures for collection, handling, storage, and 
shipment method of specimens. 
Table 7.2-1 
Clinical Laboratory Test Items 
Hematology test 
Hemoglobin (Hb), hematocrit (Hct), red blood cell count (RBC), white blood 
cell count (WBC), differential leukocyte count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes), platelets (PLT), mean corpuscular 
volume (MCV), mean corpuscular hemoglobin (MCH), mean 
corpuscular hemoglobin concentration (MCHC) 
Biochemistry test 
Aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine 
aminotransferase (ALT), total protein (TP), albumin (ALB), total bilirubin 
(T-BIL), uric acid (UA), urea nitrogen (UN), creatinine (Cr), serum glucose 
(GLU), triglyceride (TG), cholesterol (TC), γ-glutamyltransferase (γ-GTP), 
Na, K, Cl, Ca, C-reactive protein (CRP) 
Urinalysis 
pH, protein, glucose, ketone, bilirubin, urobilinogen, blood, nitrite, 
leucocytes, and specific gravity 
 
7.2.1.4 
Vital Signs (Blood Pressure, Pulse Rate, and Body 
Temperature) 
Systolic and diastolic blood pressures, pulse rate, and body temperature will be measured 
at rest according to the procedures specified by the trial site, and the date of evaluation 
and the result will be recorded in the source documents and CRF.  In case if abnormal 
values are not judged as AEs, enter the reason in source documents. 
7.2.1.5 
12-Lead Electrocardiogram 
Measure 12-lead ECG parameters according to the procedures of the trial site with paper 
feed speed at 25 mm/sec. 
The investigator or subinvestigator will record the date of measurement and 
presence/absence of abnormality in the source documents and CRF.  In case if abnormal 
findings are not judged as AEs, enter the reason in source documents. 
The sponsor will retrieve copies of all the ECG charts. 
7.2.1.6 
Confirmation of Investigational Medicinal Product Compliance 
Status and Food 
The investigator or subinvestigator will distribute patient diary to have them record the 
information on the compliance with IMP and food intake during the administration period.  
Based on the information recorded in the patient diary, the investigator or subinvestigator 
will record in the CRF the patient’s IMP compliance during the administration period, 
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whether or not the IMP was taken after meals, and the time of day that the IMP was taken 
on the day of blood sampling for PK assessment. 
7.2.2 
Efficacy Evaluation 
7.2.2.1 
Microbiological Outcome 
1) Timing 
CDI group:  screening, Day 4, Day 11 (end of treatment), at FU2 (Day 38), at the time of 
withdrawal 
Enteric infection group:  screening, Day 4, Day 8 (end of treatment), at the time of 
withdrawal 
2) Method of Examination 
Collect approximately 3 g of stool from the patient using the stool sample container 
provided by the microbiological laboratory.  The containers will be labeled with the study 
number, patient number, and sampling day.  Collect stool specimens within 48 hours 
prior to IMP administration for the screening time point and within 24 hours before the 
observation day for other time points.  Store stool samples at approximately 4°C until a 
designated courier collects them. 
The microbiological laboratory will follow the predetermined procedures and perform the 
culture and identification by centralized measurement.  The isolated strains will be stored 
in order to enable exploratory investigation in the future on the bacteriological and 
genetic characteristics other than drug sensitivity of the isolated strains. 
If the result of measurement requires notification in line with the Infectious Diseases 
Control Law, each trial site will submit notification in accordance with relevant laws, 
regulations, and notifications of each country. 
3) Method of Evaluation 
The investigator or subinvestigator will identify the causative pathogen on the basis of 
the microbiological examination results from the microbiological laboratory and record 
sampling date, the causative pathogen, and pathogen culture results in source documents 
and CRF.  If there is more than one possible causative pathogen, identify all causative 
pathogens and record the pathogen culture results by causative pathogen in source 
documents and CRF.  The sponsor will collect the microbiological examination results 
from the microbiological laboratory and judge microbiological outcome by bacterial 
strain isolated as the causative pathogen based on the change in microbiological 
examination results according to the assessment criteria shown in Table 3.3-1 and Table 
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3.3-2.  For infection due to multiple causative pathogens, microbiological outcome will 
be assessed for each individual pathogen. 
7.2.2.2 
Toxin A/B Assay 
1) Timing 
CDI group:  screening, Day 4, Day 11 (end of treatment), at FU2 (Day 38), at the time of 
withdrawal 
2) Method of Examination 
At screening, perform toxin A/B assay according to the procedures specified by the trial 
site for assessing eligibility on the basis of the test result at the trial site (when PCR and 
colonoscopy were performed, toxin A/B assay at the trial site is not indispensable).  
Record the sampling date and the test result in source documents. 
At all scheduled time points, including screening, toxin A/B assay will be centrally 
performed by the microbiological laboratory using the stool specimens for the assessment 
of microbiological outcome.  The microbiological laboratory will perform toxin A/B 
assay and report the result to the investigator or subinvestigator.  (Note:  For the enteric 
infection group, in order to assess patient eligibility, the toxin A/B assay or PCR at 
screening is also to be performed at the trial site according to the procedure specified by 
the trial site.  Record the sampling date and the test result in source documents.) 
3) Method of Evaluation 
The investigator or subinvestigator will record the sampling date in source documents 
and CRF.  The sponsor will collect the toxin A/B assay result only of the CDI group 
tested at the microbiological laboratory.  Use the result of toxin A/B assay from the 
microbiological laboratory. 
7.2.2.3 
Clinical Response 
1) Timing 
CDI group:  Day 4, Day 11 (end of treatment), at the time of withdrawal 
Enteric infection group:  Day 4, Day 8 (end of treatment), at the time of withdrawal 
2) Method of Evaluation 
The investigator or subinvestigator will refer to the information from patients (eg, patient 
diary), and assess clinical response at the time of observation (Day 4 and end of 
treatment) according to the assessment criteria shown in Table 3.3-3.  The investigator or 
subinvestigator will record the assessment date and result in source documents and CRF. 
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7.2.2.4 
Recurrence of Clostridium Difficile Infection (Clostridium 
Difficile Infection Group Only) 
1) Timing 
CDI group:  at FU2 (Day 38), at the time of withdrawal 
2) Method of Confirmation 
The investigator or subinvestigator will assess the recurrence of CDI at FU2 or 
withdrawal according to the assessment criteria shown in Table 3.3-3 for patients who 
achieved “clinical cure” at the end of treatment.  The investigator or subinvestigator will 
record the assessment date and result in source documents and CRF. 
7.2.2.5 
Time to Resolution of Diarrhea 
The sponsor will evaluate the time from the start of dosing until the first formed stool 
(except in cases where liquid or unformed stools recur), as the time to resolution of 
diarrhea on the basis of the record of fecal properties in CRF obtained according to the 
procedure of 7.2.2.6. 
7.2.2.6 
Improvement of Clinical Symptoms 
1) Timing 
CDI group:  Day 4, Day 11 (end of treatment), at FU2 (Day 38), at the time of 
withdrawal 
Enteric infection group:  Day 4, Day 8 (end of treatment), at the time of withdrawal 
2) Method 
Distribute patient diary to patients and have the patients to record daily stool count, fecal 
properties, presence/absence of bloody stool, highest body temperature, and 
presence/absence of abdominal pain, nausea, and vomiting.  If the patient is not able to 
record the information in the patient diary on his/her own, medical personnel or the 
patient's family will record the information in the diary on behalf of the patient. 
3) Method of Evaluation 
The investigator or subinvestigator will record the information on the patient diary in 
CRF.  The sponsor will evaluate the change in improvement of clinical symptoms by 
comparing the record of daily stool count, fecal properties, bloody stool, fever, abdominal 
pain, nausea, and vomiting described in CRF with those at pre-treatment. 
7.2.2.7 
Drug Sensitivity of Isolated Strain 
1) Timing 
CDI group:  screening, Day 11 (end of treatment), FU2 (Day 38) 
Enteric infection group:  screening, Day 8 (end of treatment) 
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2) Method of Examination 
The microbiological laboratory will determine the MIC of OPS-2071 for the 
isolated/identified C. difficile or the strain identified as the causative pathogen of enteric 
infection.  On the basis of the procedures specified by the microbiological laboratory, 
assess drug sensitivity. 
3) Method of Evaluation 
The investigator or subinvestigator will record the sampling date in the source documents 
and CRF.  The sponsor will collect the result of drug sensitivity test on isolated strains 
determined in the microbiological laboratory. 
7.2.3 
Pharmacokinetic Evaluation 
7.2.3.1 
Plasma Pharmacokinetics 
1) Timing 
Inpatient:  1 (± 15 minutes), 2 (± 15 minutes), and 4 (± 30 minutes) hours after morning 
administration on Day 4 
Outpatient:  Once within 12 hours after morning administration but before evening 
administration on Day 4 
2) Method 
A volume of approximately 5 mL whole blood will be collected into a lithium heparin-
containing blood collection tube.  Samples will be immediately placed on crushed ice and 
centrifuged (2000 g for 15 minutes at 4°C) within 1 hour of collection to obtain plasma.  
Two aliquots of 700 µL plasma will be transferred to two polypropylene tubes and stored 
approximately at −80°C.  The plasma samples will be labeled with the following 
information:  study number, patient number, sampling day and time point, and aliquot 
type (primary or back-up). 
Record sampling day and time point, and date and time of latest medication in the source 
documents and CRF. 
3) Shipment of Samples 
Samples will be shipped on dry ice by a designated courier to laboratory performing 
measurement of drug concentrations (hereafter, bioanalytical laboratory).  Back-up 
samples will be separately sent to the bioanalytical laboratory. 
4) Method of Determination 
Plasma concentrations of OPS-2071 will be determined using a validated liquid 
chromatography–tandem mass spectrometry (LC-MS/MS) method by the bioanalytical 
laboratory. 
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The bioanalytical laboratory will submit a report on the result of drug concentration 
measurements to the sponsor.  The report submitted to the sponsor is considered as the 
source documents.  Record in the CRF will not be required.  Remaining samples after 
measurement of drug concentrations will be stored approximately at −80°C in the 
bioanalytical laboratory until the completion of clinical study report.  After the 
completion of clinical study report, the bioanalytical laboratory will promptly discard the 
remaining samples and record it. 
7.3 
Measures to Be Taken for Patients Visiting or Planning to Visit 
Other Hospitals or Departments 
At the time of obtaining informed consent, the investigator or subinvestigator will 
confirm whether or not the patient is receiving treatment at another hospital or 
department.  If the patient is receiving treatment at another hospital or department, the 
investigator or subinvestigator will inform the attending physician of that hospital or 
department about the patient’s participation in the clinical trial and the IMP being used, 
with the patient’s consent.  The investigator or subinvestigator will also obtain and record 
in source documents and the CRF information on the treatment that the patient is 
receiving at the other hospital or department (name of disease being treated and 
information on the type of treatment or measures being implemented) and judge whether 
or not the patient should participate in the trial. 
If a patient visits another hospital or department during the trial period, the investigator or 
subinvestigator will inform the attending physician of that hospital or department about 
the patient’s participation in the clinical trial and the IMP being used, with the patient’s 
consent.  The investigator or subinvestigator will also obtain and record in source 
documents and the CRF information on the treatment that the patient receives at the other 
hospital or department (name of disease treated and information on the type of treatment 
or measures implemented) and judge whether or not the patient should continue to 
participate in the trial. 
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8 
Adverse Events 
8.1 
Definitions 
8.1.1 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use 
of an IMP, whether or not considered related to the IMPnotes) 
For this trial, OPS-2071 is regarded as the IMP, and to secure the safety of patients, AEs 
occurring from the time of signing the ICF to the start of OPS-2071 administration are 
included in the definition of AEs in addition to the definition given by ICH. 
If an event, symptom, or sign existing at the time of acquisition of informed consent 
worsens after acquisition of informed consent, or if an AE occurring between the 
acquisition of informed consent and start of OPS-2071 administration worsens after 
administration of OPS-2071, the exacerbation will be treated as a new AE. 
8.1.2 
Serious Adverse Event 
An SAE is defined as an AE corresponding to one of the events listed in the following list. 
The seriousness of AEs occurring during the period from consent to the start of IMP 
administration will also be judged. 
1. An event resulting in death 
2. A life-threatening event 
The term “life-threatening” refers to an event in which the patient was at a risk of 
death at the time of the event.  It does not refer to an event which hypothetically 
might have caused death, had it been more severe. 
3. An event requiring in-patient hospitalization or prolongation of existing 
hospitalization for treatment 
                                                 
notes) "Clinical Safety Data Management: Definitions and Standards for Expedited Reporting" 
Notification No.227 of the Examination Division, issued by the Examination Division Chief, the 
Pharmaceutical Affairs Bureau as of 20 Mar 1995 (ICH E2A)  
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E
2A_Guideline.pdf 
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4. An event resulting in persistent or significant disability/incapacity 
5. An event causing a congenital anomaly/birth defect 
6. A major event resulting in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization, but which 
may jeopardize the patient or may require intervention to prevent one of the other 
outcomes listed in 1) to 5) above.  Examples of such events are intensive treatment in 
an emergency room for bronchospasm, blood dyscrasias or convulsions that do not 
result in hospitalization; or development of drug dependency or drug abuse. 
 
Explanation of hospitalization for treatment of an SAE: 
Hospitalization for treatment means that the patient must be hospitalized at a medical 
institution for treatment of an AE, typically for at least one night.  This includes 
hospitalization for treatment of the AE in which no particular medical procedures are 
carried out (rest therapy).  However, it does not include hospitalization for undergoing 
tests or treatment for an underlying disease or complication that has not worsened since 
the patient’s entry into the trial, hospitalization for social reasons or convenience not 
intended for treatment of the AE, or hospitalization for treatment or tests scheduled prior 
to participation in the trial. 
8.2 
Response to Occurrence of Adverse Events 
8.2.1 
Actions to Be Taken for Patients 
The investigator or subinvestigator will provide adequate medical care for all clinically 
significant, trial-related AEs throughout the period of patient participation in the trial as 
well as thereafter.  If treatment for an AE is necessary, the patient will be informed of this. 
8.2.2 
Expedited Reporting of Serious Adverse Events 
(1) Serious Adverse Events Requiring Expedited Reporting 
1) Any SAEs occurring during the trial period regardless of causal relationship 
with the IMP 
2) SAEs occurring during the follow-up period (see Section 8.4, Follow-up 
Investigation of Adverse Events), if a follow-up investigation is performed, for 
which a causal relationship with the IMP cannot be ruled out, or AEs that 
become serious during the follow-up period for which a causal relationship with 
the IMP cannot be ruled out 
3) Among SAEs occurring after completion of the trial (after the follow-up 
investigation, if a follow-up investigation is performed) and reported by patients 
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to the investigator or subinvestigator, those for which the investigator or 
subinvestigator cannot rule out a causal relationship with the IMP 
(2) Procedures for Expedited Reporting 
Countries/Regions other than Japan: 
1) When an AE falling under any of the above items (1) 1) to 3) occurs, the 
investigator or subinvestigator will notify the sponsor promptly after becoming 
aware of the event (within 24 hours, in principle) orally or by telephone, e-mail, 
or facsimile (refer to Annex, Emergency Contact). 
The notification to the sponsor must include at least the following information. 
Patient’s date of birth, sex, starting date of IMP, information of AE, causal 
relationship with the IMP 
2) The investigator or subinvestigator will then promptly submit a detailed report 
on any SAEs occurring after the start of IMP administration to the head of the 
trial site and the sponsor within the period specified by the applicable regional 
requirements after becoming aware of them using the report form of the trial 
site or sponsor.  Any additional information will also be promptly relayed to the 
sponsor (within 24 hours) by e-mail or facsimile, and additional reporting will 
be performed if necessary. 
3) When the investigator or subinvestigator is requested by the sponsor, the head 
of the trial site, or the IRB to prepare additional information (autopsy report, 
terminal care report, or other required information) on a reported SAE, the 
investigator or subinvestigator will respond to the request. 
Japan: 
1) When an AE falling under any of the above items (1) 1) to 3) occurs, the 
investigator or subinvestigator will notify the sponsor promptly after becoming 
aware of the event (within 24 hours, in principle) orally or by telephone, e-mail, 
or facsimile (refer to Annex, Emergency Contact). 
The notification to the sponsor must include at least the following information. 
Patient’s date of birth, sex, starting date of IMP, information of AE, causal 
relationship with the IMP 
2) The investigator or subinvestigator will then promptly submit a detailed report 
on any SAEs occurring after the start of IMP administration to the head of the 
trial site and the sponsor within 10 days after becoming aware of them using the 
report form of the trial site or sponsor.  Any additional information will also be 
promptly relayed to the sponsor (within 24 hours) by telephone, e-mail, or 
facsimile, and additional reporting will be performed if necessary. 
3) When the investigator or subinvestigator is requested by the sponsor, the head 
of the trial site, or the IRB to prepare additional information (autopsy report, 
terminal care report, or other required information) on a reported SAE, the 
investigator or subinvestigator will respond to the request. 
 
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8.2.3 
Expedited Reporting of Non-serious Adverse Events Resulting in 
Discontinuation of Investigational Medicinal Product 
Administration 
When a non-serious AE occurs and the investigator or subinvestigator judges that IMP 
administration should be discontinued, the investigator or subinvestigator will notify the 
sponsor within 3 working days in principle after their judgment by telephone, e-mail or 
facsimile (refer to Annex, Emergency Contact). 
8.3 
Assessment of Adverse Events 
The investigator or subinvestigator will assess AEs for the following items. 
8.3.1 
Terms for Adverse Events 
If the disease responsible for an AE can be specified, the name of the diagnosed disease 
will be recorded and not the individual symptoms. 
8.3.2 
Date and Onset and Recovery 
(1) Date of onset: 
The date of onset of an AE or date of confirmation of an AE will be recorded in the 
source documents and CRF.  If an event, symptom, or sign existing at the time of 
acquisition of informed consent worsens, “the date of exacerbation” will be recorded as 
“date of onset of AE.”  Also, if an AE occurring between the acquisition of informed 
consent and start of IMP administration worsens after administration of the IMP, the 
exacerbation will be recorded as a new AE with “the date of exacerbation” recorded as 
“date of onset of exacerbated AE.” 
(2) Date of recovery: 
The date of recovery of an AE or date of confirmation of recovery of an AE will be 
recorded. 
8.3.3 
Severity 
Severity of AEs will be classified into the following three categories. 
1) Mild:  Discomfort noticed, but no disruption to daily activity 
2) Moderate:  Discomfort sufficient to limit or affect normal daily activity 
3) Severe:  Inability to work or perform normal daily activity 
 
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8.3.4 
Causal Relationship With Investigational Medicinal Product 
The causal relationship between the IMP and AEs occurring after the start of IMP 
administration will be judged according to the following two categories. 
1) Relationship is ruled out 
For reasons such as the following, the possibility of a relationship between occurrence of 
an AE and OPS-2071 is not reasonably conceivable. 
a) The event can be assumed to be caused by an underlying disease, 
complication(s) (a current condition(s) if the trial patient is a healthy adult 
patient), or previous disease(s). 
b) The event can be assumed to be associated with age, sex, or some other 
demographic factor. 
c) A temporal relationship between IMP administration and occurrence of the 
AE is unlikely. 
Example:  An AE that occurs after a considerable lapse of time from the 
conclusion of IMP administration. 
d) Considering the time course of the AE and IMP administration, a relationship 
with the IMP is unlikely. 
Example:  Despite continuous administration of the IMP, the AE disappeared 
spontaneously without any treatment (except cases in which it is judged that 
the patient became habituated to the IMP during continued administration). 
e) The event can be assumed to be caused by some other drug besides the IMP 
f) The event can be assumed to be incidental (such as an accident or incidental 
disease). 
Example:  “femoral bone fracture” occurring in a traffic accident. 
g) A relationship with the IMP can be ruled out for other reasons based on 
medical consideration. 
2) Relationship cannot be ruled out 
For reasons such as the following, the possibility of a relationship between 
occurrence of an AE and the IMP is reasonably conceivable. 
a) A relationship is predictable from the pharmacological and toxicological 
effects of the IMP. 
Examples:  Occurrence of “pancytopenia” when effects on the hematopoietic 
system have been observed in non-clinical studies, or the occurrence of 
“dehydration” when the drug has a diuretic effect. 
b) The event has been observed in previous nonclinical trials and/or clinical trials. 
Example:  An AE with high incidences in phase 1 trials. 
c) A temporal relationship is suspected between IMP administration and onset of 
the AE. 
Example:  “Allergic dermatitis” occurring several days after the start of IMP 
administration. 
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d) A relationship is suspected based on the outcome of an adverse event after 
discontinuation or dose reduction of the IMP. 
Example:  Prompt disappearance of “nausea” after discontinuation of the IMP. 
e) A relationship with the IMP cannot be ruled out for other reasons based on 
medical consideration. 
 
8.3.5 
Actions to Be Taken Regarding Investigational Medicinal Product 
Administration 
Actions to be taken regarding IMP administration following the occurrence of an AE 
after initiation of IMP administration will be selected from among the following. 
• No change 
• Discontinuation of IMP administration 
• Unknown 
• Not applicable 
 
8.3.6 
Actions to Be Taken for Adverse Events 
The performance of medical treatments (medications and/or other treatments) for AEs 
and details of the treatments will be entered in the source documents and CRF. 
8.3.7 
Outcome 
The outcome of an AE will be selected from the following six categories (one only). 
If the patient died, the date of death will be recorded in the CRF; if the patient’s condition 
was recovering/resolving, not recovered/not resolved, or unknown, the date of outcome 
confirmation will be recorded in the CRF. 
• Recovered/resolved 
• Recovering/resolving 
• Not recovered/not resolved 
• Recovered/resolved with sequelae 
• Fatal 
• Unknown (for some reason, a follow-up investigation could not be performed even 
once) 
 
8.4 
Follow-up Investigation of Adverse Events 
The term “recovered” used below means that a patient who had an AE prior to the start of 
IMP administration returned to his or her original condition, or a patient who had an AE 
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after the start of IMP administration returned to his or her condition before the start of 
IMP administration. 
1) If an AE has not resolved by the day of trial completion or the day of 
withdrawal, the investigator or subinvestigator will explain to the patient the 
need for follow-up investigation after the end of the trial and will request the 
patient’s cooperation.  The investigator or subinvestigator will conduct a 
follow-up investigation within 4 weeks after the end of the trial and record 
information regarding the AE in the source documents.  If an AE is not resolved 
by the day of trial completion or the day of withdrawal, the investigator or 
subinvestigator will record the outcome in CRF as “recovering/resolving,” “not 
recovered/not resolved,” or as otherwise appropriate. 
2) If an AE has not resolved by the day of the follow-up investigation and a causal 
relationship with the IMP cannot be ruled out, follow-up investigation will be 
continued until the event resolves or becomes stable and information regarding 
the AE will be recorded in the patient’s source documents.  If a causal 
relationship between the AE and the IMP can be ruled out, no further follow-up 
will be made beyond the day of the initial follow-up investigation. 
3) If, between the day of trial completion or day of withdrawal and the day of the 
follow-up investigation, a new SAE for which a causal relationship with the 
IMP cannot be ruled out occurs, or if an AE is not resolved by the day of trial 
completion or the day of withdrawal and for which a causal relationship with 
the IMP cannot be ruled out becomes serious, follow-up investigation will be 
conducted until the AE resolves or becomes stable, and information regarding 
the AE will be recorded in the source documents. 
4) If a serious AE for which a relationship with the IMP cannot be ruled out is 
discovered after the day of trial completion or the day of withdrawal, or after 
the day of the initial follow-up investigation (if performed), follow-up 
investigation will be conducted until the AE resolves or becomes stable or until 
follow-up of the patient becomes impossible and information regarding the AE 
will be recorded in the source documents. 
 
8.5 
Pregnancy 
If women of childbearing potential or male patients whose partners are capable of 
becoming pregnant participate in the trial, the investigator or subinvestigator will attend 
to the following. 
• Information on reproductive and developmental toxicity of the IMP 
• Drug interactions between the IMP and hormonal contraceptives 
• Information regarding pregnancy in the ICF 
• Explanation of contraceptive methods 
• Reporting and follow-up of cases of pregnancy 
 
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8.5.1 
Guidance to Patients Including Contraceptive Methods 
1) Before the start of the trial, the investigator or subinvestigator will explain to 
the patients the importance of using contraception and the risks associated with 
pregnancy of a female patient or partner of a male patient and, after patients 
have read the written information for patients and understood it, the investigator 
or subinvestigator will have patients sign the ICF. 
2) If women of childbearing potential or male patients whose partners are capable 
of becoming pregnant wish to participate in the trial, the investigator or 
subinvestigator will instruct them to practice contraception during the period 
specified in the trial protocol. 
3) Contraceptive methods must be highly effective, ie, have a failure rate of less 
than 1%.  Contraceptive methods include condoms, pills, pessaries, intrauteric 
device (IUD), implantable contraceptive devices, spermicide, vasectomy, and 
tubal ligation.  However, if a female patient or male patient’s partner is without 
question unable to become pregnant (ie, has undergone bilateral ovariectomy or 
hysterectomy or has not experienced menses for at least 12 consecutive months 
for whatever other medical reasons, or the male patient/partner has undergone 
bilateral orchidectomy), or if the patient and his/her partner remain abstinent, 
use of contraception is unnecessary. 
4) The investigator or subinvestigator will instruct the patients that if the 
contraceptive measures fail and evidence of pregnancy of the female patient or 
male patient’s partner such as delay in menstruation is observed, this should be 
promptly reported to the investigator or subinvestigator. 
 
8.5.2 
Actions to Be Taken by the Investigator or Subinvestigator When 
Pregnancy Is Suspected 
If the investigator or subinvestigator or a patient suspects that the patient has become 
pregnant before initiation of IMP administration, initiation of IMP administration will be 
withheld and a pregnancy test will be performed.  If the test result is positive, the trial 
patient will be withdrawn without receiving IMP administration.  If a pregnancy is 
suspected after initiation of IMP administration, IMP administration will be discontinued 
(refer to section 9.2 Criteria and Procedures for Withdrawal of Individual Patients). 
8.5.3 
Actions to Be Taken by the Investigator or Subinvestigator When 
a Patient Is Discovered to Be Pregnant 
When a female patient is found to be pregnant, the investigator or subinvestigator will 
withdraw the patient from the trial and perform follow-up investigation until delivery or 
end of pregnancy, and report this in writing to the sponsor. 
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After discontinuation of IMP administration, the investigator or subinvestigator will 
perform the withdrawal examinations and follow-up observation stipulated in the 
protocol, in so far as they do not affect the pregnancy. 
8.5.4 
Expedited Reporting of Pregnancy 
When a female patient or a partner of a male patient is found to be pregnant during the 
trial, the investigator or subinvestigator will promptly report this to the sponsor orally or 
by telephone or e-mail (refer to Annex, Emergency Contact).  The investigator or 
subinvestigator will then provide any additional information requested by the sponsor. 
8.5.5 
Follow-up Investigation of Pregnancy 
If a female patient becomes pregnant, the investigator or subinvestigator will perform 
follow-up investigation of the pregnancy up to delivery or the end of pregnancy and 
report the results of follow-up in writing to the sponsor.  When a patient or patient’s 
partner has delivered, it is best that the neonate be observed for at least 6 months after 
delivery. 
 
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9 
Withdrawal of Individual Patients From the Trial 
Any patient may discontinue participation in the trial at any time without medical 
disadvantage.  The investigator or subinvestigator may withdraw a patient from the trial 
at any time if it is considered necessary for medical treatment of that patient. 
9.1 
Screen Failure 
If a patient is a screen failure, the following information should be recorded in the source 
documents and CRF: 
date of investigation (the start date of the screening examination), date of informed 
consent acquisition, date of birth, sex, country where the trial was conducted, race, and 
reason for screen failure. 
9.2 
Criteria and Procedures for Withdrawal of Individual Patients 
In any of the events listed below, the investigator or subinvestigator will discontinue IMP 
administration, perform the tests to be performed at withdrawal stipulated in Section 7.1, 
Schedule and Procedures of the Trial, and promptly inform the sponsor of the withdrawal 
(Annex, Emergency Contact).  The investigator or subinvestigator will record the date 
and reason for withdrawal in the source documents and CRF. 
If withdrawal is necessitated by problems with safety, such as the occurrence of an AE or 
aggravation of the underlying disease, the investigator or subinvestigator will promptly 
take appropriate measures and perform follow-up if necessary (refer to Section 8.4 
Follow-up Investigation of Adverse Events). 
1. If the patient wishes to withdraw 
2. If it is found after the start of the trial that the patient did not meet all the 
inclusion criteria or fell under any of the exclusion criteria 
3. If a drug or therapy from either item 1 or item 7 in the list of prohibited 
concomitant drugs and therapies is used or judged to be required 
4. If an AE making continuation of trial participation difficult occurs 
5. If the female patient is found to be pregnant 
6. If symptoms of the primary disease exacerbate, and the investigator or 
subinvestigator judges that it is not appropriate to continue the trial participation 
7. If it becomes impossible to comply with the protocol for any another reason or if 
the investigator or subinvestigator judges that it is necessary to discontinue the 
trial participation for any another reason 
 
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9.3 
Follow-up Investigation of Patients Who Do not Visit the Trial Site 
When a patient stops visiting the trial site for unknown reasons, the investigator or 
subinvestigator will promptly contact the patient or patient’s family by phone or other 
means to check for AEs and to ask the patient to visit. 
1) When the patient has visited 
A withdrawal examination will be performed (see Section 7.1.7). 
2) When the patient has not visited 
The following items will be recorded in the source documents. 
• The date of investigation 
• The method of investigation 
• Whether or not the patient was contacted 
• The reason why the patient does not (or cannot) visit the trial site 
• Occurrence or non-occurrence of AEs.  If an AE has occurred, record name of the 
event, date of onset and of recovery, severity, relationship to the IMP, measures 
taken regarding IMP administration, and treatment of AE, outcome. 
• If follow-up investigation is impossible, record the reason why. 
 
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10 
Collection of Case Report Form Data and Specification of 
Source Data 
10.1 
Collection of Case Report Form Data 
1) Electronic Data Capture (EDC) will be used in the trial. 
2) Patient data will be entered directly into the database from the trial site via a 
Web browser.  These data collected by EDC will constitute the CRF.  The 
results of clinical laboratory tests, microbiological examination, toxin A/B test, 
drug sensitivity test, and drug concentration measurement with centralized 
measurement will be directly transferred from respective laboratories to the 
sponsor. 
3) For every patient who provides consent to participate in the trial, a CRF will be 
created on an EDC data entry screen that conforms to the items of CRF data 
collection described in the trial protocol. 
4) The investigator, subinvestigator, or trial associate will entry the data according 
to the manual provided by the sponsor.  If source documents are available and 
the objectivity of the data can be ensured, then the data may be recorded in a 
CRF by a trial associate. 
5) When entering data into CRFs from the trial site, a predetermined check will be 
automatically performed.  The investigator, subinvestigator, or a trial associate 
will make corrections as necessary. 
6) The sponsor will verify CRFs in comparison to source documents and conduct 
data reviews.  If additional query is necessary, the sponsor will issue an intra-
system query and the investigator, subinvestigator, or a trial associate will 
perform data correction or provide a response to the sponsor’s query as 
necessary. 
7) A history of all revisions made after the initial data entry is saved on the server 
will be automatically recorded within the system (date and time of revision, 
name of person making revision, pre- and post-revision data, reason for revision, 
date and time of query, name of person issuing query, details of query, etc). 
8) After completion of all CRF data entry and confirmation that the content is 
correct and complete, including confirmation of the audit trail, the investigator 
will attach an electronic signature. 
9) Details concerning data collection will be specified in a separate manual 
prepared in advance. 
 
10.2 
Source Documents 
1) Source documents are defined as those documents that are the source of data 
transcribed into CRFs as trial results. 
Medical records and other records (eg, medical records, nursing records, 
prescription records), patient diary, registration verification forms, patient 
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screening list, ICFs, clinical laboratory test and other measurement reports, ECG 
charts, IMP management records, and other documents 
2) The investigator or the trial site will retain all trial-related documents and 
records except CRFs in such a manner that enables the sponsor or the regulatory 
authority to have direct access to the documents and records. 
3) After completion of the trial, the sponsor will retain the original CRFs on CD-
ROM or some other appropriate electronic medium and the investigator or the 
trial site will retain copies. 
4) The original ICFs will be retained according to the method specified by each 
trial site. 
5) The bioanalytical laboratory will retain the original reports on the results of 
drug concentration measurement and documents related to the measurement. 
 
10.3 
Case Report Form Items to Be Treated as Source Data 
Not applicable 
10.4 
Data to Be Collected by the Sponsor 
1) CRFs (data following acquisition of informed consent) 
2) Copies of reports on results of drug concentration measurement 
3) Results of clinical laboratory tests, microbiological examination, toxin A/B test, 
and drug sensitivity test 
4) Copies of 12-lead ECG charts 
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11 
Statistical Analysis 
Details of the planned statistical analysis will be presented in the Statistical Analysis Plan 
(SAP). 
11.1 
Statistical Analysis Sets 
11.1.1 
Safety Analysis Set 
The safety analysis set (SS) includes all patients who received the IMP at least once and 
from whom data on at least one safety endpoint was obtained after the start of IMP 
administration. 
11.1.2 
Full Analysis Set 
The full analysis set (FAS) includes all patients who received the IMP at least once and 
from whom data on at least one efficacy endpoint was obtained after the start of IMP 
administration. 
11.1.3 
Microbiological per Protocol Set 
The microbiological per protocol set (MPPS) comprises those patients in the FAS for 
whom the causative pathogen is identified and for whom microbiological outcome is 
assessed as “Excellent”, “Good”, or “Poor” according to the Assessment Criteria of 
Microbiological Outcome (Table 3.3-2), excluding patients for whom microbiological 
outcome is assessed as “Unknown/indeterminate”. 
11.1.4 
Clinical per Protocol Set 
The clinical per protocol set (CPPS) comprises those patients in the FAS for whom all 
scheduled examinations at all specified observation time points up until the end of 
treatment or withdrawal have been performed. 
11.1.5 
Pharmacokinetics Analysis Set 
The pharmacokinetics analysis set (PKS) comprises patients in whom plasma drug 
concentration was measured at least once. 
11.2 
Handling of Data 
Baseline values are defined as the last non-missing values at screening or before IMP 
administration.  No imputation will be performed for missing data.  If a problematic 
patient or data are encountered, the sponsor will decide how to handle the patient or data, 
with advice from the expert, as necessary. 
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11.3 
Analysis Items and Method 
11.3.1 
Safety Analysis 
1) Endpoints 
Adverse events, clinical laboratory tests, vital signs (body temperature, blood pressure 
and pulse rate), 12-lead ECG 
2) Analysis Set 
SS 
3) Analysis Method 
Analysis will be performed for the entire study population and by disease group and by 
dose.  AEs that occurred after the start of treatment with IMP will be tabulated using 
MedDRA by System Organ Class (SOC) and Preferred Term (PT), with PT substituted 
for verbatim terms.  The number of patients who experienced the following events as 
well as and the incidence will be tabulated:  adverse events, adverse drug reactions, 
serious adverse events, adverse events leading to withdrawal, and adverse events by 
severity. 
Clinical laboratory tests and vital signs (body temperature, blood pressure, and pulse rate) 
will be analyzed by using frequency distributions and descriptive statistics. 
Regarding 12-lead ECG, a shift table will be prepared for judgment on abnormality at 
each time point before and after IMP administration. 
11.3.2 
Demographic and Other Baseline Characteristics 
1) Endpoints 
Country, race, age, sex, height, body weight, BMI, inpatient/outpatient, previous medical 
history, complications, diagnostic method for CDI (CDI group only), history of CDI 
(CDI group only), concomitant drugs, and clinical symptoms 
2) Analysis Sets 
SS, FAS, MPPS, and CPPS 
3) Analysis Method 
Analysis will be performed by disease group and by dose.  Frequency distribution or 
descriptive statistics for each variable will be calculated according to the nature of the 
data (continuous or discrete). 
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11.3.3 
Treatment Period 
1) Endpoints 
Number of days when IMP was administered, total dose, total number of administrations 
2) Analysis Sets 
SS, FAS, and CPPS 
3) Analysis Method 
Analysis will be performed by disease group and by dose.  Descriptive statistics will be 
calculated for number of days when IMP was administered, total dose, and total number 
of administrations. 
11.3.4 
Efficacy Analysis 
11.3.4.1 
Microbiological Outcome 
1) Endpoints 
Bacteria elimination rate 
2) Analysis Set 
MPPS 
3) Analysis Method 
Analysis will be performed by disease group and by dose, and by MIC values of OPS-
2071 against the causative strain.  The number and proportion of patients by causative 
strain, a list of causative strain by patient, and a list of the result based on bacterial 
culture at each evaluation time point will be prepared. 
Concerning microbiological outcome by causative strain, bacteria elimination rate and its 
95% CI will be calculated.  The bacteria elimination rate is the proportion of causative 
strains assessed as either “excellent” or “good” except for those assessed as 
“Unknown/indeterminate”.  In case of infection of multiple bacteria, assess the 
microbiological outcome of each infections agent. 
 
 
 
 
 
“Excellent” + “Good” 
Number of patients assessed for 
microbiological outcome 
 
Bacterial elimination rate (%) =                                                                                 × 100 
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11.3.4.2 
Toxin A/B Assay (Clostridium Difficile Infection Group Only) 
1) Endpoint 
Toxin positive rate 
2) Analysis Sets 
MPPS (CDI group only) 
3) Analysis Method 
Analysis will be performed by dose.  Based on the result of Toxin A/B assay performed 
by the microbiological laboratory, prepare a list on the result of positive/negative 
judgment in the Toxin A/B assay at each evaluation time point. 
Calculate Toxin A/B positive rate and its 95% CI.  Toxin A/B positive rate is the 
proportion of the number of Toxin positive patients against the number of evaluable 
patients in CDI group. 
 
 
 
 
 
11.3.4.3 
Clinical Response 
1) Endpoint 
Clinical response 
2) Analysis Set 
CPPS 
3) Analysis Method 
Analysis will be performed by disease group and by dose, by causative strain, and by 
MIC values of OPS-2071 against the causative strain.  Calculate frequency distribution at 
each evaluation time point and prepare a list of causative strains by patients. 
Calculate the clinical response rate and 95% CI at each evaluation time point.  Clinical 
response rate will be calculated as the proportion of the patients judged as “clinical cure” 
or “clinical improvement” against evaluable patients except for those with missing data. 
 
 
Number of toxin positive patients 
 
Toxin positive rate (%) =                                                                               × 100 
Number of patients assessed for 
microbiological outcome 
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11.3.4.4 
Recurrence of Clostridium Difficile Infection (Clostridium 
Difficile Infection Group Only) 
1) Endpoint 
CDI recurrence rate 
2) Analysis Set 
CPPS 
3) Analysis Method 
Analysis will be performed by dose in the proportion of patients judged as “clinical cure” 
at the end of treatment in CPPS. 
Prepare the list of result of judgment on CDI recurrence at FU2 or withdrawal. 
Calculate CDI recurrence rate at FU2 or withdrawal.  CDI recurrence rate is the 
proportion of the patients judged as “recurrent” against evaluable patients except for 
those with missing data. 
 
 
 
 
 
11.3.4.5 
Time to Resolution of Diarrhea 
1) Endpoint 
Days from the start of dosing to first formed stool 
2) Analysis Set 
CPPS 
3) Analysis Method 
Patients judged as “clinical cure” + 
“clinical improvement” 
 
Clinical response rate (%) =                                                                             × 100 
Evaluable patients except for those with 
missing data 
Patients judged as “recurrent” 
 
Recurrence rate (%) =                                                                                            × 100 
Evaluable patients except for those with missing data 
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Analysis will be performed by disease group and by dose.  Calculate descriptive statistics 
of days from the start of dosing to first formed stool (except cases where liquid or 
unformed stools recurs). 
11.3.4.6 
Improvement of Clinical Symptoms 
1) Endpoints 
Stool count, fecal properties, blood stool, highest body temperature, abdominal pain, 
nausea, vomiting 
2) Analysis Set 
CPPS 
3) Analysis Method 
Analysis will be performed by disease group and by dose.  Frequency distribution or 
descriptive statistics for each variable will be calculated at each evaluation time point 
according to the nature of the data (continuous or discrete). 
11.3.4.7 
Drug Sensitivity of Isolated Strain 
1) Endpoint 
MIC values 
2) Analysis Set 
C. difficile isolated/identified or the strain identified as enteric infection agents by the 
microbiological laboratory 
3) Analysis Method 
Prepare a list of kinds and number of strains of the identified causative strain.  Determine 
MIC value of OPS-2071 for the causative strain at screening and at the end of treatment 
(and FU2 [Day 38] for CDI group) to prepare a list. 
11.3.5 
Pharmacokinetics Endpoints 
11.3.5.1 
Plasma Pharmacokinetics 
1) Endpoints 
1) Plasma OPS-2071 concentration 
2) OPS-2071 pharmacokinetic parameters (Cmax, tmax and Cmax/D) 
2) Analysis Set 
PKS 
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3) Analysis Method 
1) Calculation method 
• Plasma concentration below lower limit of quantification (0.200 μg/L) will be 
considered as 0 (μg/L), and used for calculation of pharmacokinetic parameters 
and descriptive statistics. 
• Cmax, tmax and Cmax/D will be calculated for inpatients. 
• The highest concentration among all blood sampling time points will be adopted 
as Cmax. 
• Cmax/D will be calculated by dividing Cmax by dose. 
• tmax will be calculated using actual time after administration. 
2) Statistical Analysis Method 
For inpatients, calculate descriptive statistics by dose and by blood sampling time point 
for plasma drug concentration, and by dose for pharmacokinetic parameters. 
Descriptive statistics include number of patients, arithmetic mean, standard deviation 
(SD), coefficient of variation, minimum, median, and maximum for plasma drug 
concentration, and number of patients, arithmetic mean, SD, coefficient of variation, 
geometric mean, minimum, median, and maximum for pharmacokinetic parameters. 
11.4 
Procedures for Reporting Deviations From the Original Statistical 
Analysis Plan 
For deviations from the analysis method stipulated by the protocol, the detail and reason 
will be entered in SAP or pharmacokinetics analysis plan and clinical trial report. 
11.5 
Rationale for Target Number of Patients 
There will be three dosing groups of OPS-2071, ie, 100, 50, 200 mg, or 100, 200, 400 mg.  
For each dosing group, 10 patients in CDI group will be secured for assessing 
microbiological outcome.  For enteric infection group, at least five patients will be 
secured for assessing microbiological outcome as a total of Salmonella, Campylobacter, 
and pathogenic E. coli.  It is assumed that bacteria will be detected almost 100% in CDI 
patients, and 50% in patients with enteric infection.  Based on the assumption, the target 
number of patients in each dosing group was selected:  10 CDI patients and 10 patients 
with enteric infection.  The target sample sizes were selected for investigation of the 
safety, efficacy, and pharmacokinetics of OPS-2071 while limiting the exposure to a 
minimum number of patients.  The target number of patients is not selected by statistical 
methods, but selected as an evaluable sample size. 
For both the groups, the priority is to enroll patients for whom microbiological 
assessment is possible.  If a sufficient number of patients for whom microbiological 
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assessment is possible is not attained after enrolling the target number of patients (10 
patients), additional patients will be enrolled. 
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12 
Quality Control and Quality Assurance for the Trial 
To ensure the quality of the trial, trial sites, contract research organizations, 
microbiological laboratory, bioanalytical laboratory, central laboratory, and the sponsor 
will perform quality control for the trial according to their respective Standard Operating 
Procedures. 
The audit division of the sponsor company will carry out audits within the company and, 
as necessary, at the trial site and contract research organizations or organizations 
entrusted to perform related activities, and check whether quality control of the trial is 
appropriately performed according to the Standard Operating Procedures. 
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13 
General Items of Caution Pertaining to the Trial 
13.1 
Ethics and Good Clinical Practice Compliance 
This trial must be conducted in compliance with the ethical principles outlined in the 
Declaration of Helsinki, the ICH-GCP Guideline, all applicable regional regulatory 
requirements, and the protocol. 
13.2 
Institutional Review Board 
Each trial site will seek approval from an IRB/IEC according to regional regulations.  
The IRB/IEC will investigate the ethical, scientific, and medical appropriateness of the 
trial.  Further, in preparing and handling CRFs, the investigator, subinvestigator, and their 
staff must take measures to ensure adequate care in protecting patient privacy. 
13.3 
Patient Consent 
13.3.1 
Procedures for Obtaining Consent 
1) Prior to the start of the screening examination, the investigator or 
subinvestigator will fully explain the matters listed in Section 13.3.2 to each 
patient who will be included in the trial, using the ICF, and give the ICF to the 
patient.  The patient will be provided sufficient time to make a decision 
regarding participation.  After confirming that the patient has properly 
understood the explanation, the investigator or subinvestigator will obtain 
written voluntary consent for participation in the trial from the patient. 
2) The investigator or subinvestigator who has provided the explanation and the 
patient will each put their printed name and personal seal or signature on the 
ICF, and write the date on which they sign or stamp the form.  If a trial 
associate has provided a supplemental explanation of the trial, he/she will also 
put his/her printed name and personal seal or signature on the form and write 
the date on which he/she signs or stamps the form. 
3) The original of the ICF that was signed or stamped and dated will be retained 
by the investigator or subinvestigator according to the regulations of the trial 
site.  A copy of the original ICF will be given to the patient. 
4) After obtaining informed consent from a patient, the investigator or 
subinvestigator will write the date of informed consent acquisition and patient 
number in the documents for enrolled patients. 
5) If new information becomes available that may influence the willingness of the 
patient to continue participation in the trial, the investigator or subinvestigator 
will promptly inform the patient of such information and confirm the 
willingness of the patient to continue participation in the trial, and then record 
the result in the source documents.  If there is guidance regarding the recording 
of re-consent stipulated by the trial site, it will be followed. 
 
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13.3.2 
Contents of Informed Consent Form 
1) An explanation that the trial involves research 
2) The type of IRB that reviews the appropriateness of trial conduct, matters to be 
reviewed by the IRB, and other relevant descriptions of the activity of the IRB 
3) The purpose of the trial 
4) The trial procedures (including research-related aspects of the trial, inclusion 
criteria for patients, and, if random allocation is performed, the probability of 
randomization to each treatment arm) 
5) The expected duration of the patient's participation in the trial. 
6) The planned number of patients involved in the trial 
7) The foreseeable IMP-related physical and mental benefits (if no benefits are 
expected, this should be indicated) as well as risks or inconveniences to the 
patient 
8) The existence of alternative treatments for the patient, and their important 
potential benefits and risks 
9) The treatment and compensation available to the patient in the event of trial-
related injury to health 
10) That the patient's participation in the trial is voluntary and that the patient may 
refuse to participate or withdraw from the trial, at any time, without penalty or 
loss of benefits to which he or she would otherwise be entitled 
11) An explanation that the patient will be informed in a timely manner if 
information becomes available that may be relevant to his or her willingness to 
continue participation in the trial 
12) The circumstances or reasons under which the patient's participation in the trial 
should be terminated 
13) An explanation that the monitors, the auditors, the IRB, and the regulatory 
authorities will be granted direct access to the patient's original medical records 
without violating the confidentiality of the patient, and that by signing the ICF, 
the patient is authorizing such access 
14) An explanation that if the results of the trial are published, the patient's identity 
will remain confidential 
15) The anticipated expenses to the patient for participating in the trial 
16) The anticipated payment, if any, to the patient for participating in the trial 
(agreements on payment, etc) 
17) The name, position, and contact address of the investigator or subinvestigator 
18) The persons at the trial site to contact for further information regarding the trial 
and the rights of trial patients, and whom to contact in the event of trial-related 
injury to health 
19) Matters to be observed by patients 
 
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13.3.3 
Amendments to the Informed Consent Form 
If revision of the ICF becomes necessary due to newly obtained information, the 
investigator will promptly revise the ICF to include that information after conferring with 
the sponsor. 
The investigator, when revising the ICF, will report this to the head of the trial site and 
submit the revised document to the IRB designated by the trial site to obtain its approval. 
If new information becomes available that may influence the willingness of patients to 
continue participation in the trial and the ICF has been revised according to the new 
information, the investigator or subinvestigator will again obtain patients’ written 
informed consent to continue participation in the trial. 
13.4 
Management of Investigational Medicinal Products 
1) The sponsor will issue the “Procedures for Handling of Investigational 
Medicinal Products” to the persons designated by the trial site. 
2) The sponsor will issue the “Document on Investigational Medicinal Products 
Storage Conditions” to the investigator or subinvestigator, trial associates, and 
IMP manager. 
3) The sponsor will deliver the IMPs to the trial site following the start of the trial 
period contracted with the trial site. 
4) The IMP manager will manage OPS-2071 appropriately according to the 
“Procedures for Handling of Investigational Medicinal Products” prepared by 
the sponsor. 
5) The IMP manager will prepare and retain the “Record of Management and 
Storage of Investigational Medicinal Products.” 
 
13.5 
Direct Access to Source Documents and Monitoring 
13.5.1 
Direct Access to Source Documents 
The head of the trial site and the investigator must accept monitoring and audits to be 
performed by the sponsor and inspection by the IRB and Japanese and foreign regulatory 
authorities, and must make source documents and all other trial-related records available 
to these agencies for direct access (including copying).  Patients authorize such direct 
access by signing the written ICF. 
13.5.2 
Monitoring 
The sponsor bears responsibility for ethical, legal, and scientific conduct of the trial.  The 
sponsor will perform monitoring according to the “Procedures for monitoring” specified 
for this trial.  Monitoring includes periodic visits, phone calls, or other contact with the 
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trial site for the provision, obtaining, and recording of updated trial-related information 
by monitors designated by the sponsor. 
The sponsor may entrust a portion of monitoring activity to a contract research 
organization. 
13.5.3 
Documents to Be Retained by the Investigator 
The trial-related documents to be retained by the investigator will be kept in the 
investigator’s file, which will be managed by the investigator. 
13.6 
Deviations From and Changes or Amendments to the Trial 
Protocol 
13.6.1 
Deviations From the Trial Protocol 
1) The investigator or subinvestigator should not deviate from the protocol or 
change it without prior written agreement between the investigator and the 
sponsor and the written approval of the IRB of the trial site based on prior 
review. 
2) In unavoidable medical circumstances such as the need to avoid emergent risk 
to a patient, the investigator or subinvestigator may deviate from the protocol or 
change the protocol without prior written agreement from the sponsor and prior 
approval of the IRB.  In such an event, the investigator will promptly submit a 
document providing the details of and reason for the deviation or change to the 
sponsor and the head of the trial site and obtain approval from the IRB.  In 
addition, the investigator will obtain written approval from the head of the trial 
site and the written agreement of the sponsor by way of the head of the trial site. 
3) The investigator or subinvestigator will record all deviations from the protocol. 
 
13.6.2 
Amendments to the Trial Protocol 
1) The investigator will promptly submit to the sponsor, the head of the trial site, 
and the IRB by way of the head of the trial site, a written report on any changes 
in the trial that may significantly affect conduct of the trial or increase risks to 
the trial patients. 
2) The sponsor, after conferring with the investigator, will agree with the 
investigator on the contents of the revised protocol and compliance with the 
revised protocol. 
3) The sponsor will promptly submit the revised protocol to the head of the trial 
site. 
 
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13.7 
Archiving of Records 
1) The trial site will retain all the trial-related documents and records for the 
period of time indicated in a) or b) below, whichever is longer.  However, if the 
sponsor requires a longer period of archiving, the head of the trial site will 
consult with the sponsor on the period and procedures of record retention. 
a) The date an Application for Approval of a Pharmaceutical Product for OPS-
2071 is granted; or, if the head of the trial site receives notification from the 
sponsor that development has been terminated or that results of the trial will 
not be submitted with the approval application, the date 3 years after receipt of 
such notification. 
b) The date 3 years after termination or completion of the trial. 
2) The investigator will retain the trial-related documents and records as directed 
by the head of the trial site. 
3) If it becomes no longer necessary to retain the trial-related documents and 
records at the trial site, the sponsor will notify the head of the trial site. 
 
13.8 
Termination or Interruption of Part or All of the Trial 
13.8.1 
Termination or Interruption of the Trial at Individual Trial Sites 
1) In the event of termination or interruption of the trial, the investigator will 
promptly provide the head of the trial site with written notification and a written 
explanation of the details of the termination or interruption of the trial. 
2) When the sponsor has been informed by the head of a trial site that the 
investigator has terminated or interrupted the trial, the sponsor will obtain a 
detailed written explanation of the termination or interruption of the trial from 
the head of the trial site. 
 
13.8.2 
Termination or Interruption of the Entire Trial 
1) When the entire trial is to be terminated or interrupted by the sponsor, the 
sponsor will promptly provide the heads of all trial sites involved in the trial 
and the regulatory authority with written notification and a detailed written 
explanation of the reason for the termination or interruption of the trial. 
2) When the investigator has received notification of termination or interruption of 
the entire trial by the sponsor from the head of the trial site, the investigator will 
obtain a detailed written explanation of the termination or interruption of the 
trial from the head of the trial site, promptly notify the trial patients currently 
receiving IMP administration, and take necessary measures such as switching to 
appropriate alternative treatment(s). 
3) When development of OPS-2071 is terminated by the sponsor, the sponsor will 
promptly provide the heads and the investigators of all trial sites involved in the 
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trial and the regulatory authority with written notification and a detailed written 
explanation of the reason for the termination of development. 
 
13.9 
Protection of Patients’ Personal Information 
In completion and handling of CRFs, the investigator and subinvestigator will take 
adequate care to ensure protection of the personal information of patients.  Individual 
patients will be identified by patient numbers.  The sponsor will not provide the 
information obtained to any third party. 
13.10 
Compensation for Injury to Health 
Trial patients will be compensated for health damages according to the criteria 
established by the trial sponsor with reference to applicable regional regulatory 
requirement(s) for this trial will comprise medical costs and medical benefits. 
13.11 
Agreement on Publication 
The sponsor may use the findings obtained from this trial for purposes such as an 
“Application for Approval of a Pharmaceutical Product” for OPS-2071. 
When the results of this trial and relevant data are to be published in scientific journals or 
at academic meetings, the investigator will obtain prior written approval from the sponsor. 
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14 
Trial Administrative Structure 
The administrative structure of this trial is shown in Annex. 
 
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15 
Scheduled Duration of the Trial 
01 Jul 2015 through 31 Mar 2017 
 
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16 
References 
 
1 
World Health Organization. The top 10 causes of death [updated May 2014]. 
Available from: http://www.who.int/mediacentre/factsheets/fs310/en/ 
2 
Chan M, WHO Director-General. Combat drug resistance: no action today means no 
cure tomorrow.[updated 2011 Apr; cited 2013 Jan]. Available from: 
http://www.who.int/mediacentre/news/statements/2011/whd_20110407/en/index.html. 
3 
Tribble DR, Sanders JW, Pang LW, Mason C, Pitarangsi C, Baqar S, et al. Traveler’s 
diarrhea in Thailand: randomized, double-blind trial comparing single-dose and 3-day 
azithromycin-based regimens with a 3-day levofloxacin regimen. Clin Infect Dis. 
February 1, 2007; 44(3):338-46. 
4 
Cody AJ, Clarke L, Bowler IC, Dingle KE. Ciprofloxacin-resistant 
campylobacteriosis in the UK. Lancet. December 11, 2010; 376(9757):1987. 
5 
Hookman P, Barkin JS. Clostridium difficile associated infection, diarrhea and colitis. 
World J Gastroenterol. April 7, 2009; 15(13):1554-80. 
6 
Asha NJ, Tompkins D, Wilcox MH. Comparative analysis of prevalence, risk factors, 
and molecular epidemiology of antibiotic-associated diarrhea due to Clostridium 
difficile, Clostridium perfringens, and Staphylococcus aureus. J Clin Microbiol. 
August 2006; 44(8):2785-91. 
7 
Pepin J, Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S, et al. 
Emergence of fluoroquinolones as the predominant risk factor for Clostridium 
difficile-associated diarrhea: A cohort study during an epidemic in Quebec. Clin 
Infect Dis. 2005; 41:1254-60. 
8 
Ananthakrishnan AN. Clostridium difficile infection: epidemiology, risk factors and 
management. Nat Rev Gastroenterol Hepatol. 2011; 8:17-26. 
9  Saima Aslam, Richard J Hamill, Daniel M Musher; Treatment of Clostridium 
difficile- associated disease: old therapies and new strategies; Lancet Infect Dis 2005; 
5: 549–57. 
10 Oka D. Antibacterial spectrum of OPS-2071. Otsuka Study No. 034501, Otsuka 
Report No. 028199, 2012. 
11  Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and 
prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-98. 
95

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
An Open-label, Multicenter Clinical Trial to Assess the Safety and Efficacy of Three 
Different Doses of OPS-2071 in Patients with Bacterial Enteritis 
 
 
 
 
NCT Number: NCT02473393 
PRT NO.: 341-13-002 
Version Date: 03 March 2017 (Version 3.0) 


Otsuka Pharmaceutical 
 
341-13-002  
Statistical Analysis Plan 
 
TP-GDO-WW-016-02 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  05 Jun 14 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 1 of 23 
 
 PAREXEL International 
Otsuka Pharmaceutical  
341-13-002  
An Open-label, Multicenter Clinical Trial to Assess the Safety and Efficacy of Three 
Different Doses of OPS-2071 in Patients with Bacterial Enteritis  
Statistical Analysis Plan 
PAREXEL Project Number: 222307 


Otsuka Pharmaceutical Co., Ltd 
Statistical Analysis Plan 
 
TP-GDO-WW-016-02 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  05 Jun 14 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 4 of 23 
TABLE OF CONTENTS 
 
1 
INTRODUCTION ....................................................................................................... 6 
2 
STUDY OBJECTIVES ............................................................................................... 6 
3 
INVESTIGATIONAL PLAN ..................................................................................... 7 
3.1 Overall Study Design and Plan ............................................................................. 7 
3.2 Efficacy and Safety Variables .............................................................................. 8 
3.2.1 Safety endpoints: ......................................................................................... 8 
3.2.2 Efficacy endpoints: ..................................................................................... 8 
3.2.2.1 Microbiological outcome .............................................................. 8 
3.2.2.2 Toxin A/B Assay (CDI Group Only) ............................................ 9 
3.2.2.3 Clinical response ........................................................................... 9 
3.2.2.4 Recurrence of CDI (CDI group only) .......................................... 10 
3.2.2.5 Time to resolution of diarrhea ..................................................... 10 
3.2.2.6 Improvement of clinical symptoms ............................................. 10 
3.2.2.7 Drug sensitivity of isolated strain ................................................ 11 
4 
STATISTICAL METHODS ..................................................................................... 11 
4.1 Data Quality Assurance ...................................................................................... 11 
4.2 General Presentation Considerations .................................................................. 11 
4.3 Study Subjects .................................................................................................... 13 
4.3.1 Disposition of Subjects ............................................................................. 13 
4.3.2 Protocol Deviations ................................................................................... 13 
4.4 Analysis Populations .......................................................................................... 13 
4.4.1 Safety Analysis Set ................................................................................... 13 
4.4.2 Full Analysis Set ....................................................................................... 13 
4.4.3 Microbiological per Protocol Set .............................................................. 13 
4.4.4 Clinical per Protocol Set ........................................................................... 14 
4.5 Demographic and Other Baseline Characteristics .............................................. 14 
4.6 Treatment Compliance ........................................................................................ 15 
4.7 Efficacy Evaluation ............................................................................................ 15 
4.7.1 Microbiological Outcome ......................................................................... 15 
4.7.2 Toxin A/B Assay (Clostridium Difficile Infection Group Only).............. 17 
4.7.3 Clinical Response...................................................................................... 17 
4.7.4 Recurrence of Clostridium Difficile Infection (CDI group only) ............. 18 
4.7.5 Time to Resolution of Diarrhea ................................................................ 18 
4.7.6 Improvement of Clinical Symptoms ......................................................... 19 
4.7.7 Drug Sensitivity of Isolated Strain ............................................................ 19 
4.8 Safety Evaluation ................................................................................................ 20 
4.8.1 Extent of Exposure .................................................................................... 20 
4.8.2 Adverse Events ......................................................................................... 20 
4.8.3 Clinical Laboratory Evaluation ................................................................. 21 
4.8.4 Vital Signs, Physical Findings and Other Observations Related to Safety22 
4.8.5 Data Review Committee [DRC] ............................................................... 22 
4.9 Determination of Sample Size ............................................................................ 22 
4.10 
Changes in the Conduct of the Study or Planned Analysis ...................... 23 
5 
REFERENCES .......................................................................................................... 23 


Otsuka Pharmaceutical Co., Ltd 
Statistical Analysis Plan 
 
TP-GDO-WW-016-02 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  05 Jun 14 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 5 of 23 
LIST OF ABBREVIATIONS 
 
 
AE 
Adverse Event 
BER 
Bacterial Elimination Rate 
BMI 
Body Mass Index 
CDAD 
Clostridium difficile-associated diarrhea 
CDI 
Clostridium difficile infection 
CI 
Confidence Interval 
CPFX 
Ciprofloxacin 
CPPS 
Clinical Per Protocol Set 
CRF 
Case Report Form 
CRR 
Clinical Response Rate 
DRC 
Data Review Committee 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FU 
Follow-up 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIC 
Minimum Inhibitory Concentration 
RR 
Recurrence Rate 
SAE 
Serious Adverse Event 
SAP  
Statistical Analysis Plan 
SS 
Safety Set 
TEAE 
Treatment-Emergent Adverse Event 
TPR 
Toxin Positive Rate 
 


Otsuka Pharmaceutical Co., Ltd 
Statistical Analysis Plan 
 
TP-GDO-WW-016-02 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  05 Jun 14 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 6 of 23 
1 
INTRODUCTION 
OPS-2071 is a novel anti-enteric infection agent with a quinolone structure that has been 
shown to have potent antibacterial activity against various bacteria known to cause 
general enteric infections, including Clostridium Difficile Infection   
 
This study is designed as a multi-center, open label phase 2a trial to assess the safety and 
efficacy (microbiological outcome and clinical response) of three different doses of OPS-
2071 in patients with bacterial enteritis. 
 
For the trial population of this study, patients with bacterial enteritis will be divided into 
two groups, a CDI group for patients with bacterial enteritis associated with C. difficile 
infection and an enteric infection group for patients with bacterial enteritis for which the 
causative pathogen is Salmonella, Campylobacter, and pathogenic E. coli. The safety and 
efficacy will be assessed in each group. 
 
This SAP is based upon the following study documents: 
 Study Protocol, Version 3.0 (July 15, 2016) 
 electronic Case Report Form (CRF), Version 4.0 (May 16, 2016) 
 
2 
STUDY OBJECTIVES 
The objectives of this trial are: 
 
Primary objectives: 
 
 
To assess the safety and efficacy of oral multiple doses of OPS-2071 in patients with 
bacterial enteritis associated with CDI or enteric infection (caused by Salmonella, 
Campylobacter, or pathogenic E. coli) 
 
To assess the pharmacokinetics of multiple doses of OPS-2071 in patients with 
bacterial enteritis associated with CDI or enteric infection. 
 
Secondary objectives: 
 
 
To assess the recurrence rate of CDI in patients with bacterial enteritis associated 
with CDI after multiple doses of OPS-2071. 
 
To assess the time to resolution of diarrhea in patients with bacterial enteritis 
associated with CDI or enteric infection after multiple doses of OPS-2071. 
 
To assess the improvement of clinical symptoms in patients with bacterial enteritis 
associated with CDI or enteric infection after multiple doses of OPS-2071. 
 
To assess the sensitivity to OPS-2071 of the causative pathogen strain isolated from 
patients with bacterial enteritis associated with CDI or enteric infection. 


Otsuka Pharmaceutical Co., Ltd 
Statistical Analysis Plan 
 
TP-GDO-WW-016-02 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  05 Jun 14 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 7 of 23 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a multi-center, open-label trial to assess the safety and efficacy (microbiological 
outcome and clinical response) of three different doses of OPS-2071 in patients with 
bacterial enteritis. 
 
In the trial design, 100 mg/day, considered to be the clinically recommended dose, is set 
for the starting dose. If there are no safety concerns and efficacy is confirmed in the 100 
mg group, safety and efficacy will be assessed in the 200 mg group. By further 
confirming the safety and efficacy of OPS-2071 in the 50 mg group, the low dose cohort, 
at the same time, exploratory information on the recommended dose will be obtained. If 
efficacy at 100 mg/day is not confirmed and there are no safety concerns, the safety and 
efficacy of OPS-2071 will be assessed at 200 mg/day and then at 400 mg/day in a 
sequential ascending manner. Thus, the trial has a dose increase/decrease design. A Data 
Review Committee (DRC) will be established as a third-party organization for assessing 
the safety and efficacy of each dose escalation based on a consistent perspective of 
specialists. 
 
The target number of enrollment is 10 patients in each dosage of the CDI group, and 10 
patients in each dosage of the enteric infection group.  
 
Outline of the trial design is shown in in Figure 3.1-1. 
 
 
 
 
Figure 3.1-1 
Outline of Trial Design 
 
200 mg group
200 mg/day
（10 patients）
50 mg group
50 mg/day
（10 patients）
400 mg group
400 mg/day
（10 patients）
200 mg group
200 mg/day
（10 patients）
Data Review Committee
Data Review Committee
100 mg group
100 mg/day
（10 patients）
2. If there are no safety concerns 
and IMP is considered not effective in 
the 100 mg group
1. If there are no safety concerns 
and IMP is considered 
effective in the 100 mg group
Randomization


Otsuka Pharmaceutical Co., Ltd 
Statistical Analysis Plan 
 
TP-GDO-WW-016-02 
CONFIDENTIAL 
Project Document Version No. 3.0 
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Project Document Effective Date: Date of last signature 
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The trial period of each patient will start on the day of informed consent to the day when 
scheduled examinations are completed (on Day 38 for the CDI group and on Day 14 for 
the enteric infection group or at the end of withdrawal examination).  This trial will make 
no distinction between inpatients and outpatients.  Trial schedule is shown in Figure 3.1-2 
 
 
Figure 3.1-2 
Trial Schedule 
*Performed only in CDI group 
 
For the analysis, the outputs will be prepared under the following plans. 
Plan A:  Dosage groups 50 mg, 100 mg, 200 mg of each disease group. 
Plan B:  Dosage groups 100 mg, 200 mg, 400 mg of each disease group. 
 
3.2 
Efficacy and Safety Variables 
3.2.1 Safety endpoints: 
 
Adverse events 
 
Clinical laboratory tests (hematological, biochemical test and urinalysis) ,  
 
Vital signs (body temperature, blood pressure and pulse rate),  
 
12-lead electrocardiogram (ECG) 
3.2.2 Efficacy endpoints: 
3.2.2.1 Microbiological outcome  
 
Microbiological outcome will be judged according to the assessment criteria shown in 
Table 3.2-1 and Table 3.2-2 for the bacterial strain isolated as the causative pathogen 
based on the data from the microbiological examination.  For infection due to multiple 
CDI group
-1
.
4 .
11
.
.
Enteric infection group
-1
.
4 .
8
.
.
-2
-2
1
1
10
7
24
14
Day
Day
38
-
Follow-up 1
Follow-up 2 *
Treatment period
Acquisition of informed consent/Screening
IMP allocation/start of administration
Observation
End of IMP administration
Observation at the end of administration


Otsuka Pharmaceutical Co., Ltd 
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causative pathogens, microbiological outcome will be assessed for each individual 
pathogen.  
Table 3.2-1 
Assessment Table for Microbiological Outcome 
Time of Observation 
Assessment of 
Microbiological 
Outcome 
Baseline 
Day 4 
End of Treatment 
+ 
– 
– 
Excellent 
+ 
+ 
– 
Good 
− 
+ 
Not applicable 
+ 
+ 
+ 
Poor 
− 
+ 
– 
+ 
Not applicable 
Others 
Unknown/ 
indeterminate 
+:  culture positive, −:  culture negative 
Not applicable:  Bacterial culture test was not performed.  The causative pathogen was not isolated 
or identified. 
 
Table 3.2-2 
Assessment Criteria for Microbiological Outcome 
Assessment of 
Microbiological 
Outcome 
Definition 
Excellent 
Pathogen is absent from bacterial culture obtained at Day 4 and at the end of 
treatment. 
Good 
Pathogen is still present in bacterial culture obtained at Day 4, and absent from 
bacterial culture at the end of treatment. 
Poor 
Pathogen is still present in bacterial culture obtained at the end of treatment. 
Unknown/indeterminate 
Applicable to none of the above but falls under the cases below for example. 
 
Cultures are not available because of withdrawal from the study or other 
reasons. 
 
Culture was obtained after the use of prohibited concomitant 
drugs/therapies. 
 
Any other circumstance, which makes it impossible to define the 
microbiological response. 
 
3.2.2.2 
Toxin A/B Assay (CDI Group Only) 
Assess positive or negative for toxin A/B. 
 
3.2.2.3 Clinical response 
 
The investigator or subinvestigator will refer to the information from patients (eg. patient 
diary), and assess clinical response at the time of observation (Day 4 and end of 
treatment) according to the assessment criteria shown in Table 3.2-3. 
 
 


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Table 3.2-3 
Assessment Criteria for Clinical Response 
Clinical 
Response 
Assessment 
Definition 
Clinical cure 
Meeting all the following criteria within 24 hours before observation 
 
No liquid or unformed stool 
 
No abdominal symptoms and no other symptoms (fever, nausea, vomiting) 
 
No need of medication or therapy to treat CDI or enteric infection 
Clinical 
improvement 
Fulfilling at least one of the following criteria within 24 hours before observation 
 
Liquid or unformed stools ≤ 2 times/day 
 
No abdominal symptoms and no other symptoms (fever, nausea, vomiting) 
 
No need of medication or therapy to treat CDI or enteric infection 
Clinical failure 
Fulfilling none of the above-mentioned clinical improvement criteria. 
Patients who received medication or therapy to treat CDI or enteric infection prior to 
the time of observation are to be assessed as “clinical failure”. 
 
3.2.2.4 Recurrence of CDI (CDI group only) 
 
The investigator or subinvestigator will assess the recurrence of CDI at Follow-up 2 or 
withdrawal according to the assessment criteria shown in Table 3.2-4 for patients who 
achieved “clinical cure” at the end of treatment. 
Table 3.2-4 
Assessment Criteria for Recurrence of Clostridium Difficile Infection 
Assessment of 
Recurrence of 
CDI 
Definition 
Sustained cure 
No recurrence 
Recurrence 
Meeting all the following criteria 
 
New episode of diarrhea is occurred in the period from the end of treatment to 
FU2 or withdrawal (liquid or unformed stools ≥ 3 times/day within 24 hours) 
 
Medication or therapy is required to treat CDI in the period from the end of 
treatment to FU2 or withdrawal 
 
A positive toxin A/B assay at FU2 or withdrawal (positive for either or both 
toxins) 
   
3.2.2.5 Time to resolution of diarrhea 
The time from the start of dosing until the first formed stool (except in cases where liquid 
or unformed stools recurs) will be evaluated as time to resolution of diarrhea. 
 
3.2.2.6 Improvement of clinical symptoms 
 
Assess the improvement of clinical symptoms, i.e., daily stool count, fecal properties, 
bloody stool, fever, abdominal pain, nausea, and vomiting. 


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3.2.2.7 Drug sensitivity of isolated strain 
Determine the minimum inhibitory concentration (MIC) of OPS-2071 for the 
isolated/identified C. difficile or the strain identified as the causative pathogen of enteric 
infection. 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently 
confirmed for consistency, integrity and in accordance with standard PAREXEL 
procedures. 
 
4.2 
General Presentation Considerations 
The important terms are defined as below: 
Term 
Definition 
Screen failure 
A screen failure is a patient from whom written informed 
consent was obtained, but to whom the investigational medicinal 
product was not assigned. 
Trial start date for 
individual patient 
The day of obtaining the patient’s written informed consent 
Trial completion date 
for individual patient 
CDI group:  The completion day of follow-up 2 (FU2) or 
withdrawal examination for individual patients 
Enteric infection group:  The completion day of follow-up 1 
(FU1) or withdrawal examination for individual patients 
Trial withdrawal date 
for individual patient 
The day when withdrawal is considered necessary by the 
investigator or sub-investigator for individual patient or the day 
of withdrawal examination 
Trial period for 
individual patient 
Period from the day of obtaining the patient’s informed consent 
to the day of trial completion.  It does not include the follow-up 
period after the trial completion date for individual patient. 
 
Continuous data will be summarized in terms of the mean, standard deviation (SD), 
median, minimum, maximum and number of observations, unless otherwise stated.  The 
minimum and maximum will be reported to the same number of decimal places as the 
raw data recorded in the database.  The mean, median, lower quartile and upper quartile 
will be reported to one more decimal place than the raw data recorded in the database.  
The SD will be reported to two more decimal places than the raw data recorded in the 
database.  In general, the maximum number of decimal places reported shall be four for 
any summary statistic. 
 


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Categorical data will be summarized in terms of the number of subjects providing data at 
the relevant time point (n), frequency counts and percentages.  Any planned collapsing of 
categories will be detailed in the SAP text and the data displays.   
Percentages will be presented to one decimal place. Percentages will not be presented for 
zero counts.  Percentages will be calculated using n as the denominator.  
 
Changes from baseline in categorical data will be summarized using shift tables where 
appropriate. 
 
Confidence intervals will be presented to one more decimal place than the raw data. 
 
All report outputs will be produced using SAS® version 9.2 or a later version in a secure 
and validated environment.   
 
Baseline 
Baseline is defined as the last available screening or pre-treatment assessment. 
Allowance window 
Assessments taken outside of protocol allowable windows will be displayed only in the 
listing according to the CRF assessment recorded by the Investigator and will not be 
included in the summaries. 
Unscheduled assessments 
Extra assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing adverse events) will be 
included in listings but not summaries. Listing will include all enrolled subjects in 
principle. 
Withdrawal assessments 
Withdrawal assessments will be summarized according to the CRF assessments recorded 
by the investigator at the time of withdrawal.  
Study day 
The first day of IMP administration will be defined as DAY 1.  
Study day =  
        The Date -  Date of 1st IMP administration + 1,   if  the Date >= Date of  the 1st 
IMP administration; 
        The Date -  Date of 1st IMP administration,         if  the Date   <  Date of  the 1st 
IMP administration. 
 


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4.3 
Study Subjects 
4.3.1 Disposition of Subjects 
A clear accounting of the disposition of all subjects who enter the study will be provided, 
from screening to study completion. 
 
 
A summary of subjects with informed consents, screen failure subjects by major 
reasons, subjects completed the study, subjects discontinued with reasons under each 
dosage by disease group and overall.  
 
A summary of subject disposition per site and country by disease group and overall.  
4.3.2 Protocol Deviations 
All protocol deviations will be defined in the protocol deviation specification.  
 
The following outputs will be provided. 
 A summary of subjects with major protocol deviation in each country/region and site 
by treatment arm and overall and by type of deviation  
 A by-subject listing of all protocol deviations. 
 
4.4 
Analysis Populations 
4.4.1 
Safety Analysis Set 
The safety analysis set (SS) includes all patients who received the IMP at least once and 
from whom data on at least one safety endpoint was obtained after the start of IMP 
administration. 
 
4.4.2 
Full Analysis Set 
The full analysis set (FAS) includes all patients who received the IMP at least once and 
from whom data on at least one efficacy endpoint was obtained after the start of IMP 
administration. 
 
4.4.3 
Microbiological per Protocol Set 
The microbiological per protocol set (MPPS) comprises those patients in the FAS for 
whom the causative pathogen is identified and for whom microbiological outcome is 
assessed as “Excellent”, “Good”, or “Poor” according to the Assessment Criteria of 
Microbiological Outcome (Table 3.2-2), excluding patients for whom microbiological 
outcome is assessed as “Unknown/indeterminate”. 
 


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4.4.4 
Clinical per Protocol Set 
The clinical per protocol set (CPPS) comprises those patients in the FAS for whom all 
scheduled examinations at all specified observation time points up until the end of 
treatment or withdrawal have been performed. 
 
4.4.5 
Pharmacokinetics Analysis Set 
The pharmacokinetics analysis set (PKS) comprises patients in whom plasma drug 
concentration was measured at least once. Outpatients are not included in PKS. 
 
4.5 
Demographic and Other Baseline Characteristics 
1) Endpoint: 
 
Demographic: Country, Ethnicity, Age, Sex, Body height, Body weight, BMI, 
History of hospitalization 
 
Medical history or concomitant disease 
 
Prior and concomitant medication/therapy (WHO Drug Dictionary Enhanced/ATC 
and Preferred name) 
 
Causative strains 
 
For CDI group only:   
 Diagnostic procedure of CDI 
 Medical history of CDI: number of episodes so far 
 
Confirmation of clinical symptoms: 
 Stool frequency per day 
 Form of stool  
 Presence of symptoms: Bloody stool, Abdominal pain,  Nausea, Vomiting , Fever 
 
2) Analysis Population: 
SS, FAS, MPPS, CPPS, PKS 
 
3) Analysis Method: 
Under each disease group, frequency counts and percentage or descriptive statistics 
for each variable will be calculated according to the nature of the data (continuous or 
discrete) by dosage group and overall. 
 
Under each disease group, the following summaries will be provided. 
 
A summary of demographic variables by dosage group and overall. 
 
A summary of medical history or concomitant disease by dosage group and overall 
 
A summary of prior and concomitant medication/therapy by dosage group and 
overall. 
 
A summary of diagnosis and medical history of CDI. (CDI group only) 
 
A summary of confirmation of clinical symptoms by dosage group and overall 
 
Disposition of subjects by the causative strains (FAS, MPPS, CPPS) 
 
A summary of causative strains with MIC values (FAS only) 
The following by-subject listings will also be provided. 


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 
A by-subject listing of demographic characteristics 
 
A by-subject listing of medical history and concomitant disease 
 
A by-subject listing of prior and concomitant medication/ therapy 
 
A by-subject listing of confirmation of clinical symptoms 
 
A by-subject listing of CDI diagnosis and CDI medical history 
 
4.6 
Treatment Compliance 
1) Definition: 
Under each disease group, the treatment compliance of each dosage group will be 
defined as the following: 
                     
 
100
)
(
 
 
)
(
 
 
(%)


mg
IMP
of
dose
total
Scheduled
mg
IMP
of
dose
total
Actual
Compliance
 
    The schedule number of IMP administrations will be calculated based on the following   
 
Treatment period:  10 days for CDI group and 7 days for enteric infection group 
     
Disease / Dosing Group 
Dosage of OPS-2071 
Scheduled Total Dose 
CDI 50 mg  
50 mg/day 
50 x 10 = 500 mg  
CDI 100 mg  
100 mg/day 
100 x 10= 1000 mg 
CDI 200 mg  
200 mg/day 
200 x 10= 2000 mg 
CDI 400 mg  
400 mg/day 
400 x 10 = 4000 mg 
Enteric Infection  50 mg  
50 mg/day 
50 x 7 = 350 mg  
Enteric Infection 100 mg  
100 mg/day 
100 x 7= 700 mg 
Enteric Infection  200 mg  
200 mg/day 
200 x 7= 1400 mg 
Enteric Infection  400 mg  
400 mg/day 
400 x 7 = 2800 mg 
2) Analysis population : 
SS, FAS, MPPS, CPPS, PKS 
 
3) Analysis method: 
 
Under each disease group, a summary of treatment compliance by dosage group and 
overall. 
 
A by-subject listing of treatment compliance.  
 
4.7 
Efficacy Evaluation 
4.7.1 Microbiological Outcome 
1) Endpoint: 
Bacterial Elimination Rate (BER) 
 
Definition:  Bacterial elimination rate is defined as the proportion of causative strains 
assessed as either “excellent” or “good” except for those assessed as 
“Unknown/indeterminate”. 
 
BER (%) = 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑎𝑠𝑠𝑒𝑠𝑠𝑒𝑑 𝑎𝑠 𝐸𝑥𝑐𝑒𝑙𝑙𝑒𝑛𝑡 𝑜𝑟 𝐺𝑜𝑜𝑑
𝐴𝑙𝑙 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑖𝑛 𝑀𝑃𝑃𝑆 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛
 ×100 


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2) Analysis Population: 
FAS, MPPS 
 
3) Analysis Method: 
Under each disease group, the following summaries will be provided. 
 
 
A summary of BER (%) by the MIC value of OPS-2071 and  causative strains by 
dosage group and overall. (MPPS only) 
 
 
A summary of assessment of criteria and BER (%) by the MIC value against each 
causative strain, dosage group and overall.  
 
 
A summary of BER (%) and its 95% CI by causative strains, dosage group and 
overall. (MPPS only) 
 
 
A summary of assessment criteria, BER (%) and its 95% CIs by causative strains, 
dosage group and overall. 
 
A summary of subject disposition by causative strains. 
 
-  For CDI, causative strain is C.difficile 
-  For enteric infection group, a summary of 3 causative strains (E.coli, Salmonella 
sp. and Campylobacter) and all causative strains will be generated. 
 
-  All 95% CIs described will be calculated using the exact method based on the 
relationship between Binomial distribution and F-distribution (Clopper-Pearson  
method). [1][2] 
 
Lower limit= 
1
1+𝑛−𝑥+1
𝑥
 𝐹2(𝑛−𝑥+1),2𝑥,0.025×100 
 
Upper limit= 
𝑥+1
𝑛−𝑥 𝐹2(𝑥+1),2(𝑛−𝑥),0.025
1+𝑥+1
𝑛−𝑥 𝐹2(𝑥+1),2(𝑛−𝑥),0.025×100 
        
           Where n is the number of all subjects evaluated and x is the number of subjects 
assessed as Excellent or Good. Also, upper 2.5% point of F-distribution will be used 
for calculation.  
    -  MIC value is defined as the lowest concentration of antimicrobial agent that 
inhibited growth of the organism in the ager spots, after confirming the growth in the 
drug-free ager as growth control. 
   -  MIC value measures in reports: >128, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.12, 0.06, 
0.03, 0.015, 0.008, 0.004, 0.002 and ≤0.001 μg/ml. 
       The following listing will be provided.  
 
 
A by-subject listing of causative strains and bacterial culture outcome evaluated at 
each time point. 
 


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The following graph will be provided.  
 
Bar chart group of BER (%) by dosage group of each causative strain in each disease 
group.(MPPS only) 
4.7.2 Toxin A/B Assay (CDI Group Only) 
1) Endpoint: 
Toxin Positive Rate (TPR) 
 
Definition: Toxin positive rate is defined as the proportion of the number of Toxin 
positive patients against the number of evaluable patients in CDI group. 
 
TPR (%) = 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑇𝑜𝑥𝑖𝑛 𝑝𝑜𝑠𝑖𝑡𝑖𝑣𝑒 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠
𝐴𝑙𝑙 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑖𝑛 𝑀𝑃𝑃𝑆 𝑝𝑜𝑝𝑢𝑙𝑎𝑡𝑖𝑜𝑛 ×100 
 
2) Analysis Population: 
FAS, MPPS (CDI group only) 
 
3) Analysis Method: 
The following summaries will be provided. 
 
 
A summary of TPR (%) and its 95% CI at each time point by dosage group and 
overall. 
The following listing will be provided. 
 
A by-subject listing of toxin A/B assay outcome at each time point. 
4.7.3 Clinical Response 
1) Endpoint: 
  Clinical Response Rate (CRR) 
 
Definition: Clinical response rate is defined as the proportion of the patients judged as 
“clinical cure” or “clinical improvement” against evaluable patients except for those with 
unknown outcome. 
  
        CRR (%) = 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑎𝑠𝑠𝑒𝑠𝑠𝑒𝑑 𝑎𝑠 Clinical Cure or Improvement
𝐴𝑙𝑙 𝑠𝑢𝑏𝑗𝑒𝑡𝑐𝑠 𝑖𝑛 𝐶𝑃𝑃𝑆−𝑈𝑛𝑘𝑛𝑜𝑤𝑛
×100 
 
2) Analysis Population: 
CPPS 
 
3) Analysis Method: 
Under each disease group, the following summaries will be provided. 
 
 
A summary of CRR (%) and its 95% CI by dosage group and overall at each time 
point.  
 
A summary of assessment criteria, CRR (%) and its 95% CI by dosage group and 
overall at each time point.  


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 
A summary of assessment criteria, CRR (%) and its 95% CI by causative strains, 
dosage group and overall at each time point. 
 
A summary of CRR (%) by the MIC value of OPS-2071 and the causative strains 
by dosage group and overall. 
 
A summary of assessment of criteria and CRR (%) by the MIC value against 
each causative strain, dosage group and overall 
 
The following listing will be provided.  
 
A by-subject listing of causative strains and clinical response assessment at each 
time point.  
 
The following graph will be provided. 
 
Bar chart group of CRR (%) by dosage group of each causative strain in each 
disease group at each time point. 
4.7.4 Recurrence of Clostridium Difficile Infection (CDI group only) 
1) Endpoint: 
CDI Recurrence Rate (RR) 
 
     CDI RR(%) =  
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑠𝑢𝑏𝑗𝑒𝑐𝑡𝑠 𝑎𝑠𝑠𝑒𝑠𝑠𝑒𝑑 𝑎𝑠 Recurrence
𝐴𝑙𝑙 𝑠𝑢𝑏𝑗𝑒𝑡𝑐𝑠 𝑗𝑢𝑑𝑔𝑒𝑑 𝑎𝑠 "Clinical cure"𝑖𝑛 𝐶𝑃𝑃𝑆×100 
 
2) Analysis Population: 
 
Analysis will be performed on subjects that are judged as “clinical cure” at the end of 
IMP administration in CPPS. (CDI group only) 
 
3) Analysis Method: 
The following summaries will be provided.  
 
 
A summary of CDI RR (%) at FU2 or withdrawal by dosage group and overall.  
 
  The following listing will be provided. 
 
A by-subject listing of recurrence outcome at FU2 or withdrawal. 
4.7.5 Time to Resolution of Diarrhea 
1) Endpoint: 
Duration (days) from 1st day of IMP administration to the first formed stool that 
occurred before the last administration date. 
     Date of first formed stool- Date of first IMP administration + 1 
Where recurrence of liquid stool or unformed stool prior to the last administration 
date will be excluded. 
 
2) Analysis Population: 
CPPS 
 
3) Analysis Method: 


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Under each disease group, the following summaries will be provided.  
 
A summary of descriptive statistics of days to resolution by dosage group and 
overall. 
 
    The following listing will be provided.  
 
A by-subject listing of days to resolution of diarrhea.  
4.7.6 Improvement of Clinical Symptoms 
1) Endpoint: 
Stool count, fecal properties, bloody stool, highest body temperature, abdominal pain, 
nausea, vomiting  
 
2) Analysis Population: 
CPPS 
 
3) Analysis Method: 
Under each disease group, the following summaries will be provided.  
 
A summary of descriptive statistics or frequency distributions (according to the 
nature of the data) for each variable by dosage group and overall at each time point. 
 
      The following listing will be provided. 
 
A by- subject listing of all the clinical symptoms.  
 
    Under each disease group, the following graph will be provided. 
 
Trend diagram of average stool count (with SD) at each time point by 
disease/dosage group 
 
Trend diagrams of stool count of all subjects at each time point by disease/dosage 
group. 
4.7.7 Drug Sensitivity of Isolated Strain 
1) Endpoint: 
MIC values 
 
2) Analysis Population: 
MPPS, FAS 
 
3)   Analysis Method: 
       The following summary will be provided. 
 
Microbiological test for causative strains. 
       The following listing will be provided. 
 
A listing of MIC values against each causative strains at screening and at the end of 
treatment. 
 


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4.8 
Safety Evaluation 
4.8.1 Extent of Exposure  
1) Definition: 
Days of IMP administered, total dose administered, total number of IMP 
administrations 
 
2) Analysis Population: 
SS, FAS, CPPS, MPPS, PKS 
 
3) Analysis Method: 
Under each disease group, the following summaries will be provided. 
 
A summary of descriptive statistics of extent of exposure by dosage group and 
overall. 
 
The following listing will be provided. 
 
A by-subject listing of exposure extent.  
4.8.2 Adverse Events 
1) Definition: 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA).  
AEs will be tabulated by System Organ Class (SOC) and Preferred term (PT) with PT 
substituted for verbatim terms. 
 
Treatment-emergent AEs will be tabulated and are defined as those AEs that either 
start or worsen in severity on or after the date of first dose of IMP administration. 
 
An adverse drug reaction (ADR) is defined as a response to a drug which is noxious 
and unintended, and which occurs at doses normally used in man for the prophylaxis, 
diagnosis, or therapy of disease, or for the modifications of physiological function. 
(WHO definition) 
 
When dates are missing or partially missing, AEs will be assumed to be treatment-
emergent, unless there is clear evidence to suggest that the AE started prior to the 
first dose of IMP administration. 
 
SAE, death and AEs leading to discontinuation will be considered separately. 
 
2) Analysis Population: 
SS 
 
3) Analysis Method: 
Under each disease group, the following summaries will be provided. 
 
 
A summary of the number and percentage of subjects reporting a treatment-
emergent AE or ADR by dosage group and overall, SOC and PT 


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 
A summary of the most common treatment-emergent AEs or ADRs by dosage 
group and overall, SOC and PT (reported by 30% of subjects in any group) 
 
A summary of the number and percentage of subjects reporting a treatment-
emergent AE or ADR by dosage group and overall, severity, SOC and PT 
 
A summary of the number and percentage of subjects reporting a treatment-
emergent AE or ADR leading to death by dosage group and overall, SOC and PT. 
 
A summary of the number and percentage of subjects reporting a serious 
treatment-emergent AE or ADR by dosage group and overall, SOC and PT. 
 
A summary of the number and percentage of subjects reporting a treatment-
emergent AE or ADR leading to discontinuation by dosage group and overall, 
SOC and PT. 
 
A summary of all the above. 
 
By-subject listings of all AEs (including non-treatment-emergent events) will be 
generated.  
 
A by-subject listing of all AEs  
 
A by-subject listing of all deaths that occurred during the study 
 
A by-subject listing of all SAEs 
 
A by-subject listing of all AEs that led to withdrawal. 
For by-severity summaries, for each subject reporting multiple AEs, the worst 
severity recorded will be used. 
4.8.3 Clinical Laboratory Evaluation 
1) Definition: 
A subject will be defined as having a potentially clinically abnormality if any of the 
following conditions are satisfied for a specific laboratory parameter. 
 
A laboratory result within the normal range at baseline and either a result below 
the lower limit of the normal range or above the upper limit of the normal range 
at any post-baseline time point. 
 
A laboratory result below the lower limit of the normal range at baseline and a 
laboratory result above the upper limit of the normal range at any post-baseline 
time point. 
 
A laboratory result above the upper limit of the normal range at baseline and a 
laboratory result below the lower limit of the normal range at any post-baseline 
time point. 
2) Analysis Population: 
SS 
3) Analysis Method: 
Under each disease group, the following summaries will be generated: 
 
A summary of each laboratory parameter and its change from baseline by dosage 
group and overall at each time point. 
 
A summary of the number and percentage of subjects experiencing low, normal 
and high values by dosage group and overall at baseline and at each post-baseline 
time point. (shift table) 


Otsuka Pharmaceutical Co., Ltd 
Statistical Analysis Plan 
 
TP-GDO-WW-016-02 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  05 Jun 14 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
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 
A summary of incidences of potentially clinically abnormalities by dosage group 
and overall. 
The following listing will be provided.  
 
A by-subject listing of all laboratory data will be generated with reference range 
provided and abnormal values will be marked. 
4.8.4 Vital Signs, Physical Findings and Other Observations Related to Safety 
1) Definition: 
Vital signs (blood pressure, pulse rate, body temperature), 12-lead ECG. 
 
2) Analysis Population : 
SS 
 
3) Analysis Method: 
      Under each disease group, the following summaries will be provided. 
 
 
A summary of descriptive statistics or frequency distributions (according to the 
nature of the data) for each vital sign variable by dosage group and overall at 
each time point. 
 
A summary of the number and percentage of subjects experiencing normal, not 
clinically significant abnormal and clinically significant abnormal ECG result by 
dosage group and overall at baseline and at each post-baseline time point. (shift 
table) 
 
 The following listing will be provided. 
 
A by-subject listing of vital signs and 12-lead ECG. 
4.8.5 Data Review Committee [DRC] 
This is an open-label trial and in order to ensure objectivity in efficacy assessment, a 
DRC will be established as a third-party organization to assess the safety and efficacy at 
each dose based on a consistent perspective of specialist. The DRC procedures will be 
specified in a separate document.  
 
4.9 
Determination of Sample Size 
There will be three dosing groups of OPS-2071, i.e., 100, 50, 200 mg, or 100, 200, 400 
mg.  For each dosing group, 10 patients in CDI group will be secured for assessing 
microbiological outcome.  For enteric infection group, at least five patients will be 
secured for assessing microbiological outcome as a total of Salmonella, Campylobacter, 
and pathogenic E. coli.  It is assumed that bacteria will be detected almost 100% in CDI 
patients, and 50% in patients with enteric infection.  Based on the assumption, the target 
number of patients in each dosing group was selected:  10 CDI patients and 10 patients 
with enteric infection.  The target sample sizes were selected for investigation of the 
safety, efficacy, and pharmacokinetics of OPS-2071 while limiting the exposure to a 
minimum number of patients.  The target number of patients is not selected by statistical 
methods, but selected as an evaluable sample size. 


Otsuka Pharmaceutical Co., Ltd 
Statistical Analysis Plan 
 
TP-GDO-WW-016-02 
CONFIDENTIAL 
Project Document Version No. 3.0 
Effective Date:  05 Jun 14 
Project Document Effective Date: Date of last signature 
Related to:  SOP-GDO-WW-019 
Page 23 of 23 
For both the groups, the priority is to enroll patients for whom microbiological 
assessment is possible.  If a sufficient number of patients for whom microbiological 
assessment is possible is not attained after enrolling the target number of patients (10 
patients), additional patients will be enrolled. 
 
4.10 Changes in the Conduct of the Study or Planned Analysis 
PK analysis will be performed by sponsor and it is not included in this SAP. In PKS, 
outpatients are not included. 
 
In the following analysis section, some analysis populations are added to the populations 
described in the protocol. 
4.5 Demographic and Baseline Characteristics: PKS 
 
4.6 Treatment Period: MPPS, PKS 
4.7.1 Microbiological Outcome: FAS 
4.7.2 Toxin A/B Assay: FAS 
4.7.7 Drug Sensitivity of Isolated Strain: FAS 
 
Regarding time to resolution of diarrhea, only the period from 1st day of IMP 
administration to the last administration date will be considered.  
5 
REFERENCES 
 [1] Blyth, C.R., Approximate Binomial Confidence Limits, Journal of the American 
Statistical Association,1986; 81(395):843-855. 
 [2] Clopper, C. and Pearson, E.S. The use of confidence or fiducial limits illustrated in 
the case of the binomial. Biometrika, 1934; 26, pp. 404-413 
  
DOCUMENT CHANGE RECORD 
Version 
Number 
Document 
Date 
Summary of Changes Made 
1.1 
2015/10/16 
4.6 Treatment compliance 
Changed the definition of compliance (tabletstotal dose). 
1.2 
2016/3/15 
4.4.5 Pharmacokinetics Analysis Set 
Added the exclusion of outpatients. 
2.0 
2016/3/18 
Version 2 
2.1 
2017/2/20 
4.5 Demographic and Other Baseline Characteristics 
Added causative strains 
4.7.1 Microbiological Outcome 
Specified Analysis population  
4.10 Changes in the Conduct of the Study or Planned Analysis 
Additional Analysis populations are described. 
2.2 
2017/3/01 
Corrected typo 
4.5 Demographic and Other Baseline Characteristics 
 
3.0 
2017/3/03 
Version 3