Single Center, Open Label, Controlled Study to Assess the Safety & Efficacy of Oral Ciprodiazole Versus Currently Used Ciprofloxacin & Metronidazole Tablets in Pelvi-abdominal Infections and Following IV Antibiotics in Post-operative Period
Phase: PHASE4
Conditions: Surgical Site Infections
Sponsor: MinaPharm Pharmaceuticals

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Single center, Open Label, controlled Study to assess the safety & 
efficacy of Oral Ciprodiazole ® Tablets (Ciprofolxacin/ 
Metronidazole) versus currently used Ciprofloxacin Tablets & 
Metronidazole tablets in pelvi-abdominal infections and 
following IV antibiotics in post-operative period, for pelvi-
abdominal surgeries or acute conditions 
 
Clinical Study Protocol No.: CIPRO-001 
Version 1- amendment 1 
Dated 20 Mar 2022  
 
 
Sponsor:    MINAPHARM Pharmaceuticals 
Minapharm Representative 
Doris Ezzat 
Medical Manager 
Address: El-Bardissi st. 
2 T Takseem Asmaa Fahmy st., 
Heliopolis, cairo - Egypt. 
Mob.: (+2) 01224460397 
 
Clinical Project Manager: 
Nagy Research MEACRO 
Address: 63 Road 104, Maadi 
Office Mobile: +20 1221700717 
Office Tel: +22 527 5071, +22 527 5072 
Office Fax: +22 5244338 

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Trial Protocol Agreement 
 
Protocol Name: Single center, Open Label, controlled Study to assess the safety & 
efficacy of Oral Ciprodiazole ® Tablets (Ciprofolxacin/Metronidazole) versus 
currently used Ciprofloxacin Tablets & Metronidazole tablets in pelvi-abdominal 
infections and following IV antibiotics in post-operative period, for pelvi-abdominal 
surgeries or acute conditions 
 
Clinical Study Protocol No.: CIPRO-001 
Version: 1 Amendment 1 
Dated: 20 March 22 
 
I,………………………………………….., the Investigator, have read and 
understood the above-referenced Minapharm Pharmaceuticals study Protocol 
and have fully discussed the objectives of this observational study and the 
contents of this protocol with the sponsor’s team. 
I agree to conduct according to this study protocol and to comply with its 
requirements, ethical and safety considerations. 
I understand that, should the decision be made by the sponsor to terminate 
prematurely or suspend the study at any time for whatever reason; such 
decision will be communicated to me in writing. Conversely, should I decide 
to withdraw from execution of the study, I will communicate such decision in 
writing to the Sponsor. 
INVESTIGATOR 
SPONSOR 
Name: Ahmed Farag El Kased 
Name: Doris Ezzat 
Title: 
Title: Clinical department Head 
Date: 
Date: 
Signature: 
Signature: 

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TABLE OF CONTENTS: 
 
 
1- Responsible Parties ................................................................................................... 6 
1.1Sponsor: 
6 
1.2 CRO 
6 
1.3 Principal investigators: .................................................................................................. 6 
1.4 Coordinating investigators: ........................................................................................... 6 
2- Study Abstract ........................................................................................................... 7 
3- List of Abbreviations .............................................................................................. 12 
4- Amendments & Updates ......................................................................................... 13 
5- Study Milestones ..................................................................................................... 13 
6- Introduction & Background .................................................................................... 13 
7- Rationale & Correlative Studies ............................................................................. 14 
7.1 Rationale: 
14 
7.2 Correlative Studies: ..................................................................................................... 15 
8- Treatment: ............................................................................................................... 15 
8.1 Ciprodiazole ® Tablets: ............................................................................................... 15 
8.2 Ciprofloxacin Hydrochlorid: ....................................................................................... 16 
8.3 Metronidazole: ............................................................................................................. 16 
8.4 Dosage & Administration: ........................................................................................... 17 
8.4.1 Ciprodiazole ® Tablets: .................................................................................. 17 
8.4.2 Ciprofloxacin ® Tablets: ................................................................................. 17 
8.4.3 Metronidazole ® Tablets: .............................................................................. 18 
8.5 Precautions: 18 
8.5.1 Storage and Drug Accountability: ................................................................... 18 
8.5.2 Dispensing ................................................................................................. 18 
8.6 Risks & Benefits of study drug ................................................................................... 19 
8.7 Discontinuation and Modification of Dosing of Ciprodiazole ®: ................................ 19 
8.8 Concomitant Medication: ............................................................................................ 19 
9- Research Question & Study Objectives .................................................................. 20 
9.1 
Primary Objective: ................................................................................ 20 
9.1.1 Primary Safety: ........................................................................................... 20 
9.1.2 Primary Efficacy: ......................................................................................... 20 

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9.2 
Secondary Objective: ............................................................................ 20 
9.2.1 Secondary Safety: ....................................................................................... 20 
9.2.2 Secondary Efficacy: ..................................................................................... 20 
10- 
Research Methods ................................................................................... 20 
10.1 Study Design: ............................................................................................................ 20 
10.2 Study Setting: ............................................................................................................ 21 
10.2.1 Inclusion Criteria: ...................................................................................... 21 
10.2.2 Exclusion Criteria: ...................................................................................... 21 
10.2.3 Discontinuation/Withdrawal of participants from the study: ............................. 22 
10.2.4 Assessments to be done: ............................................................................ 22 
10.3 Variables: 23 
10.3.1 
Primary Endpoints: ................................................................................ 23 
10.3.2 
Secondary Endpoints: ............................................................................. 23 
10.4 Data Sources: ............................................................................................................. 24 
10.5 Study Size 24 
10.5.1 Determination of Sample Size ...................................................................... 24 
10.5.2 Sample Size & Treatment Groups: ................................................................ 24 
10.5.3 Randomization: ......................................................................................... 25 
10.6 Data Management ...................................................................................................... 25 
10.7 Data Analysis ............................................................................................................. 25 
10.7.1 Analysis populations .................................................................................. 25 
10.7.2 Statistical methods .................................................................................... 25 
10.7.3 Analysis variables ...................................................................................... 25 
10.7.4 Main criteria ............................................................................................ 26 
10.7.5 Other criteria ............................................................................................ 26 
10.7.6 Primary Safety analysis ............................................................................... 26 
10.7.7 
Primary Efficacy analysis: ........................................................................ 27 
10.7.8 
Secondary Safety analysis: ...................................................................... 27 
10.7.9 
Secondary Efficacy analysis: ..................................................................... 28 
10.7.10 Interim analysis ....................................................................................... 29 
10.8 Quality Control .......................................................................................................... 29 
10.9 Limitation of the research methods ........................................................................... 29 
11- 
Protection of Human Subjects ................................................................. 29 
12- 
Study Procedures: .................................................................................... 30 

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12.1 Informed consent: ...................................................................................................... 30 
12.2 Patient Enrollment ..................................................................................................... 30 
12.3 Schedule of visits ....................................................................................................... 31 
12.3.1 Visit 1 (Screening & treatment initiation): ...................................................... 32 
12.3.2 Follow-up 1 Visit (Day 8)  ............................................................................ 34 
12.3.3 Follow-up 2 Visit & End of Study Visit (Day 15): ............................................... 34 
13- 
Management & Reporting of Adverse Events ........................................ 35 
13.1 Adverse Events (AEs): .............................................................................................. 35 
13.2 Serious Adverse Events (SAEs  (  ............................................................................... 37 
14- 
Plans for disseminating & communicating study results ........................ 38 
14.1 Progress Report ......................................................................................................... 38 
14.2. Final Study Report .................................................................................................... 38 
15- 
Confidentiality and publication ............................................................... 39 
15.1 Use of information ..................................................................................................... 39 
16- 
Archiving ................................................................................................. 39 
17- 
Responsibility of Participants .................................................................. 39 
17.1 Responsibility of Investigators .................................................................................. 39 
17.2 Responsibility of CRO: ............................................................................................. 40 
17.3 Responsibility of the Monitor .................................................................................... 41 
17.4 Responsibility of the Sponsor .................................................................................... 41 
17.5 Responsibility of the Data Manager .......................................................................... 42 
18- 
Audit and Inspection ............................................................................... 42 
19- 
References ............................................................................................... 43 
 
 
TABLE OF TABLES: 
Table 1: Schedule of Visits ................................................................................................... 31 
Table 2: Child-Pugh Score .................................................................................................... 33 
Table 3: Child-Pugh Classes ................................................................................................. 34 

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1  Responsible Parties 
1.1. Sponsor: 
MINAPHARM Pharmaceuticals 
Address: El-Bardissi st., 2 T Takseem Asmaa fahmy st., Heliopolis, cairo-Egypt. 
Tel: 02-24143170 
 
Sponsor Responsible Personnel: 
 Doris Ezzat, Medical Manager- Minapharm Pharmaceuticals. 
 
1.1 1.2 CRO 
Nagy Research MEACRO 
Address: 63 Road 104, Maadi 
Office Mobile: +20 1221700717 
Office Tel: +22 527 5071, +22 527 5072 
Office Fax: +22 5244338 
 
CRO Responsible Personnel: 
 Magda Shafik, MBBCh, MSc, Clinical Department Head-Nagy Research MEACRO, 
MBBCh, Faculty of Medicine - Cairo University (Dec. 1979), MSc: Master Degree in 
Internal Medical – Faculty of Medicine - Cairo University (Nov. 1986) 
 Zahraa Ismail, B.Sc. in Pharmacy- Faculty of Pharmacy, Helwan University (2010), 
Medical Writer – CRA 
 
1.2 1.3 Principal investigators:  
Dr. Ahmed Farag El kased, PHD, Professor of Oncology and General Surgery, Faculty of 
Medicine - Menoufia University 
 
1.3 1.4 Coordinating investigators:  
Dr. Fatma Ibrahim Youssef, Lecturer of General Surgery, Faculty of Medicine, Menoufia 
University 
 

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2 Study Abstract 
 
TITLE 
Single center, Open Label, controlled Study to assess the 
safety & efficacy of Oral Ciprodiazole ® Tablets 
(Ciprofloxacin/Metronidazole) 
versus 
currently 
used 
Ciprofloxacin Tablets & Metronidazole tablets in pelvi-
abdominal infections and following IV antibiotics in post-
operative period, for pelvi-abdominal surgeries or acute 
conditions  
CLINICAL STUDY 
PROTOCOL NUMBER 
& VERSION 
CIPRO-001 
Version 1 - Dated 15 Nov 2018 
MAIN AUTHOR NAME 
& AFFILIATION 
Lydia Bahig 
Clinical Research Associate, Nagy Research CRO 
PHYSICIANS/ 
LOCATION 
Principle Investigator: Dr. Ahmed Farag El Kased 
Location: Menoufia University Hospital 
RATIONALE & 
BACKGROUND 
Ciprodiazole (Ciprofloxacin & Metronidazole) is active 
against a broad spectrum of obligate anaerobic bacteria, 
including Bacteroids Species (spp.), Fusobacterium spp., 
Clostridium spp., Treponema spp. and various anaerobic 
cocci. The action is trichomonicidal, and bactericidal. So, it is 
indicated in the treatment of Pelvi-abdominal infections 
caused by gram negative bacteria such as E. coil, 
Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella 
pneumonia, Bacteroides fragilis or others. 
In this study, we compare the safety and efficacy of oral 
Ciprodiazole 500 mg (Ciprofloxacin /Metronidazole) versus 
currently used Ciprofloxacin Tablets & Metronidazole tablets 
in pelvi-abdominal infections and following IV antibiotics in 
post-operative period, for pelvi-abdominal surgeries or acute 
conditions 
RESEARCH 
QUESTION & STUDY 
OBJECTIVES 
 
Primary Objectives:  
1) Primary Safety: 
To compare safety of oral Ciprodiazole ® tablets 
(Ciprofloxacin/Metronidazole) 
versus currently used 
Ciprofloxacin Tablets & Metronidazole tablets for pelvi-
abdominal infections, either non-operative or post-
operative following IV antibiotics.  

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2) Primary Efficacy: 
To compare efficacy of oral Ciprodiazole ® tablets 
(Ciprofolxacin/Metronidazole) 
versus currently used 
Ciprofloxacin Tablets & Metronidazole tablets for pelvi-
abdominal infections, either non-operative or post-
operative following IV antibiotics.  
Secondary Objective 
1) Secondary Safety: 
- 
Presence of any signs/symptoms of post-operative wound 
infection such as redness, fever or wound discharge. 
- 
Presence of undesirable effects on total leukocyte count 
and liver enzymes (SGOT & SGPT)  
2) Secondary Efficacy: 
- 
To compare the complete resolution or improvement of 
Pelvi-abdominal infection between ciprodiazole® versus 
combined treatment, based on pelvi-abdominal ultrasound 
and others 
- 
To compare the days for complete healing of post-
operative wounds between ciprodiazole® versus combined 
treatment  
STUDY DESIGN 
Comparative, randomized, Single center, Open label study to 
compare the safety and efficacy of oral Ciprodiazole 500 mg 
(Ciprofloxacin /Metronidazole) versus currently used 
Ciprofloxacin Tablets & Metronidazole tablets in pelvi-
abdominal infections and following IV antibiotics in post-
operative period, for pelvi-abdominal surgeries or acute 
conditions   
A study population of 312 patients who had pelvi-abdominal 
infection or started IV antibiotics for 48 hours, post-operative 
or till be able to tolerate oral intake in post-operative period, 
for pelvi-abdominal surgeries or acute conditions. They will 
be randomized by computer, to receive Ciprodiazole ® tablets 
(Ciprofloxacin/Metronidazole) versus currently used 
Ciprofloxacin Tablets & Metronidazole tablets for a duration 
not exceeding 15 days 
STUDY DURATION 
 Subjects will be enrolled for 12 months including 
screening visit 
 Follow up for 15 days from enrolment 
STUDY 
POPULATION 
312 Egyptian Patients with pelvi-abdominal infection or 
started IV antibiotics in post-operative period, for pelvi - 
abdominal surgeries and/or acute conditions  
 
 
Inclusion Criteria: 
1. Egyptian male and female patients aged between 18-65 

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SELECTION 
CRITERIA 
years’ old 
2. Subjects having pelvi-abdominal infections such as and not 
limited to: Ulcerative Colitis, Diverticulitis, Cholecystitis 
and Pelvic Inflammatory Diseases (PID), as oophoritis 
and salpingo-oophoritis. 
3. Subjects during post-operative period for pelvi-abdominal 
surgery and following IV medication with Metronidazole 
injection plus third generation cephalosporin. 
4. Subjects who are willing to sign Informed Consent Form 
(ICF) and ready to comply with the protocol for the 
duration of the study 
Exclusion Criteria: 
 
1. Subjects with a history of hypersensitivity to any of the 
active ingredients of the treatments used 
2. Subjects who are receiving or received any other 
antibiotics during the previous two weeks, rather than 
IV treatment in the first post-operative 48 hours, 
mentioned in the protocol 
3. Subjects 
with 
Pelvi-abdominal 
infection 
and 
performed surgery after failure of oral antibiotics. 
4. Subjects having surgeries such as colorectal surgeries.  
5. Subjects with any medical condition requiring the usage of 
the following medications:  
-Drugs that induce microsomal liver enzymes, such as 
Phenytoin or Phenobarbital. 
-Drugs that decrease microsomal liver enzymes 
activity, such as cetrimide. 
-Theophylline  
-Corticosteroids  
-Antacids containing magnesium and aluminum, 
supplements and other products containing calcium, 
iron or zinc 
-Tizanidine  
6. Subjects with uncontrolled diabetes mellitus; FBG > 
200 mg/ml 
7. All subjects with renal impairment (S. Creatinine > 
1.5 mg/dL)  
8. All subjects with hepatic impairment (Child-Pugh 
Score B-C) 
9. Subjects with liver enzymes (SGOT & SGPT > 2 
Normal range) 

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10. Pregnant or breast feeding women  
MEDICINAL 
PRODUCT 
Ciprodiazole ® Tablets (Ciprofloxacin hydrochloride 500 mg 
& Metronidazole 500 mg) 
VARIABLES 
Primary Endpoints: 
1- Primary Safety: 
- 
Incidence of serious/non-serious adverse events 
2- Primary Efficacy: 
- 
Complete resolution for pelvi-abdominal infection 
based on pelvi-abdominal ultrasound and others and/or 
clinical response 
- 
Complete healing of the of post-operative wounds  
Secondary Endpoints:  
1- Secondary Safety: 
- 
Presence of any signs/symptoms of post-operative 
wound infection such as redness, fever or wound 
discharge. 
- 
Change in Total Leukocyte count and Liver enzymes 
(SGOT, SGPT) between baseline (visit 1) to End of 
study visit (Follow up 2 V) 
2- Secondary Efficacy: 
- 
Describe complete resolution, improvement, failure or 
relapse of pelvi-abdominal infection based on pelvi-
abdominal ultrasound and others and/or clinical 
response 
- 
Days for complete healing of post-operative wounds 
after 8 days of treatment (Follow-up 1 V) & 15 days of 
treatment (End of study visit) between the 2 groups 
ASSESSMENT 
SCHEDULE 
Subjects will be enrolled for 12 months including screening 
visit 
 Visit 1: Screening and treatment initiation visit, Day 0   
 Follow-up 1 visit: Day 8 (+/-) 3 days 
 Follow-up 2 visit & End of study visit: Day 15 (+/-) 3 
days 
DATA SOURCES 
All visits’ assessments will be kept in the source files for each 
patient and in Case Report Form (CRF), which will be 
verified by the responsible Clinical Research Associate 
(CRA). 
STUDY SIZE 
312 patients with pelvi-abdominal infection and/or who 
started IV antibiotics in post-operative period, for pelvi-

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abdominal surgeries. They will be randomized by computer, 
into 
2 
treatment 
groups; 
Ciprodiazole 
® 
tablets 
(Ciprofloxacin/Metronidazole) 
versus 
currently 
used 
Ciprofloxacin Tablets & Metronidazole tablets, from the 
surgical department in Menoufia University Hospital and 
some patients might be referred from other departments in 
Menoufia University Hospital such as and not limited to; the 
department of Gynecology and Obstetrics  
DATA ANALYSIS 
 
Descriptive analysis of the collected data. All enrolled 
patients will be included in the safety analysis. 
All quantitative primary and secondary end point variables 
will be described 
Data from primary and secondary endpoints will be 
summarized using appropriate summary statistics i.e.  
Number of subjects (n), mean, Standard Deviation (SD), 
median and range. 
STUDY 
MILESTONES 
Planned Timelines: 
First Patient First Visit (FPFV): 01 March 21 
First Patient First Treatment (FPFT): 01 March 21 
Last Patient First Treatment (LPFT): 31 Dec 22 
Last Patient Last Visit (LPLV): 15 January 23 
Database Lock: 15 March 23 
Final Study Report: 31 May 23 

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3 List of Abbreviations 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase  
ALT      
Alanine Transaminase 
AST       
Aspartate Aminotransferase 
CBC 
Complete Blood Count  
CRF  
Case Report Form 
CRO  
Clinical Research Organization 
DVT 
Deep Vein Thrombosis 
EOT 
End of Treatment 
EPVC 
Egyptian Pharmaco Vigilance Center  
FBS 
Fasting Blood Sugar 
FPFT 
First Patient First Treatment 
FPFV 
First Patient First Visit 
G6PD 
Glucose-6-Phosphate Dehydrogenase  
GCP  
Good Clinical Practice 
ICF 
Informed Consent Form  
INR 
International Normalized Ratio 
IAIs 
Intra-Abdominal Infections 
IRB  
Institutional Review Board 
ITT 
Intention to Treat 
LPLT 
Last Patient Last Treatment 
LPLV 
Last Patient Last Visit 
No. 
Number of subjects  
PID 
Pelvic Inflammatory Diseases  
PP 
Per Protocol  
PP 
Post-operative Peritonitis 
PT 
Prothrombin Time  
SAE  
Serious Adverse Event  
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SD 
Standard Deviation 
SIV 
Site Initiation Visit 
SPP. 
Species 
WHO  
World Health Organization 

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4 Amendments & Updates 
Not applicable 
5  Study Milestones 
 Screening and Enrollment Period: 12 months 
Planned Timelines: 
 
FPFV Date 
FPFT Date 
LPFT Date 
LPLV Date 
01 Mar 21 
01 Mar21 
31 Dec 22  
15 Jan 23 
 
Database Lock Date 
Final Study Report 
15 March 23 
31 May 23 
6 Introduction & Background 
Intra-Abdominal Infections (IAIs) include many pathological conditions, ranging from 
uncomplicated IAIs to complicated peritonitis; either localized peritonitis or diffuse 
peritonitis, depending on the ability of the host to contain the process within a part of the 
abdominal cavity. ]1[ 
IAIs are also classified into community-acquired intra-abdominal infections (CA-IAIs) 
and healthcare-acquired intra-abdominal infections (HA-IAIs). CA-IAIs are acquired in 
community, while HA-IAIs develop in hospitalized patients or residents of long-term care 
facilities. They are characterized by increased mortality because of both underlying 
patient health status and increased likelihood of infection caused by multi drugs resistant 
organisms. ]2[ 
The diagnosis of IAI is based primarily on clinical assessment. Classic symptoms of IAIs 
include abdominal pain and a systemic inflammatory response, including fever, tachycardia, 
and tachypnea. Abdominal rigidity suggests the presence of peritonitis.]3[ 
Patients with uncomplicated IAIs can be managed with either surgical source control or 
antibiotics alone, while the treatment of patients with complicated IAIs involves both source 
control and antibiotic therapy. 
[
3
]  
The most common Post-operative IAI is Post-Operative Peritonitis (PP). It is a life-
threatening hospital-acquired IAI with high rates of mortality [4]. The most common cause of 
PP is an anastomotic leakage [5]. The diagnosis of PP may be difficult because there are no 
absolutely specific clinical signs and laboratory tests to reject or confirm the diagnosis. 
Treating patients with PP requires supportive therapy of organ dysfunction, source control of 
infection, and intensive antimicrobial therapy [3  [  

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Pelvi-abdominal infections are the most communal infectious complications challenged by 
the surgeon. Actual managing needs prompt finding, well-timed and suitable clinical 
intervention and satisfactory antimicrobial treatment. Meanwhile nation results usually are 
not obtainable for the first 48 - 27
 
h next surgical procedure, experimental antimicrobial 
treatment necessity cover the most prospective pathogens, i.e. a combination of Gram-
positive and Gram-negative aerobic and anaerobic bacteria that contain the typical flora of 
the gastrointestinal tract. Bacteroides fragilis and Escherichia coli are the two furthermost 
communal isolates in furthermost studies of intra-abdominal infections [6, 7, 8, 9[ 
Also, the most common postoperative complications are postoperative fever, postoperative 
infection, atelectasis, embolism and Deep Vein Thrombosis (DVT). Postoperative infections 
include postoperative sepsis, urinary tract infection, chest infection, peritonitis, pelvic 
abscess, and surgical site infection. The highest incidence of postoperative complications is 
between one and three days after the operation. However, specific complications occur in the 
following distinct temporal patterns: early postoperative, several days after the operation, 
throughout the postoperative period and in the late postoperative period. ] 
[
10  
Pelvic inflammatory disease (PID) is one of pelvi-abdominal infections that ranges from acute 
salpingitis to salpingo-oophoritis and ultimately pelvic abscess, if the disease process 
proceeds unabated. Morbidity is high, 20% of affected women become infertile,]11[ 30% 
develop chronic pelvic pain and around 1% of those who conceive have an ectopic 
pregnancy.]12[ There are neither pathognomonic symptoms nor specific laboratory tests to 
diagnose PID. However, specimens from the vagina and cervix should be taken for direct 
microscopy, culture and sensitivity prior to starting empirical treatment. ]13[ In the absence of 
generalized peritonitis or septicemia, most PID patients may be treated initially with oral 
antimicrobials. When intravenous antimicrobials are initiated, they should be continued for 
24 hours after clinical response before converting to oral therapy. A 14-day course is 
recommended for adequate treatment. Surgical intervention may be required to either 
confirm the diagnosis of PID or surgical drainage of pelvic abscesses. Also, it should be 
considered in the following conditions: clinical failure with oral therapy, severe PID, 
inability to tolerate an oral regimen and in pregnancy. ]12 - 13[ 
7 
 Rationale & Correlative Studies 
7.1 Rationale: 
Ciprodiazole® (Ciprofloxacin & Metronidazole) is active against a broad spectrum of 
obligate anaerobic bacteria, including Bacteroids Species (spp.), Fusobacterium spp., 
Clostridium spp., Treponema spp. and various anaerobic cocci. The action is trichomonicidal 
and bactericidal. So, it is indicated in the treatment of Pelvi-abdominal caused by Gram 
negative bacteria such as E. coil, Pseudomonas aeruginosa, Proteus mirabilis, Klebsiella 
pneumonia, or Bacteroides fragilis or others. 
In this study, we compare the safety and efficacy of oral Ciprodiazole 500 mg® 
(Ciprofloxacin /Metronidazole) versus currently used Ciprofloxacin Tablets & Metronidazole 
tablets in pelvi-abdominal infections and/or following IV antibiotics in post-operative period, 
for pelvi-abdominal surgeries or acute conditions   

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7.2 Correlative Studies: 
The results of a randomized trial comparing sequential Intravenous (IV) / oral treatment with 
Ciprofloxacin plus Metronidazole to lmipenem/ Cilastatin for IAIs showed that Ciprofloxacin 
plus Metronidazole were found to be effective for the treatment of serious and complicated 
IAIs. In addition, sequential IV/ oral therapy with Ciprofloxacin plus Metronidazole was 
efficacious in patients able to tolerate oral intake.]14[ 
The comparison study of IV / oral Ciprofloxacin plus Metronidazole versus Piperacillin / 
Tazobactam in the treatment of complicated IAIs proved that initial administration of IV 
Ciprofloxacin plus Metronidazole followed by oral Ciprofloxacin plus Metronidazole therapy 
is clinically more effective than IV Piperacillin/Tazobactam for the treatment of patients with 
complicated IAIs. ]15[ 
A meta-analysis of comparative trials of Ciprofloxacin/metronidazole versus β – lactam in 
treatment of IAIs suggested that the ciprofloxacin/metronidazole combination may be 
superior to β – lactam-based therapeutic regimens in the treatment of IAIs with regard to cure 
of infections, although no difference in mortality was found. ]16[ 
8 Treatment: 
The treatment will be prescribed in the usual manner in accordance with the terms of the 
local marketing authorization with regards to dose, population and indication. 
8.1 Ciprodiazole ® Tablets: 
Each film coated tablet of Ciprodiazole ® consists of Ciprofloxacin hydrochloride 500 mg, 
Metronidazole 500 mg, and excipients; pregelatinized starch, sodium starch glycolate, P.V.P 
K 30, lactose monohydrate 200 mesh, sodium lauryl sulphate, magnesium stearate, and 
wincoat green. It is indicated for Pelvi-abdominal infections caused by E. coli, Pseudomonas 
aeruginosa, Proteus mirabilis, Klebsiella pneumonia, or Bacteroides fragilis and 
diverticulitis. Ciprodiazole ® is manufactured by Minapharm under Marketing Authorization 
Number: 26357/2009, dated 01/10/2009 
After oral administration, Ciprofloxacin is well absorbed from the abdominal tract. Oral 
bioavailability is approximately 70 % ]17[ and a peak plasma concentration of about 2.5 mcg 
per ml is achieved after 1 to 2 hours after a dose of 500 mg by mouth. Metronidazole is 
rapidly absorbed, 80 % is absorbed in one hour. The peak concentration is achieved after 1 to 
2 hours after the oral administration. Metronidazole passes the placenta and the maternal 
milk. The essential excretion is through the liver and the bile. They are absorbed readily and 
almost completely from the gastrointestinal tract. Serum concentrations reach their peak 
within one hour of oral ingestion. 
Ciprodiazole is contraindicated in the following conditions: 
- 
Hypersensitivity to ciprofloxacin or other antibiotics of Quinolones group such as 
Orfloxacin, Norfloxacin, Trovofloxacin, and Ofloxacin. 
- 
Hypersensitivity to the metronidazole or other nitroimidazole derivatives 
- 
Children and adolescents below 16 years. 
- 
Epilepsy or other seizure disorders. 

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- 
Patients with Glucose-6-Phosphate Dehydrogenase (G6PD) enzyme deficiency. 
 
Sponsor will provide the study treatment for the patients’ whole duration according to 
regulation of Local Health Authorities involved in the product supply since the drug is being 
used according to the approved marketing label. 
The investigator and the research team must evaluate all adverse events and laboratory 
abnormalities during the study. 
A drug-related toxicity or laboratory value outside of the reference range; that is judged by 
the investigator as having a “reasonable possibility" of being related to the study drug; will 
be considered as an adverse event. 
Drug-Toxicity is deemed “clinically significant" based on the medical judgment of the 
investigator.  Laboratory abnormalities will be managed as deemed clinically appropriate by 
the investigator until resolved. 
The investigator should ensure that any study drug interruptions or dose modifications and 
associated adverse events are promptly entered into the medical records. 
8.2  Ciprofloxacin Hydrochloride: 
Ciprofloxacin is a synthetic broad spectrum fluoroquinolone antibiotic. It acts by inhibiting 
DNA gyrase, which is essential in the reproduction of bacterial DNA. This agent is more 
active against Gram-negative bacteria than Gram-positive bacteria and aerobic organisms 
commonly encountered in pelvi-abdominal infections. ]18 - 19[ 
Ciprofloxacin is indicated for the treatment of the following infections caused by susceptible 
organisms: urinary tract infections, acute uncomplicated cystitis, chronic bacterial prostatitis, 
lower respiratory tract infections, acute sinusitis, skin and skin structure infections, bone and 
joint 
infections, 
complicated 
Pelvi-abdominal 
infections 
(used 
in 
combination 
with metronidazole)
[
41
]
, infectious diarrhea, typhoid fever (enteric fever), uncomplicated 
cervical and urethral gonorrhea, inhalational anthrax (post-exposure), and to prevent 
infections occurring after operations.  
Ciprofloxacin is well absorbed from the abdominal tract. Oral bioavailability is 
approximately 70% ]17[ and a peak plasma concentration of about 2.5 mcg per ml is achieved 
after 1 to 2 hours after a dose of 500 mg by mouth. The serum elimination half-life in 
subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of 
an orally administered dose is excreted in the urine as unchanged drug. ]18[ 
Ciprofloxacin is contraindicated in subjects with a history of hypersensitivity to ciprofloxacin 
or any member of the fluoroquinolone class of antimicrobial agents. The most frequently 
reported drug related events, from clinical trials for all indications of ciprofloxacin therapy 
were nausea, diarrhea, liver function tests abnormality, vomiting, and rash.  
8.3 Metronidazole: 
Metronidazole belongs to a group of medicines called anti-infective agents. It may be used to 
treat infections, caused by bacteria of the blood, brain, bone, lung, stomach lining and pelvic 
area, following childbirth or an operation. Also, it is used to treat urinary or genital infections 
caused by Trichomonas Vaginalis, Gardnerella Vaginalis, Giardia lambia and Entamoeba 
histolytica, gum and teeth infections, infected leg ulcers or pressure sores, stomach ulcers 
caused by Helicobacter pylori or to prevent infections occurring after operations. 

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Metronidazole is a prodrug. Unionized metronidazole is selective for anaerobic bacteria due 
to their ability to reduce metronidazole to its active form. This reduced metronidazole then 
covalently binds to DNA, disrupt its helical structure, inhibiting bacterial nucleic acid 
synthesis and resulting in bacterial cell death. 
After oral administration, Metronidazole is rapidly absorbed, 80 % is absorbed in one hour. 
The peak concentration is achieved after 1 to 2 hours after the oral administration. 
Metronidazole passes the placenta and the maternal milk. The serum elimination half-life in 
subjects is 8 hours. The essential excretion is through the liver and the bile.  
The most common side effects include: allergic reactions such as skin rash, swelling of the 
face, lips, tongue or throat, fever or difficulty in breathing.  
Metronidazole is contraindicated in case of Hypersensitivity to Metronidazole and First 
trimester of pregnancy, while it should be administered with caution to patients with the 
following conditions: 
- Convulsive seizures and peripheral neuropathy 
- Patients with active neurological disorders 
- Decreased Neutrophils or a history of blood dyscrasias 
- Prolonged QT interval on ECG 
- Severe liver disease 
8.4 Dosage & Administration: 
8.4.1 Ciprodiazole ® Tablets: 
The recommended dosage of ciprodiazole® is 1 tablet every 12 hours for a duration not 
exceeding 15 days, according to the investigator’s decision. The tablet should be swallowed 
with plenty of water. 
8.4.2 Ciprofloxacin ® Tablets: 
The recommended dosage of Ciprofloxacin tablets is 500 mg every 12 hours for 7 to 14 days, 
according to the investigator’s decision. Tablets should be swallowed with plenty of fluid, 
during or after meals. It is contraindicated to be taken with dairy products such as milk or 
yoghurt or with fortified fruit juices (e.g. calcium-fortified orange juice). 
The usual dose of Ciprofloxacin should be modified in patients with severe renal impairment, 
as the following table of the dosage guidelines, according to the Creatinine Clearance (CrCl): 
 
CrCl (mL/min) 
Dose 
> 50  
Usual Dosage 
30 – 50  
250 – 500 mg every 12 h 
5 – 29  
250 – 500 mg every 18 h 
Patients on hemodialysis or 
Peritoneal dialysis 
250 – 500 mg every 24 h 
(after dialysis) 

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8.4.3 Metronidazole ® Tablets: 
Tablets should be swallowed with plenty of water, during or after meals. The recommended 
dose is 7.5 mg/kg every 6 hours (approx. 500 mg for a 70-kg adult every 6 hours). A 
maximum of 4 g should not be exceeded during a 24-hour period for 7 to 10 days, according 
to the investigator’s decision. 
For patients with severe renal impairment (CrCl < 30), the dose of Metronidazole ® Tablets 
should be reduced by 50% 
8.5 8.5 Precautions: 
Fluoroquinolones are contraindicated with patients with known history of myasthenia gravis, 
because they have neuromuscular blocking activity and may exacerbate muscle weakness.  
The overdose may lead to loss of appetite, diarrhea, metallic taste, headache, dizziness, 
insomnia or drowsiness. 
The following is a list of possible side effects that may occur, rarely, from the use of 
Ciprodiazole ® tablets: 
- 
Allergic reactions such as rash, itching, and swelling of the mouth, face, lips, or 
tongue  
- 
Nausea, headache, anorexia, diarrhea, unpleasant metallic taste, stomach cramps pain, 
vomiting, fainting, and fever. 
- 
Reversible neutropenia (leukopenia), and blood dyscrasias. 
- 
Dysuria, darkening of urine, cystitis, bloody stools, abdominal and vaginal yeast 
infection.  
- 
Tendon inflammation and damage. 
- 
Irregular heartbeat and loss of consciousness. 
- 
Mood or mental changes such as anxiety, confusion, depression, and sleeplessness. 
- 
Convulsive seizures and peripheral neuropathy tremors. 
- 
Jaundice. 
8.5.1 Storage and Drug Accountability:  
Study drugs are to be stored at room temperature up to 30 degrees C (86 degrees F). Keep 
them in the original containers. Store away from heat, moisture, and light. Do not store in the 
bathroom. Keep them out of the reach of children and away from pets. 
All empty, partially used, and unused blisters will be retained by the Investigator (at room 
temperature) until they are returned to the pharmacist and to be checked by monitor. 
8.5.2 Dispensing 
The Sponsor will be responsible for providing the study drugs either Ciprodiazole ® Tablets 
(Ciprofloxacin/Metronidazole) or Ciprofloxacin Tablets & Metronidazole tablets to the 
patients in a quantity enough to be used till the end of the study and will record the patient’s 
number and initials.  
 
 

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8.6 Risks & Benefits of study drug 
Benefit: Ciprodiazole® (Ciprofloxacin & Metronidazole) is active against a broad spectrum 
of aerobic/anaerobic bacteria. So, it is indicated in pelvi-abdominal infections and/or 
following IV antibiotics in post-operative period, for pelvi-abdominal surgeries or acute 
conditions, it will be supplied by the sponsor. 
Risk: The most frequently reported side effects of ciprofloxacin are nausea, diarrhea, liver 
function tests abnormality, vomiting, and rash.  
The most common side effects of Metronidazole are allergic reactions such as skin rash, 
swelling of the face, lips, tongue or throat, fever or difficulty in breathing.  
8.7 Discontinuation and Modification of Dosing of Ciprodiazole ®: 
 The usual dose should be reduced in patients with severe renal disease  
 In the event that a positive result is obtained on a pregnancy test for a patient, the 
administration of Ciprofloxacin and Metronidazole must be discontinued immediately. 
8.8 Concomitant Medication: 
Throughout the study, Investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those listed in 
the exclusion criteria. If these are required, the participant will be withdrawn. A medication, 
other than the study medication (Ciprofloxacin or Metronidazole) taken during the study will 
be recorded in the CRF. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins 
and/or herbal supplements) that the subject is receiving from 2 weeks prior to study drug 
administration and during the study, must be recorded in the paper case report form along 
with the reason for use, date(s) of administration including start and end dates, and dosage 
information including dose, route and frequency. 
The investigator should review all concomitant medications for any potential interactions. 
Ciprodiazole ® Tablets (Ciprofloxacin hydrochloride & Metronidazole) is contraindicated 
with administration of tizanidine, because this may cause low blood pressure and sleepiness 
Ciprodiazole ® Tablets is contraindicated with administration of antacids containing 
magnesium and aluminum, supplements and other products containing calcium, iron or zinc 
because they reduce the effect of Ciprofloxacin. 
Metronidazole potentiates the anticoagulant effect of Warfarin and other oral coumarin 
anticoagulants resulting in a prolongation of prothrombin time. 
The simultaneous administration of drugs that induce microsomal liver enzymes, such as 
Phenytoin or Phenobarbital, may accelerate the elimination of metronidazole while the 
simultaneous administration of drugs that decrease microsomal liver enzymes activity, such 
as cetrimide, may prolong the half-life and decrease plasma clearance of metronidazole. 
Ciprofloxacin may increase the effects of caffeine. 
Serious and fatal reactions have occurred when Ciprofloxacin was taken in combination with 
theophylline. These reactions have included cardiac arrest, seizures, status epilepticus, and 
respiratory failure.  

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Tendon disorders (tendinitis) have been rarely encountered in some cases related to 
concomitant use of quinolone with corticosteroids. 
9 Research Question & Study Objectives 
9.1 Primary Objective: 
9.1.1 Primary Safety: 
To compare safety of oral Ciprodiazole® tablets (Ciprofolxacin/Metronidazole) versus 
currently used Ciprofloxacin Tablets & Metronidazole tablets in pelvi-abdominal infections, 
either non-operative or post- operative following IV antibiotics. 
9.1.2 Primary Efficacy: 
To compare efficacy of oral Ciprodiazole® tablets (Ciprofolxacin/Metronidazole) versus 
currently used Ciprofloxacin Tablets & Metronidazole tablets in pelvi-abdominal infections, 
either non-operative or post- operative following IV antibiotics  
9.2 Secondary Objective: 
9.2.1 Secondary Safety: 
- 
Presence of any signs/symptoms of post-operative wound infection such as redness, fever 
or wound discharge. 
- 
Presence of undesirable effects on total leukocyte count and liver enzymes (SGOT & 
SGPT)  
9.2.2 Secondary Efficacy: 
- 
To compare the complete resolution or improvement of Pelvi-abdominal infection 
between ciprodiazole® versus combined treatment, based on pelvi-abdominal ultrasound 
and others 
- 
To compare the days for complete healing of post-operative wounds between 
ciprodiazole® versus combined treatment 
10 Research Methods 
10.1 Study Design: 
This is a single center, open Label, controlled, interventional phase IV Study conducted in 
Menoufia University Hospital in Egypt to compare the safety and efficacy of oral 
Ciprodiazole® tablets (Ciprofloxacin/Metronidazole) versus currently used Ciprofloxacin 
Tablets & Metronidazole tablets in pelvi-abdominal infection and following IV antibiotics in 
post-operative period, for pelvi-abdominal surgeries or acute conditions   
This study is a clinical trial that will enroll 312 patients, who had pelvi-abdominal infection 
and/or started IV antibiotics for 48 hours, post-operative or till be able to tolerate oral intake 
in post-operative period, for pelvi-abdominal surgeries. They will be divided into two 

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treatment groups; group A: patients are treated with Ciprodiazole 
® tablets 
(Ciprofloxacin/Metronidazole) and group B (control group): patients are treated with the 
currently used Ciprofloxacin Tablets & Metronidazole tablets, using computer-generated 
randomization list, generated by the Data Management department (DM) of the CRO (Nagy 
Research) for the 2 groups who will be enrolled in this study will agree to the release of 
information and sign an informed consent.  Subjects included in this study are enrolled for 
the collection of data that reflect the care they receive under routine clinical circumstances. 
All provided care should be according to protocol and the local standard of medical care. 
The screening and enrollment period is planned to be 12 months. Subject will start receiving 
the treatment for a duration not exceeding 15 days. And with post-operative cases, subject 
will start receiving the treatment after IV antibiotics for 48 hours or till be able to tolerate 
oral intake. Follow up will be for 15 days from enrolment till End of treatment. 
10.2 Study Setting: 
 
 
Subjects will consent to the collection of study related information while on the study. 
Subjects will be informed that data will be collected about their health while they are 
enrolled in this study.  They may choose to withdraw at any time.  Subjects will be advised 
that data collected in this study will be provided to the Sponsor, and may be reported to 
regulatory authorities or published in scientific journals.  In any of these events, the 
subjects’ identities will not be revealed. 
10.2.1 Inclusion Criteria: 
Subjects meeting all of the following criteria will be considered for enrollment in the study: 
1. Egyptian male and female patients aged between 18-65 years’ old 
2. Subjects having pelvi-abdominal infections such as and not limited to: Ulcerative colitis, 
Diverticulitis, Cholecystitis, and PID (e.g oophoritis and salpingo-oophoritis). 
3. Subjects during post-operative period for pelvi-abdominal surgery and following IV 
medication with Metronidazole injection plus third generation cephalosporin. 
4. Subjects who are willing to sign Informed Consent Form (ICF) and ready to comply with 
the protocol for the duration of the study 
10.2.2 Exclusion Criteria: 
Subjects presenting with any of the following will not be included in the study: 
1. Subjects with a history of hypersensitivity to any of the active ingredients of the 
treatments used 
2. Subjects who are receiving or received any other antibiotics during the previous two 
weeks, rather than IV treatment in the first post-operative 48 hours, mentioned in the 
protocol (Metronidazole injection plus third generation cephalosporin) 
3. Subjects with Pelvi-abdominal infection and performed surgery after failure of 
oral antibiotics. 
4. Subjects having surgeries such as colorectal surgeries, appendectomy and ovarian 
cystectomy 
5. Subjects with any medical condition requiring the usage of the following 
medications:  

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a. Drugs that induce microsomal liver enzymes, such as Phenytoin or 
Phenobarbital, may accelerate the elimination of metronidazole  
b. Drugs that decrease microsomal liver enzymes activity, such as cetrimide, 
may prolong the half-life and decrease plasma clearance of metronidazole. 
c. Administration of theophylline in combination with Ciprofloxacin may lead 
to cardiac arrest, seizures, status epilepticus, and respiratory failure  
d. Administration of corticosteroids in combination with Ciprofloxacin may 
lead to tendinitis 
e. Antacids containing magnesium and aluminum, supplements and other 
products containing calcium, iron or zinc as they reduce the effect of 
Ciprofloxacin. 
f. Tizanidine because this may cause low blood pressure and sleepiness 
6. Subjects with uncontrolled diabetes mellitus; FBG > 200 mg/ml 
7. Subjects with renal impairment (S. Creatinine > 1.5 mg/dL)  
8. Subjects with hepatic impairment (Child-Pugh Score B-C) 
9. Subjects with liver enzymes (SGOT, SGPT) > 2 times Normal range. 
10. Pregnant or breast feeding women  
10.2.3 Discontinuation/Withdrawal of participants from the study: 
 
Each participant has the right to withdraw from the study at any time.  
In addition, the investigator may discontinue a participant from the study at any time 
if the investigator considers it necessary for any reason including: 
1. Ineligibility (either arising during the study or retrospective having been 
overlooked at screening) 
2. Significant protocol deviation 
3. Significant non-compliance with treatment regimen or study requirements 
4. Disease progressions which requires discontinuation of the study 
medication or results in inability to continue to comply with study 
procedures. 
5. Consent withdrawn by subject. 
6. Lost to follow up 
7. SAE or death 
8. If a female subject becomes pregnant 
9. Subjects which have Cholecystitis and it will be operated upon.   
The reason for withdrawal will be recorded in the CRF. If the participant is 
withdrawn due to an adverse event, the investigator will arrange for follow-up visits 
or telephone calls until the adverse event has resolved or stabilized. 
10.2.4 Assessments to be done: 
1- Screening Visit Assessments:  
 The enrollment period will be 12 months including the screening visit. Screening 
assessments will be completed and treatment will be initiated within visit 1. 
 During this visit, patients will be screened for fulfillment of the inclusion and 
exclusion criteria and written informed consent will be obtained. 
 Screening assessments will include physical examination, medical history, patient 
demographics, vital signs, concomitant medications, safety laboratory tests 

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(including Fasting Blood Sugar (FBS), Total leukocyte count, Liver enzymes (SGOT 
& SGPT), Total Bilirubin and S. Creatinine), Child-Pugh Score (for hepatic 
impairment) and, β-HCG (for females of child bearing potential only) and pelvi-
abdominal Ultrasound & others. 
 Presence of any signs/symptoms of post-operative wound infection such as redness, 
fever or wound discharge will be recorded (in case of post-operative subjects) 
2- Follow-up 1 Visit:(Day 8):  
 On-treatment assessments include physical examination, vital signs, AEs, SAEs, 
concomitant medication and study drug dosing compliance  
  Days for complete healing will be checked  
 Complete resolution, improvement, failure or relapse of Pelvi- abdominal infection 
 Presence of any signs/symptoms of post-operative wound infection such as redness, 
fever or wound discharge will be recorded (in case of post-operative subjects) 
 
3- Follow-up 2 Visit & End of study visit (Day 15):  
 Assessments include physical examination for vital signs, AEs, SAEs, concomitant 
medication, and study drug dosing compliance  
 Pelvi-abdominal Ultrasound and others will be done, if needed upon Physician’s 
decision. 
  Days for complete healing will be checked  
 Complete resolution, improvement, failure or relapse of Pelvi- abdominal infection 
 Presence of any signs/symptoms of post-operative wound infection such as redness, 
fever or wound discharge will be recorded (in case of post-operative subjects) 
 Safety laboratory tests (including Total Leucocytic count, Liver enzymes (SGOT & 
SGPT), Total Bilirubin and S. Creatinine) 
 The End of Study Form must be completed. 
10.3 Variables: 
10.3.1 Primary Endpoints:  
1- Primary Safety: 
Incidence of serious/non-serious adverse events 
2- Primary Efficacy: 
- 
Complete resolution for pelvi-abdominal infection based on pelvi-abdominal 
ultrasound and others and/or clinical response 
- 
Complete healing of post-operative wounds  
10.3.2 Secondary Endpoints:  
1- Secondary Safety: 
- 
 Presence of any signs/symptoms of post-operative wound infection such as 
redness, fever or wound discharge. 
- 
Change in Total leukocytes count and Liver enzymes (SGOT, SGPT), between 
baseline (visit 1) to End of study visit (Follow up 2 visit) 

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- 
 
2- Secondary Efficacy: 
- 
Describe complete resolution, improvement, failure or relapse of pelvi- abdominal 
infection based on pelvi-abdominal ultrasound and others and or clinical response. 
- 
Days for complete healing of post-operative wounds after 8 days of treatment (Follow-up 
1 V) & 15 days of treatment (End of study visit) between the 2 groups 
10.4 Data Sources: 
All visits assessments will be kept in the source files for each patient and in CRF, which will 
be verified by the CRA responsible. 
10.5 Study Size 
Subjects having pelvi-abdominal infection, in post-operative period of pelvi-abdominal 
surgeries or acute conditions will be selected from the surgical department in Menoufia 
University Hospital and some subjects might be referred from other departments in 
Menoufia University Hospital such as and not limited to; the department of Gynecology 
and Obstetrics. Patients will be asked to participate in the study and sign the informed 
consent, then screening for inclusion and exclusion criteria will be done and recorded in the 
patient’s medical records (either enrolled or screening failure). 
10.5.1 Determination of Sample Size 
As the primary objective is to assess the safety of oral Ciprodiazole ® tablets (Ciprofolxacin 
/Metronidazole) versus currently used Ciprofloxacin Tablets & Metronidazole tablets 
following IV antibiotics in post-operative period, for pelvi-abdominal surgeries, and based 
on the previous study “Comparison of Intravenous/Oral Ciprofloxacin Plus Metronidazole 
Versus Piperacillin / Tazobactam in the Treatment of Complicated Intra-abdominal 
Infections”.[15]  Overall clinical resolution rates were statistically superior for CIP+MET 
(74%) compared with PIP/TAZO (63%). Mean length of stay was 14 days for CIP1MET 
and 17 days for PIP/TAZO patients. 
So, the following parameters are used to calculate the expected sample of the study: 
 Design: non-inferiority 
 Sample Size = 312 Subjects (1:1) 
 Ciprodiazole Sample Size (Experimental group) = 156 subjects 
 Current used regimen Sample Size (Control group) = 156 subjects 
 Confidence level 95% (α error = 5%) 
 
Power = 80% 
 
Non-Inferiority margin = 2% 
10.5.2 Sample Size & Treatment Groups:  
Total of 312 Egyptian patients who have pelvi-abdominal infection or started IV antibiotics 
in post-operative period, for pelvi-abdominal surgeries will be enrolled in the study and 
randomized, using a computer system, with a ratio of 1:1, into two categories as follows: 
 
1. Group will receive Ciprodiazole ® tablets; 156 patients  
2. Group will receive Ciprofloxacin Tablets & Metronidazole tablets; 156 patients  

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10.5.3 Randomization: 
Subjects will be randomized into the two treatment groups with a balanced ratio of 1:1. 
Randomization by block Computer-generated randomization lists will be established by 
Data Management department (DM) of CRO (Nagy Research). The number of patients of 
the two treatment groups will be balanced (ratio 1:1). (156 Ciprodiazole ®: 156 
Ciprofloxacin Tablets & Metronidazole tablets). 
A document describing the procedure of constitution of the randomization lists will be 
stored confidentially at Nagy Research CRO 
Block size: 2, 4 
The Randomization list will be done using website: 
(https://www.sealedenvelope.com/simple-randomiser/v1/lists) 
10.6 Data Management  
Data will be entered into a computer database with independent double data entry and will 
be validated with computer checks and manual review against source files. The patient’s 
data will remain confidential, since only the patients’ initials are on the CRFs. Queries will 
be sent to the investigators using data clarification forms, and resolved by the investigators 
who will sign and date the respective data clarification forms. Corresponding changes in the 
database will be made, documented, and independently verified. Subjects who drop out will 
fill the reason for premature end of the study and will be documented. 
10.7 Data Analysis 
10.7.1 Analysis populations 
 
Analysis of all efficacy variables will be performed only for patients who completed the 
study without protocol violation (as per protocol).  
Analysis of all safety variables will be performed for all patients (intent-to-treat 
population), who received even 1 dose of the treatment; either Ciprodiazole ® tablets or 
currently used Ciprofloxacin Tablets & Metronidazole tablets. 
10.7.2 Statistical methods 
 
This section provides specifications for preparation of final Statistical Analysis Plan (SAP), 
which will be issued prior to database lock. Any differences compared to this statistical 
section should be identified and documented in final SAP. Analysis will be done using 
SPSS version 21. 
10.7.3 Analysis variables 
Descriptive Analysis: 
 Descriptive analysis of the collected data. All enrolled patients will be included in the 
safety analysis. 
 All quantitative primary and secondary end point variables will be described  
 Data from primary and secondary endpoints will be summarized using appropriate 
summary statistics i.e. n (number of subjects), mean, Standard Deviation (SD), median 
and range. 

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Comparative Analysis:  
 All tests will be performed on the 5% level of significance. 
 Chi² test for unpaired categorical variables. 
 Paired t-test to estimate the change in numerical variables throughout the study visits. 
 Student t-test to estimate the comparison between the subgroups for the numerical 
variables.  
 P-values less than 0.05 will be considered statistically significant  
10.7.4 Main criteria 
 To compare safety of oral Ciprodiazole ® tablets (Ciprofolxacin/Metronidazole) versus 
currently used Ciprofloxacin Tablets & Metronidazole tablets in pelvi-abdominal 
infections, either non-operative or post-operative following IV antibiotics. 
 To compare efficacy of oral Ciprodiazole ® tablets (Ciprofolxacin/Metronidazole) versus 
currently used Ciprofloxacin Tablets & Metronidazole tablets in pelvi-abdominal 
infections, either non-operative or post-operative following IV antibiotics. 
10.7.5 Other criteria 
 To describe presence of any signs/symptoms of post-operative wound infection such as 
redness, fever or wound discharge. 
  To describe presence of undesirable effects on total leukocyte count and liver enzymes 
(SGOT & SGPT) between baseline (visit 1) to End of study visit (Follow up 2 V) 
 To compare the complete resolution, improvement, failure or relapse of Pelvi- abdominal 
infection between ciprodiazole® versus combined treatment, based on pelvi-abdominal 
ultrasound and others 
 
To compare the number of days for complete healing of post-operative wounds between 
ciprodiazole® versus combined treatment 
10.7.6 Primary Safety analysis 
A. Number of participants experiencing Serious Adverse Events (SAEs). [Time Frame: 
visit 1 to End of study visit]. 
 Frequency distribution (number & percent) of occurrence of SAEs necessitating a 
change or discontinuation of treatment. Chi² test will be used to determine p-value 
and significance between the 2 groups. 
 Frequency distribution (number & percent) of type and severity of SAEs. Chi² test 
will be used to determine p-value and significance between the 2 groups. 
B. Number of participants experiencing Adverse Events (AEs) leading to permanent 
discontinuation of the study drug. [Time Frame: visit 1 to End of study visit]. 
 Frequency distribution (number & percent) of causes of treatment discontinuations. 
Chi² test will be used to determine p-value and significance between the 2 groups. 
 Frequency distribution (number & percent) of occurrence of AEs necessitating a 
change or discontinuation of treatment. Chi² test will be used to determine p-value 
and significance between the 2 groups. 

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 Frequency distribution (number & percent) of type and severity of AEs. Chi² test will 
be used to determine p-value and significance between the 2 groups. 
10.7.7 Primary Efficacy analysis: 
A. Complete resolution for Pelvi- abdominal infection based on pelvi-abdominal 
Ultrasound  
 Frequency distribution (number & percent) of complete resolution for pelvi- 
abdominal infection. Chi² test will be used to determine p-value and significance 
between the 2 groups. 
B. Complete healing of the post-operative wounds [Time Frame: Follow-up 1 V to End 
of study visit]. 
 Frequency distribution (number & percent) of complete healing of the post-operative 
wounds. Chi² test will be used to determine p-value and significance between the 2 
groups. 
 Frequency distribution (number & percent) of incomplete healing of the post-
operative wounds. Chi² test will be used to determine p-value and significance 
between the 2 groups. 
 Frequency distribution (number & percent) of no healing of the post-operative 
wounds. Chi² test will be used to determine p-value and significance between the 2 
groups. 
10.7.8 Secondary Safety analysis: 
A. Presence of any signs/symptoms of post-operative wound infection such as redness, 
fever or wound discharge [Time Frame: visit 1 to End of study visit]. 
Frequency distribution (number & percent) of presence of any signs/symptoms of post-
operative wound infection such as redness, fever or wound discharge. Chi² test will be 
used to determine p-value and significance between the 2 groups. 
 
B. Change in Total leukocytes count between baseline (visit 1) to End of study visit  
Descriptive analysis (mean, Standard Deviation, Median, Interquartile Range, Minimum 
and Maximum) of total leucocyte will be from baseline (visit 1) to End of study visit. 
Percent change will be calculated between baseline to End of study. Paired t-test will be 
used to determine p-value and significance between baseline and at the end of the study. 
Unpaired t-test will be used to determine the p-value and significance between Changes 
in total leucocyte between 2 groups. 

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C. Change in Liver enzymes (SGOT) between baseline (visit 1) to End of study visit 
Descriptive analysis (mean, Standard Deviation, Median, Interquartile Range, Minimum 
and Maximum) of Liver enzymes (SGOT) will be from baseline (visit 1) to End of study 
visit. Percent change will be calculated between baseline to End of study. Paired t-test 
will be used to determine p-value and significance between baseline and at the end of 
the study. Unpaired t-test will be used to determine the p-value and significance between 
Changes in Liver enzymes (SGOT) between 2 groups. 
 
D. Change in Liver enzymes (SGPT) between baseline (visit 1) to End of study visit 
Descriptive analysis (mean, Standard Deviation, Median, Interquartile Range, Minimum 
and Maximum) of Liver enzymes (SGPT)will be from baseline (visit 1) to End of study 
visit. Percent change will be calculated between baseline to End of study. Paired t-test 
will be used to determine p-value and significance between baseline and at the end of 
the study. Unpaired t-test will be used to determine the p-value and significance between 
Changes in Liver enzymes (SGPT) between 2 groups. 
10.7.9 Secondary Efficacy analysis: 
A. Complete resolution, improvement, failure or relapse of Pelvi- abdominal infection 
 Frequency distribution (number & percent) of complete resolution, improvement, 
failure or relapse for Pelvi- abdominal infection. Chi² test will be used to determine p-
value and significance between the 2 groups. 
 Frequency distribution (number & percent) of improvement for Pelvi- abdominal 
infection. Chi² test will be used to determine p-value and significance between the 2 
groups. 
 Frequency distribution (number & percent) of failure for Pelvi- abdominal infection. 
Chi² test will be used to determine p-value and significance between the 2 groups. 
 Frequency distribution (number & percent) of relapse for Pelvi- abdominal infection. 
Chi² test will be used to determine p-value and significance between the 2 groups. 
B. Days for complete healing of post-operative wounds after 8 days of treatment 
(Follow up 1 visit) & 15 days of treatment (Follow up 2 visit or End of study visit) 
Descriptive analysis (mean, Standard Deviation, Median, Interquartile Range, Minimum 
and Maximum) of days for complete healing versus combined treatment will be after 8 
days of treatment (Follow-up 1 V) & 15 days of treatment (End of study visit). Percent 
change will be calculated between baseline to End of study. Paired t-test will be used to 
determine p-value and significance between baseline and at the end of the study. 
Unpaired t-test will be used to determine the p-value and significance between Changes 
in complete healing between 2 groups. 

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10.7.10 Interim analysis 
Optional 
10.7 Quality Control  
10.8.1Quality Assurance 
To ensure uniformity of study procedures across centers, the protocol, case report form, and 
safety reporting procedures will be reviewed with the investigators and his/her personnel 
responsible for the conduct of the study. Adherence to the protocol and verification of 
source data will be achieved through monitoring visits to the center. During the course of 
study monitoring, the entire study documentation will be checked for completeness and 
plausibility by the responsible CRA. Once the CRF is completed and signed, the CRA takes 
the data management copy and the data is entered into the database for analysis. CRFs will 
be kept in secure locked place or lockers. 
10.8 Limitation of the research methods 
Any issues relating to confounding, bias, generalizability, and random error are considered as 
a limitation to the study results. This study is randomized, open label, controlled study, which 
avoids bias from the physicians, patients or biostatistician.  Also, the study results are taken 
upon source document verification with the CRF in order to ensure the quality and non-bias 
of the data. 
11 Protection of Human Subjects 
This study will be conducted according to Good Clinical Practice (ICH-GCP) and in 
accordance with the Declaration of Helsinki as adopted by the 18th World Medical 
Assembly 1964 and subsequent amendments: Tokyo (1975), Venice (1983), Hong Kong 
(1989), Somerset West, Republic of South Africa (1996) and Edinburgh (2000).  
This study will be conducted in compliance to Good Clinical Practice (ICH-GCP) and in 
accordance with the Declaration of Helsinki, with a qualified principle investigator. 
Before the start of the study, subjects who appear suitable for inclusion in the study will be 
informed, as outlined in the protocol, about the objective, nature, scope, and potential 
benefits and risks of the study and any discomfort it may entail. The subject will be allowed 
sufficient time to reach a decision. The subject's consent will be documented on the form 
provided, which will be retained by the investigator; a copy of the informed consent 
declaration will be given to the subject to retain. Under the circumstances where signed 
informed consent is difficult to obtain from subjects due to illiteracy, witness should sign 
that the subject has been informed about all details of informed consent. The informed 
consent will be also signed and dated by the person who obtained the informed consent and 
signed/finger printed by the study participant, or his legal representative.  
The subject will be assured that all personal data would be treated in strict confidence. In the 
event that information of relevance to the subject became available during the study, this 
will be communicated to the subject. The subject has the right to withdraw the informed 
consent at any time. No study-specific investigations would be performed and no study-

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specific medication will be administered before informed consent is obtained .Case Report 
Forms will be provided for each subject's data to be recorded. 
12 Study Procedures: 
12.1 Informed consent: 
 The investigator must provide the patient with relevant, comprehensive, verbal and 
written information regarding the objectives and procedures of the study as well as 
the possible risks involved, as per ICH-GCP guidelines. 
 The patient should have enough time and opportunity to inquire about study details.  
All their questions should be answered in satisfying manner.  
 The patient must be informed about their right to withdraw from the study at any 
time, without having to give a reason. 
 Signed and dated informed consent must be obtained from all patients and in case of 
an illiterate patient, the patient will finger print with a witness who will sign and date, 
before undertaking any study related procedures, without any pressure or unduly 
influence from the treating doctor. 
12.2 Patient Enrollment 
After signing the informed consent form, each potential subject will be screened for 
eligibility based on the inclusion and exclusion criteria specified. Randomization will be 
done.  
All visits will occur as closely as possible to the scheduled visit dates with window of 3 days. 
In case of a premature discontinuation of the study, the subject, will be, if possible called in 
for a last visit. Even if the subject would not be able to attend, the 'End of Study' forms will 
be completed . 

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12.3 12.3 Schedule of visits  
 
Table 1: Schedule of Visits 
Observation 
Visit 1 
(Screening & 
treatment) 
(Follow-up 1 
V) 
(Follow-up 2 
V) 
End of Study 
Time lines 
Day 0 
Day 8 
Day 15 
Informed 
consent 
document 
signed 
X 
 
 
Review 
Inclusion/Exclusion 
criteria 
X 
 
 
Patient Demographics 
X 
 
 
Significant medical history and 
current disease status 
X 
 
 
Physical examination  
X 
X 
X 
Vital Signs 
X 
X 
X 
Child-Pugh Score 
X 
 
 
Concomitant medications  
X 
X 
X 
Safety Laboratory Tests: 
 
FBS 
Total Leucocytic count 
SGOT (ALT) 
SGPT (AST) 
Total Bilirubin 
S. Creatinine 
X 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Serum β-HCG: (for females in 
childbearing period) 
X 
 
 
Pelvi-abdominal Ultrasound & 
others (Optional) 
X 
 
X  
Study Drug Dispensed 
X 
X 
 
Drug Accountability 
 
X 
X 

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Observation 
Visit 1 
(Screening & 
treatment) 
(Follow-up 1 
V) 
(Follow-up 2 
V) 
End of Study 
Time lines 
Day 0 
Day 8 
Day 15 
Presence of any signs/symptoms 
of 
post-operative 
wound 
infection such as redness, fever 
or wound discharge. (in case of 
post-operative subjects) 
X 
X 
X 
Days for complete healing 
 
X 
X 
Complete resolution, 
improvement, failure or relapse 
of pelvi - abdominal infection 
 
X 
X 
AE 
 
X 
X 
SAE 
 
X 
X 
Study Completion Form 
 
 
X 
The subsequent visits will occur as follows : 
 Visit 1 (Screening & treatment initiation Visit): Day 0 
 
Follow-up V1: Day 8 (+/-) 3 days 
 
Follow-up V2 & End of Study Visit: Day 15 (+/-) 3 days 
12.3.1 Visit 1 (Screening & treatment initiation): 
- 
During this visit, subjects will be informed about the study.  If they are willing to 
participate in the study, they will sign the written ICF.  A copy of the signed ICF 
will be given to the subject. In addition, the subjects will be evaluated for study 
eligibility according to the inclusion and exclusion criteria. 
- 
Screening Assessments will include: physical examination, vital signs, 
demographic data (Age & Gender), medical history and concomitant medications. 
- 
Presence of any signs/symptoms of post-operative wound infection such as 
redness, fever or wound discharge will be recorded (in case of post-operative 
subjects) 
- 
Child-Pugh Score will be calculated for liver impairment and pelvi-abdominal 
Ultrasound and others will be done 
- 
Lab results will be checked for: (Fasting Blood Sugar (FBS), Total leukocytes 
count, liver enzymes (SGOT & SGPT), Total Bilirubin and S. Creatinine), and 
Serum β-HCG for females of child bearing potential only  
- 
The Investigator will keep a log of all subjects, who will sign the ICF.  Even if the 
subject would not pass the screening, his/her signed consent form will be retained 

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in the Investigator file and will be considered as screening failure. The reason(s) 
for screen failure will be recorded in the screen failure form in the screening log. 
- 
All data related to screening visit must be reviewed (signed and dated) by the 
Investigator to ensure that the subject will be eligible for the study, before 
dispensing the study drug. 
- 
Randomization will be done and subjects will be administered the study products; 
either Ciprodiazole® tablets or Ciprofloxacin Tablets & Metronidazole tablets. 
- 
Study products sufficient for the next 7 days will be supplied; either Ciprodiazole® 
tablets or Ciprofloxacin Tablets & Metronidazole tablets, and storage conditions 
will be explained. Study products supplied will be recorded. 
- 
Subjects will be asked to come after 7 days of treatment and bring the empty 
blisters of medication received, with window of 3 days. 
In case of any premature discontinuation of the study, the subject will be, if possible, 
called in for a last visit. Even if the subject was not able to attend the last visit, the End of 
Study Form must be completed. 
Child-Pugh Score will be recorded, as follows:  
The score employs five clinical measures of liver disease. Each measure is scored 1-3, 
with 3 indicating most severe derangement. [20] 
Table 2: Child-Pugh Score 
Measure 
1 point 
2 points 
3 points 
Total bilirubin,  
μmol/l (mg/dl) 
<34 (<2) 
34-50 (2-3) 
>50 (>3) 
Serum albumin, g/dl 
>3.5 
2.8-3.5 
<2.8 
Prothrombin 
time, 
prolongation (secs) 
<4.0 
4.0-6.0 
> 6.0 
Ascites 
None 
Mild 
Moderate to Severe 
Hepatic 
encephalopathy 
None 
Grade I-II (or suppressed 
with medication) 
Grade III-IV  
(or refractory) 
In primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC), the bilirubin 
references are changed to reflect the fact that these diseases feature high conjugated 
bilirubin levels.  The upper limit for 1 point is 68 μmol/l (4 mg/dl) and the upper limit for 
2 points is 170 μmol/l (10 mg/dl). 

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Chronic liver disease is classified into Child-Pugh class A to C, employing the added 
score from above.  
Table 3: Child-Pugh Classes 
Points 
Class 
5-6 
A 
7-9 
B 
10-15 
C 
The Investigator will keep a log of all subjects who will sign the consent form.  Even if the 
subject would not pass the screening, his/her signed consent form will be retained in the 
Investigator file. 
12.3.2 Follow-up 1 Visit (Day 8)  
It could the end of treatment for some subjects. 
The following procedures will be done this visit, and all relevant information will be 
recorded in the source document and forms: 
- 
Subjects will undergo thorough general physical examination and Vital signs 
- 
Presence of any signs/symptoms of post-operative wound infection such as 
redness, fever or wound discharge will be recorded (in case of post-operative 
subjects) 
- 
Any changes in concomitant medication, illness and treatment will be recorded.  
- 
Checking if any AE or SAEs happened and recording them in their separate forms.  
- 
Days for complete healing will be checked, if happened. 
- 
Complete resolution, improvement, failure or, relapse of Pelvi- abdominal 
infection will be recorded 
- 
Subjects will be asked to come after 15 days of the treatment (Day 15) for follow 
up, with window of 3 days  
- 
In case of any premature discontinuation of the study, the subject will be, if 
possible, called in for a last visit. Even if the subject was not able to attend the last 
visit, the End of Study Form must be completed. 
- 
In case of complete resolution, end of the study lab testing will be asked and 
recorded and End of the study Form will be completed 
12.3.3 Follow-up 2 Visit & End of Study Visit (Day 15): 
It is the end of study visit for subjects. 

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The following procedures will be done during this visit, and all relevant information will 
be recorded in the source document and forms: 
- 
Subjects will undergo thorough general physical examination and Vital signs  
- 
Presence of any signs/symptoms of post-operative wound infection such as 
redness, fever or wound discharge will be recorded (in case of post- operative 
subjects) 
- 
Any changes in concomitant medication, illness and treatment will be recorded.  
- 
Checking if any AE or SAEs happened and recording them in their separate forms. 
Days for complete healing will be checked.   
- 
Complete resolution, improvement, failure or, relapse of Pelvi- abdominal 
infection will be recorded  
- 
Lab results will be checked for: S. Creatinine, Total leukocytes count, Liver 
enzymes (SGOT, SGPT), and total bilirubin 
- 
Pelvi-abdominal Ultrasound and others will be done, if needed. 
- 
The End of Study Form must be completed. 
13 Management & Reporting of Adverse Events 
The physician is responsible for the safety of the patient.  The sponsor is responsible for 
the safety of his product and for reporting safety issues to the regulatory bodies according 
to appropriate regulations. In order for all parties to comply with their responsibilities, it is 
important that the physician documents and processes quality and safety issues in the 
following manner.  
13.1 Adverse Events (AEs): 
An AE is any undesirable medical event occurring to a subject in a clinical trial, whether 
or not considered related to the trial product(s). This includes events not seen at baseline 
or worsened if present at baseline. The following will not be recorded as AEs, if 
recorded at screening visit: Pre-existing conditions found as a result of screening 
procedures. 
Assessment of Intensity/Severity: 
The intensity or severity of an AE is defined as follows : 
 Mild: Transient symptoms, no interference with the subject's daily activities. 
 Moderate: Marked symptoms, moderate interference with the subject's daily 
activities. 
 Severe: Considerable interference with the subject's daily activities, unacceptable  
Assessment of Causality (as per WHO-UMC) 
 
The relationship of each AE to the study drug where there is a demonstrable cause-
effect association between two events, assessed by the investigator: 

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Causality Term 
Assessment of Causality 
Certain 
•Event or laboratory test abnormality, with plausible time 
relationship to drug intake  
•Cannot be explained by disease or other drugs  
•Response to withdrawal plausible (pharmacologically, 
pathologically)  
•Event definitive pharmacologically or phenomenological (i.e. an 
objective and specific medical disorder or a recognized 
pharmacological phenomenon)  
• Re-challenge satisfactory, if necessary 
Probable /Likely 
•Event or laboratory test abnormality, with reasonable time 
relationship to drug intake  
•Unlikely to be attributed to disease or other drugs •Response to 
withdrawal clinically reasonable  
• Re-challenge not required 
Possible 
•Event or laboratory test abnormality, with reasonable time 
relationship to drug intake  
•Could also be explained by disease or other drugs •Information on 
drug withdrawal may be lacking or unclear 
 
Unlikely 
•Event or laboratory test abnormality, with a time to drug intake that 
makes a relationship improbable (but not impossible)  
•Disease or other drugs provide plausible explanations 
Conditional/ 
Unclassified 
•Event or laboratory test abnormality  
•More data for proper assessment needed, or additional data under 
examination 
Un-assessable 
/Unclassifiable 
•Report suggesting an adverse reaction  
•Cannot be judged because information is insufficient or 
contradictory  
•Data cannot be supplemented or verified 
 
Outcome categories  
The outcome of each AE is recorded on the CRF, according to the following definitions : 
 Death Related to Adverse Event: if the termination of life as a result of an adverse 
event.  
 Not Recovered or Not Resolved: to indicate that the event has not improved or 
recuperated.   
 Recovered or Resolved: if the event has improved or recuperated.  
 Recovered or Resolved with Sequelae: if the subject recuperated but retained 
pathological conditions resulting from the prior disease or injury.  
 Recovering or Resolving: if the event is improving but has not yet fully recovered  
 Unknown: if the outcome was not known, not observed or not recorded 

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Clinical Laboratory Adverse Events (CLAEs)  
A Clinical laboratory AE is any abnormal clinical laboratory value that suggests a 
disease and/or organ toxicity and is of a severity, which requires active management i.e. 
change of dose, discontinuation of drug, more frequent follow-up or diagnostic 
investigation.  
13.2 Serious Adverse Events (SAEs  (  
A SAE is any adverse drug experience that at any dose results in any of the following 
outcomes : 
 Death 
 A life-threatening experience  
 Subject hospitalization or prolongation of existing hospitalization  
 A persistent or significant disability/incapacity  
 Congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious drug experience when, based upon 
appropriate medical judgment, they jeopardize the health of the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
In case of unexpected pregnancy for the study subject or study subject’s spouse, 
pregnancy reporting will be completed; for the outcome of the pregnancy and if there are 
any congenital anomaly. 
Non-serious Adverse Event: A non-serious adverse event is any AE, which does not 
fulfill the definition of a SAE . 
Collection, Recording, and Reporting of Adverse Events :  
 Any information regarding any adverse event will be collected and reported from 
the first study related activity till the end of the study and post-treatment follow-
up period . 
 At each contact, the subject will be asked about adverse events. 
 All adverse events, either observed by the Investigator or reported by the subject, 
will be recorded by Investigator and evaluated . 
Adverse events will be assessed at each visit. The subject will be asked about the adverse 
events.  Adverse events will be recorded both in the source document and the CRF.  The 
Investigator needs to record the diagnosis, if available. If no diagnosis will be available, 
the Investigator records each sign and symptom as an individual adverse event. The 
patient is given the investigator’s number to contact him 24/7 in case of any adverse 
event.  
All adverse events will be collected and recorded by the Investigator on the Adverse 
Event Form of the CRF and to the monitor for safety reporting. One single Adverse 
Event Form must be used per adverse event from start to resolution of the event. CIOMS 
form will be completed for all serious adverse events & reported to the Egyptian 
Pharmacovigilance Center (EPVC) as per the GVP timelines (During 15 calendar days 
for SAEs & 90 calendar days for non-serious AEs). Follow-up of all adverse events till 
resolution or stabilization. The reporting of SAE to the national medicines regulatory 
authority is a must, within 24 hours of PI notification, as per the IRB/EC of site and 
RHD of Egyptian MOH. 
 

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During subject's participation in the study, the Investigator/Institution will ensure that 
adequate medical care will be provided to the subject for any adverse event including 
clinically significant laboratory values related to the study. When the Investigator 
becomes aware of the adverse event, he/she will inform the subject and does the 
necessary follow-up.  
Only unresolved AEs will be followed up actively until the AE has resolved or 
stabilized.  No active follow-up with the subjects will be made during this period for 
occurrence of new adverse events. 
14 Plans for disseminating & communicating study results 
14.1 Progress Report 
Timely progress reports will be submitted according to the national medicines regulatory 
authority. The content of the progress report includes all the available data that are judged 
relevant to the progress of the study. 
14.2 Final Study Report  
The final study report will be submitted as soon as possible within 3 months of database 
lock. If the study is discontinued for any reason; a final report will be submitted and the 
reasons for terminating will be provided. The title, version and date of the protocol and 
author will be written in the title page. 
The final study report will follow Arab GVP content & include but not limited to: 
An abstract of the study, rationale and background, research methods, demographic, 
baseline characteristics, safety parameters will be analyzed for the total population of all 
enrolled (randomized) subjects. Efficacy analysis will be performed for the 'Per Protocol 
populations only. ITT patients will be analyzed for safety in the results section; results 
and limitations will be discussed in the discussion section of the report. 
Population is defined as follows : 
 Intention to Treat (ITT): all enrolled subjects with at least one baseline and one 
post-baseline visit.  
 Per Protocol (PP): all enrolled subjects who completed according to the protocol 
with no protocol deviations.  
Continuous variables will be summarized using mean, standard deviation, median, and 
range (minimum and maximum), while categorical variables will be summarized using 
proportions (counts and percentages) . 
Data on subject disposition (number of subjects enrolled, number of drop-outs, and 
reasons for drop-out), demographics (gender, age, weight, height), and other baseline 
characteristics (physical examination results, vital signs, and laboratory assessments) 
will be summarized. 
All biostatical results and analysis will be done as per endpoints as per protocol, as per 
section 10.7. 
Additionally, for each treatment, the incidences of all treatment emergent AEs will be 
tabulated by body system and preferred term (to which each AE will be mapped, using 
World Health Organization Adverse Reaction Terminology (WHO-ART), version 
1998/04). Other information regarding AEs, such as intensity, seriousness, causality, and 
discontinuations due to AEs, will be also tabulated by treatment. AEs that are reported 

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more than once by a subject will be counted only once for that subject at the maximum 
intensity. 
Concomitant medications will be tabulated by generic drug names, based on World 
Health Organization Drug Dictionary (WHO-DD), version 1998/04. 
15  Confidentiality and publication  
Patient names must be kept confidential and should not appear on any CRF page or study 
specific documents. 
The sponsor and health authorities are obligated to respect medical secrecy and to refrain 
from divulging any personal patient information  
15.1 Use of information  
The study data are the property of the sponsor (Minapharm Pharmaceuticals). The 
investigator and any of the research staff shall obtain written approval from the sponsor 
prior to the publication/communication of the results of any work carried out during or in 
relation to the study 
16  Archiving  
The investigators should retain all essential study-related documents e.g. signed protocol, 
investigator’s brochure, CRFs, medical records, laboratory reports, etc. in accordance 
with the applicable regulatory requirements of his/her country. 
The study-related documents should be kept together in the investigator site file provided 
to the investigator by the sponsor for minimum 5 years. 
17  Responsibility of Participants 
17.1 Responsibility of Investigators 
The investigators will conduct the study in accordance with ICH-E6, all applicable laws 
in the country where the study is conducted and in accordance with this study protocol 
The responsibilities of the investigator are summarized below but not limited to: 
1. Patient’s information and consent 
2. Information on the overall results of the study 
3. Information to other practitioners 
4. Adverse Events recording 
5. Data Recording in paper CRF 
6. Record Retention 
7. Use of study-related information 
8. Medicinal Product 
9. Quality Control 
10. Study Discontinuation 
11. Delegation of investigator duties 
12. Study Agreement Discontinuation 
13. Collect unused/returned drug from patients 

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14. Return collected unused/returned drugs to CRO; on behalf of Minapharm  
17.2 Responsibility of CRO: 
1. 
Design and write the protocol. 
2. 
Design the statistical section of the protocol 
3. 
Design CRFs 
4. 
Design informed consent 
5. 
Collect regulatory documents (EC of site and RHD of MOH) 
6. 
Develop investigator agreement template 
7. 
Prepare investigator’s signatures on participation in study 
8. 
Prepare Ethics Committee/ RHD of MOH file  
9. 
Ethics Committee followed by RHD of MOH submissions and collecting 
approvals. 
10. 
Follow up reports to Ethics Committee / RHD of MOH 
11. 
Design & distribute study site staff manual 
12. 
Train study site staff for GCP, CRF completion and safety notification: PI, 
co-investigators & rest of site staff 
13. 
Conduct initiation visits 
14. 
Set up trial master file (TMF) and Investigator Site File (ISF) for Principle 
Investigators 
15. 
Design study tracking system 
16. 
Randomization list 
17. 
Provide pharmacy briefing (temperature & etc.,) 
18. 
Conduct drug accountability 
19. 
Collect unused/returned drug from investigators 
20. 
Destroy unused/returned drug 
21. 
Conduct SIV, Follow-Up Monitoring visits and Close out visits. 
22. 
Provide site management 
23. 
Resolve CRF queries 
24. 
Provide project management services 
25. 
Revise SAE reports and send all AE cases (serious & non-serious) to EC & 
regulatory (RHD of MOH and EPVC) 
26. 
Prepare and submit regular interim report to EC of site and RHD of MOH 
including safety reporting of all adverse events whether serious or non-
serious. 
27. 
Design/build database 

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28. 
Generate queries 
29. 
Lock database 
30. 
Ship project-related documents to Sponsor 
31. 
Create statistical analysis plan 
32. 
Write statistical report 
33. 
Write interim and final clinical study report 
34. 
Write publication manuscript 
35. 
Assist on publication of paper in medical journal 
17.3 Responsibility of the Monitor 
The responsibilities of the study monitor are defined in ICH-E6, Chapter 5.  The 
monitor, who is mandated by the sponsor, must ensure that the study is conducted in 
accordance with GCP guidelines and all applicable local laws and that the rights, the 
security and well-being of the patients are respected. 
Responsibilities include: 
1. Communication 
2. Training 
3. Compliance 
4. Source Data Verification 
5. IP (in association with the sponsor). 
17.4 Responsibility of the Sponsor 
The sponsor; the pharmaceutical company (MINAPHARM) which is responsible and 
initiates the clinical investigation. 
Responsibilities include: 
1. Selecting qualified investigators.  
2. Determine investigator budget. 
3. Providing the investigators with the information they need to conduct an investigation 
properly.  
4. Identify the laboratory and other investigation centers 
5. Prepare Contract for laboratory 
6. Contracting an insurance company for the clinical study 
7. Ensuring proper monitoring of the investigation.  
8. Ensuring that the investigation is conducted in accordance with the general 
investigational plan and protocol.  
9. Shipping medicinal new drugs only to sites which are participating in the 
investigation.  
10. Giving each participating clinical investigator/ site an investigator brochure.  

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11. Reviewing and evaluating the evidence related to the safety and effectiveness of the 
drug as it is obtained from the investigator.  
12. If determining that its medicinal drug presents an unreasonable and significant risk to 
subjects, the sponsor will discontinue those investigations that present the risk, notify 
the medicine authorities, all institutional review boards and all investigators who have 
at any time participated in the investigation of the discontinuance.  
13. Reporting all adverse events to EPVC (Egyptian Pharmaco Vigilance Center) as per 
the GVP timelines 
17.5 Responsibility of the Data Manager 
The primary responsibility of data manager is to enter data from case report forms 
(CRFs) to computed database. The data manager is responsible for collecting all source 
documentation and worksheets prepared by all members of the research team and then 
transcribing the data on to the appropriate collection tool for submission to the sponsor. 
Specific responsibilities include but are not limited to the following: 
  Source document archiving after receiving from CRA. 
  File and pull study records 
  Case report form design, design CRF completion guidelines and its entry by 
assigned personnel 
  Review data for accuracy and completeness 
  Clarify data with research staff as necessary 
  Enter data into the computer 
  Correct/revise data as appropriate 
  Maintain back-up system for computerized data 
18 Audit and Inspection 
An audit/inspection may be carried out by qualified sponsor staff, by subcontracted 
auditors or by representatives of national or foreign health authorities to ensure that the 
study is conducted as per protocol and in accordance with regulatory requirements, and 
to ensure the validity of the data. 
Participation in this study implies acceptance to cooperate in any potential 
audit/inspection. Audit/inspection may take place after the end of the study.  

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19 References 
                                                
 
 
1- Sartelli M. A focus on intra-abdominal infections. World J Emerg Surg. 2010; 5:9. 
2- Pieracci FM, Barie PS. Management of severe sepsis of abdominal origin. Scand J 
Surg. 2007;96(3):184–196 
3- Sartelli M, Chichom-Mefire A, Labricciosa FM, Hardcastle T, Abu-Zidan FM, Adesunkanmi 
AK, et al. The management of intra-abdominal infections from a global perspective: 2017 
WSES guidelines for management of intra-abdominal infections. World J Emerg Surg. 
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