Clinical trial NCT03331263
Conditions: Surgical Skin Preparation
Sponsor: Medline Industries
Start date: 2017-07-21; Completion date: 2017-08-06
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A single 2% topical application of ReadyPrep® CHG was applied on either the abdomen (Treatment-1) or the groin (Treatment-2) whereas Treatment-3 consisted of a control treatment where the same procedure as Treatment-1 and -2 was performed, but without the topical application of ReadyPrep® CHG. The treatments were separated by a wash-out of 7 calendar days.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Chlorhexidine Gluconate
Intervention descriptions: intervention 1: 2% CHG

Protocol documents:
Prot_000.pdf: 
 
Medline Industries, Inc. Three Lakes Drive, Northfield, IL 60093 
 
 
Medline Industries, Inc. 
 
Three Lakes Drive  
 
1.847.949.5500 
www.medline.com  
 
Northfield, IL 60093  
                Toll Free: 1.800.MEDLINE  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SINGLE DOSE PHARMACOKINETIC STUDY TO ASSESS THE SYSTEMIC 
EXPOSURE OF CHLORHEXIDINE FROM ReadyPrep® CHG (2% CHLORHEXIDINE 
GLUCONATE CLOTH) 
 
Algorithme Pharma Protocol Number: 
MDL-P2-670 
Medline Protocol Number 
R17-023 
Investigational Product: 
ReadyPrep® CHG  
(2% Chlorhexidine Gluconate Cloth) 
Regulations: 
FDA 
Sponsor: 
Medline Industries, Inc. 
Three Lakes Drive 
Northfield, IL 60093 
Sponsor’s contact person: 
Alannah Minarcik 
Clinical Research Associate II 
Tel.: 847-643-3515 
Fax: 866-758-4660 
Email: AMinarcik@medline.com 
 
The study will be conducted in accordance with standards of Good Clinical Practice, as defined 
by the International Conference on Harmonisation and all applicable federal and local 
regulations. 
Protocol Version 
Date 
1.0 (Original) 
2017/06/14 
2.2 (Amendment 01) 
2017/07/13 
 
CONFIDENTIALITY STATEMENT 
 
The information provided in this document is strictly confidential and is available for review to investigator(s) 
and to the appropriate Independent Ethics Committee (IEC) or Institutional Review Board (IRB). It may not be 
used, divulged, published or otherwise disclosed without the written authorization from Algorithme Pharma or 
the Sponsor. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................................ 2 
LIST OF TABLES ....................................................................................................................................................... 4 
STUDY SYNOPSIS ..................................................................................................................................................... 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................................. 8 
FACILITIES .............................................................................................................................................................. 10 
PROTOCOL APPROVAL ....................................................................................................................................... 12 
PROTOCOL APPROVAL ....................................................................................................................................... 13 
PROTOCOL APPROVAL ....................................................................................................................................... 14 
1. INTRODUCTION .............................................................................................................................................. 15 
2. STUDY OBJECTIVES ...................................................................................................................................... 16 
3. STUDY TREATMENTS .................................................................................................................................... 16 
3.1. 
INVESTIGATIONAL PRODUCT .......................................................................................................................... 16 
3.2. 
PACKAGING AND LABELING ............................................................................................................................ 16 
3.3. RANDOMIZATION AND UNBLINDING PROCEDURES ......................................................................................... 16 
3.3.1. Treatment assignment ............................................................................................................................ 16 
3.3.2. Un-blinding procedure ........................................................................................................................... 17 
3.4. DRUG ACCOUNTABILITY ................................................................................................................................ 17 
4. STUDY DESIGN AND DURATION ................................................................................................................ 17 
5. SELECTION OF STUDY POPULATION ...................................................................................................... 18 
5.1. NUMBER OF SUBJECTS .................................................................................................................................... 18 
5.2. INCLUSION CRITERIA ..................................................................................................................................... 18 
5.3. EXCLUSION CRITERIA .................................................................................................................................... 19 
5.4. CRITERIA FOR REMOVAL OF A SUBJECT ......................................................................................................... 21 
5.5. RESTRICTIONS ................................................................................................................................................ 22 
5.5.1. Medications ............................................................................................................................................ 22 
5.5.2. Alcohol ................................................................................................................................................... 23 
5.5.3. Xanthines ............................................................................................................................................... 23 
5.5.4. Fluids ...................................................................................................................................................... 23 
5.5.5. Food ....................................................................................................................................................... 23 
5.5.6. Grapefruit, Seville Oranges, poppy-seed and pomelo-containing beverages and food .......................... 24 
5.5.7. Posture and physical activities ............................................................................................................... 24 
5.5.8. Contraceptive regimen throughout the study ......................................................................................... 24 
5.5.9. Other Activities ...................................................................................................................................... 24 
6. CLINICAL PROCEDURES .............................................................................................................................. 25 
6.1. DESCRIPTION OF STUDY DAYS ........................................................................................................................ 25 
6.1.1. Pre-trial evaluation ................................................................................................................................. 25 
6.1.2. Study days .............................................................................................................................................. 26 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.1.3. End of the study ..................................................................................................................................... 28 
6.2. SAMPLING DURING THE STUDY ...................................................................................................................... 29 
6.2.1. Blood sampling ...................................................................................................................................... 29 
6.2.2. Urine sampling ....................................................................................................................................... 30 
6.2.3. Sample processing, storage and shipping ............................................................................................... 30 
6.3. SAFETY MONITORING ..................................................................................................................................... 30 
6.3.1. Vital signs .............................................................................................................................................. 30 
6.3.2. ECG records ........................................................................................................................................... 30 
6.3.3. Visual skin evaluation ............................................................................................................................ 30 
6.3.4. Other measurements ............................................................................................................................... 30 
7. ADVERSE EVENTS .......................................................................................................................................... 31 
7.1. DEFINITIONS .................................................................................................................................................. 31 
7.2. SEVERITY ASSESSMENT ............................................................................................................................. 32 
7.3. CAUSALITY ASSESSMENT ............................................................................................................................... 33 
7.4. DOCUMENTATION AND REPORTING OF ADVERSE EVENTS ............................................................................... 33 
7.5. SERIOUS ADVERSE EVENT REPORTING REQUIREMENTS ............................................................... 34 
7.6. PREGNANCY ................................................................................................................................................... 34 
8. METHODS OF EVALUATION ....................................................................................................................... 35 
8.1. DRUG CONCENTRATIONS ................................................................................................................................ 35 
8.1.1. Bioanalytical assays ............................................................................................................................... 35 
8.1.2. Aberrant values and retested samples .................................................................................................... 35 
8.1.3. Incurred sample reproducibility ............................................................................................................. 36 
8.2. SAFETY DATA ................................................................................................................................................. 36 
9. PHARMACOKINETICS AND STATISTICS ................................................................................................. 36 
9.1. SUBJECTS TO ANALYZE .................................................................................................................................. 36 
9.2. PHARMACOKINETIC ANALYSIS ....................................................................................................................... 37 
9.3. 
STATISTICAL ANALYSIS .................................................................................................................................. 38 
9.4. SAMPLE SIZE JUSTIFICATION .......................................................................................................................... 38 
10. REGULATORY REQUIREMENTS ................................................................................................................ 39 
10.1. LIABILITIES .................................................................................................................................................... 39 
10.2. STATEMENT OF INVESTIGATOR ...................................................................................................................... 39 
10.3. DELEGATION OF INVESTIGATOR DUTIES ......................................................................................................... 39 
10.4. INSTITUTIONAL REVIEW BOARD (IRB) .......................................................................................................... 39 
10.5. INFORMED CONSENT FORM (ICF) .................................................................................................................. 40 
10.6. CASE REPORT FORM ...................................................................................................................................... 40 
10.7. RECORD RETENTION ....................................................................................................................................... 40 
10.8. QUALITY ASSURANCE/QUALITY CONTROL ..................................................................................................... 40 
10.9. MONITORING OF THE STUDY .......................................................................................................................... 41 
10.10. DATA MANAGEMENT AND PROCESSING ....................................................................................................... 41 
10.11. PREMATURE TERMINATION OR SUSPENSION OF A STUDY .............................................................................. 41 
10.12. ADHERENCE TO PROTOCOL .......................................................................................................................... 41 
11. REFERENCES ................................................................................................................................................... 42 
APPENDIX 1: AMENDMENT 01 ........................................................................................................................... 46 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF TABLES 
 
Table 1. Study Design and Schedule of Assessments................................................................... 43 
Table 2. Blood Sampling Schedule ............................................................................................... 44 
Table 3. Pharmacokinetic Parameters ........................................................................................... 45 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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STUDY SYNOPSIS 
 
Title of Study:  
Single Dose Pharmacokinetic Study to Assess the Systemic Exposure of 
Chlorhexidine from ReadyPrep® CHG (2% Chlorhexidine Gluconate 
Cloth) 
 
Phase:  
 
Phase I study 
 
Investigational Product: 
ReadyPrep® CHG (2% Chlorhexidine Gluconate Cloth) 
Manufacturer: Medline Industries, Inc., USA 
Treatments:  
 
Treatment-1: Abdominal application of ReadyPrep® CHG 
Treatment-2: Groin application of ReadyPrep® CHG 
Treatment-3: Control treatment with no application 
 
Objective: 
The primary objective of this study is to demonstrate that no or negligible 
systemic exposure occurs after a single topical application of ReadyPrep® 
CHG. 
 
The secondary objective of this study is to determine the safety and 
tolerability of a single topical application of ReadyPrep® CHG in healthy 
volunteers after a single topical application. 
 
Study Design: 
Single center, randomized, single dose, laboratory-blinded, 3-period, 3-
sequence, crossover design.  
 
Subjects: 
Twelve (12) subjects will be included in the study 
 
Main Inclusion Criteria: Male and female volunteers, non- or ex-smokers, ≥ 18 and ≤ 60 years 
of age (inclusive) with a body mass index (BMI) greater than or equal to 
19.00 and below or equal to 32.00 kg/m2 and a body weight ≥ 55 kg will 
be selected according to the inclusion and exclusion criteria. They will be 
healthy according to medical history, complete physical examination 
(including vital signs and skin examination) and laboratory tests (general 
biochemistry, hematology, urinalysis) 
including negative Human 
Immunodeficiency Virus (HIV), Hepatitis B and Hepatitis C tests as well 
as negative drug screening of alcohol, and drugs of abuse. For female 
subjects, a pregnancy test must be negative. 
 
Administration: 
In Treatment-1 and -2, a single topical application of ReadyPrep® CHG 
consisting of a 3-minute vigorous rub followed by a 1 minute dry time will 
be done at the application site. In one study period, the application site 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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will be the abdomen (surface area of approximately 5 x 5 inches) and in 
the other study period, the application site will be the groin (surface area 
of approximately 5 x 2 inches). 
 
 
Treatment-3 will consist of a control treatment where the same procedures 
as Treatment-1 and -2 will be performed, but without the topical 
application of ReadyPrep® CHG. 
 
Subjects will remain seated for at least the first 4 hours following each 
treatment. 
 
Blood Sampling: 
In each study period, 12 blood samples will be collected. Baseline levels 
will be assessed before each treatment. For baseline assessment, 3 blood 
samples will be collected prior to each treatment while the others will be 
collected up to 24 hours after each treatment. 
 
Housing: 
From at least 10 hours prior to each treatment until 24 hours following 
each treatment.  
 
Wash-out: 
The treatment will be separated by at least 7 calendar days. 
 
Tests during study: Drug and alcohol screening will be performed before each period of the 
study. 
 
For female subjects, a pregnancy test will be performed before each period 
of the study. 
 
General biochemistry tests will be performed before each period of the 
study. 
 
Vital signs will be measured prior to and approximately 12 and 24 hours 
following each treatment. 
 
Visual skin evaluation at the application site will be performed prior to 
and approximately 4, 8 and 24 hours after treatment.  
 
Poststudy Tests: 
Hematology, general biochemistry tests (including a pregnancy test for 
female subjects) and urinalysis will be repeated at the end of the study. 
 
A complete physical examination (including vital signs) will be 
performed. 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Safety data: 
Safety will be evaluated through the assessment of adverse events (AE), 
laboratory tests, vital signs, visual skin evaluation and physical 
examination. 
 
Bioanalysis: 
Chlorhexidine plasma concentrations will be measured by a validated 
bioanalytical method. 
 
Pharmacokinetics: In the event that chlorhexidine levels are measurable, the pharmacokinetic 
parameters will be estimated with and without baseline adjustment. Main 
absorption and disposition parameters will be assessed using a non-
compartmental approach with a log-linear terminal phase assumption. 
Trapezoidal rule will be used to estimate the area under the curve. The 
pharmacokinetic parameters of interest will be Cmax, AUC0-T and AUC0-∞. 
Other parameters including Tmax, AUC0-T/∞, λZ, Thalf, Cl/F and Vd/F will be 
calculated and provided for information purposes only. 
 
Statistics: 
No statistical analysis will be performed. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE: 
 
Adverse Event 
ALT:  
Alanine Aminotransferase 
ANDA: 
Abbreviated New Drug Application 
ASA:  
Acetylsalicylic Acid 
AST:  
Aspartate Aminotransferase 
BLQ: 
Below Limit of Quantitation 
BMI:   
Body Mass Index 
BPM:  
Beats Per Minute 
BUN:  
Blood Urea Nitrogen 
CV: 
 
Coefficient of Variation 
CFR:  
Code of Federal Regulations 
CRF:  
Case Report Form 
CYP:  
Cytochrome P450 
EDTA: 
Ethylene Diamine Tetraacetic Acid 
EMA:  
European Medicines Agency 
FDA:  
Food and Drug Administration 
g: 
 
Relative Centrifugal Force 
GCP:  
Good Clinical Practice 
GLP:  
Good Laboratory Practice 
GMP:  
Good Manufacturing Practice 
h: 
 
Hour 
HBsAG (B): Hepatitis B Surface Antigen 
HCV (C): 
Hepatitis C Virus 
HIV:  
Human Immunodeficiency Virus 
ICF: 
 
Informed Consent Form 
ICH:  
International Conference on Harmonisation 
IEC: 
 
Independent Ethics Committee 
IRB: 
 
Institutional Review Board 
kg: 
 
Kilogram 
L: 
 
Liter 
ln: 
 
Neperian log transformation 
LOQ:  
Limit of Quantitation 
MCV:  
Mean Corpuscular Volume 
MedDRA: 
Medical Dictionary for Regulatory Activities 
mg: 
 
Milligram 
min: 
 
Minute 
mL: 
 
Milliliters 
mmHg: 
Millimeter of Mercury 
NDA:  
New Drug Application 
ng: 
 
Nanograms 
NSAIDs: 
Non-steroidal Anti-inflammatory Drugs 
OTC:  
Over-the-counter 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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pH: 
The Logarithm, On The Base 10, of The Reciprocal of The Hydrogen Ion 
Concentration 
PK: 
 
Pharmacokinetic 
PR: 
 
Time between P and R wave 
PT: 
 
Preferred Term 
QA: 
 
Quality Assurance 
QC: 
 
Quality Control 
QRS:  
Complex between Q and S wave 
QTc:  
QT Interval Corrected for Heart Rate 
SAE:  
Serious Adverse Event 
SOC:  
System Organ Class 
SOP:  
Standard Operating Procedure 
SRA:   
Scientific and Regulatory Affairs 
ST: 
 
ST segment of the Electrocardiogram 
T: 
 
T wave of the Electrocardiogram 
ULQ:  
Upper Limit of Quantitation 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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FACILITIES 
 
AUTHOR OF THE PROTOCOL: 
Julie Basque, MSc., Senior Clinical Research Scientist 
Algorithme Pharma  
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
 
CLINICAL FACILITY: 
 
James Carlson, PharmD, Principal Investigator  
 
 
Jeffrey Peterson, MD, Medical Investigator  
 
 
Algorithme Pharma USA LLC 
 
 
4837 Amber Valley Pkwy S 
Fargo, ND 58104 
 
PHARMACY:  
 
 
Retain Pharmacy Solutions 
4837 Amber Valley Pkwy S 
Fargo, ND 58104 
 
BIOMEDICAL FACILITY: 
 
Sanford Health 
737 Broadway 
Fargo, ND 58122 
 
BIOANALYTICAL FACILITY: 
Yves Moras, V-P, Bioanalytical Services  
 
 
 
 
Algorithme Pharma  
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
 
PHARMACOKINETIC FACILITY: Marc Lefebvre, PhD, V-P, Scientific and Regulatory Affairs 
 
 
 
 
 
Algorithme Pharma  
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 
 
STATISTICAL FACILITY: 
Pascal Guibord, MSc, Senior Director, Biometrics  
 
 
 
 
Algorithme Pharma  
1200 Beaumont Ave. 
Mount-Royal, Quebec, Canada 
H3P 3P1 
 
DATA MANAGEMENT FACILITY: David Cote, Specialist, Data Management 
 
 
 
 
 
Algorithme Pharma  
1200 Beaumont Ave. 
Mount-Royal, Quebec, Canada 
H3P 3P1 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROJECT MANAGEMENT: 
 
Joanna Pohl, PhD., Project Manager 
Algorithme Pharma  
575 Armand-Frappier Blvd. 
Laval, Quebec, Canada 
H7V 4B3 






 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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PROTOCOL APPROVAL 
 
 
ALGORITHME PHARMA PROTOCOL NUMBER: MDL-P2-670 
MEDLINE PROJECT No R17-023 
 
 
TITLE: SINGLE DOSE PHARMACOKINETIC STUDY TO ASSESS THE SYSTEMIC 
EXPOSURE OF CHLORHEXIDINE FROM ReadyPrep® CHG (2% CHLORHEXIDINE 
GLUCONATE CLOTH) 
 
 
 
 
On behalf of the sponsor, I am aware of, and agree to comply with, all of the procedures 
contained within this protocol: 
 
 
 
_____________________________ 
____________________ 
Alannah Minarcik 
Date (yyyy/mm/dd) 
Sponsor's Representative 
Medline Industries, Inc. 
 
 
 
Alannah 
Minarcik
Digitally signed by Alannah Minarcik 
DN: cn=Alannah Minarcik, o=Medline 
Industries, Inc., ou=Research and 
Development, 
email=aminarcik@medline.com, c=US 
Date: 2017.07.20 14:51:29 -05'00'


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1. INTRODUCTION 
Chlorhexidine [CHD; 1,1’-hexamethylenebis[5-(4-chlorophenyl) biguanide]] has a wide 
spectrum of bactericidal and antiviral activity and is a common ingredient in various 
formulations ranging from skin disinfectants in healthcare products to antiplaque agents in 
dentistry. The presence of two symmetrically positioned basic chlorophenyl guanide groups 
attached to a lipophilic hexamethylene chain aid in rapid absorption through the outer 
bacterial cell wall, causing irreversible bacterial membrane injury, cytoplasmic leakage, and 
enzyme inhibition. Chlorhexidine exists as various forms of salts: diacetate, dihydrochloride, 
or digluconate, mainly differing by their solubilizing abilities in aqueous or oily media. 
Chlorhexidine digluconate (or gluconate), as most soluble in water or alcohol, is the most 
used form in topical dermatology or cosmetic preparations.1,2 
As chlorhexidine is not significantly absorbed through intact skin3 no systemic adverse 
events are expected. However, skin reaction could occur. 
ReadyPrep® CHG is composed of 2% chlorhexidine gluconate (CHG) solution on a single 
fiber, polyester cloth. Each cloth contains 500 mg CHG. The sponsor is developing 
ReadyPrep® CHG (2% Chlorhexidine Gluconate Cloth) for patient preoperative skin 
preparation. 
In order to better understand and control for the presence of chlorhexidine in the 
environment, baseline levels will be assessed in each study period and a control treatment 
arm will be included. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2. STUDY OBJECTIVES 
The primary objective of this study is to demonstrate that no or negligible systemic exposure 
occurs after a single topical application of ReadyPrep® CHG. 
The secondary objective of this study is to determine the safety and tolerability of a single 
topical application of ReadyPrep® CHG in healthy volunteers after a single topical 
application. 
3. STUDY TREATMENTS 
3.1. INVESTIGATIONAL PRODUCT 
 
ReadyPrep® CHG (2% Chlorhexidine Gluconate Cloth) 
Manufacturer: Medline Industries Inc., USA 
 
DOSAGE FORM: 
Cloth for topical application.  
 
DOSAGE: 
Single topical application of ReadyPrep® CHG (2% Chlorhexidine 
Gluconate Cloth) on either the abdomen or the groin. 
The investigational product will be provided by the sponsor. The lot number and the 
measured content of the dosage form (when available) will be included in the final 
report.  
3.2. PACKAGING AND LABELING 
The sponsor will be responsible for ensuring the investigational product is 
manufactured in accordance with Good Manufacturing Practice (GMP); the labeling 
should also comply with applicable regulatory requirement(s). 
The investigational products will be dispensed according by Algorithme Pharma, 
unless the sponsor supplies Algorithme Pharma with pre-labeled individual dosing 
samples. 
3.3. RANDOMIZATION AND UNBLINDING PROCEDURES 
3.3.1. Treatment assignment 
Algorithme Pharma will generate the randomization code with a computer 
program according to the study design, the number of subjects and the sequence 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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of treatment. The random allocation of each sequence of treatment to each subject 
will be done in such a way that the study is balanced. Once generated, the 
randomization code will be final and will not be modifiable. 
3.3.2. Un-blinding procedure 
The randomization code will not be available to the personnel of the bioanalytical 
facility until the bioanalytical tables have been finalized and audited by the 
Quality Assurance (QA) department.  
3.4. DRUG ACCOUNTABILITY 
Algorithme Pharma will maintain an inventory record of the investigational products 
received, stored in a secure restricted area, and dispensed as per State law. 
Investigational products will be provided to study subjects only. 
At the conclusion of the study, all unused investigational products and all medication 
containers will be returned to the sponsor unless the sponsor has approved other 
arrangements. A final report of investigational product accountability will be prepared 
and maintained. 
4. STUDY DESIGN AND DURATION 
In two study periods, the ReadyPrep® CHG formulation will be administered as a single 
topical application to either the abdomen or the groin. Another study period will consist of a 
control treatment without topical application of ReadyPrep® CHG.  
Treatment-1: Abdominal application of ReadyPrep® CHG 
Treatment-2: Groin application of ReadyPrep® CHG 
Treatment-3: Control treatment with no application 
Twelve (12) healthy male or female subjects will be included in the studyaccording to the 
following randomized, 3-sequence, 3-period, crossover design: 
 
 
Period 1 
Period 2 
Period 3 
Sequence 1 (n= 4) Treatment-1 
Treatment-2 
Treatment-3 
Sequence 2 (n= 4) Treatment-2 
Treatment-3 
Treatment-1 
Sequence 3 (n= 4) Treatment-3 
Treatment-1 
Treatment-2 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The drug applications will be separated by at least 7 calendar days. The duration of the 
clinical part of this study is expected to be approximately 17 days. The actual overall study 
duration may vary. 
5. SELECTION OF STUDY POPULATION 
5.1. NUMBER OF SUBJECTS 
Twelve (12) subjects will be selected for inclusion in the study. A subject who 
withdraws subsequent to the pre-trial evaluations but before the application of the 
investigational product will not be considered as a drop-out and will not be included in 
the database. Standbys should be recruited and be available to replace a subject who 
withdraws prior to the first drug application. Drop-outs will not be replaced. 
Justification for the number of subjects is presented in section 9.4. 
An effort will be made to include similar proportions of males and females in the 
study. 
5.2. INCLUSION CRITERIA 
Volunteers meeting all of the following criteria will be considered for enrollment in 
the study. A signed copy of the informed consent form will be provided to each 
subject. 
1. Availability for the entire study  
 
2. Motivated volunteer and absence of intellectual problems likely to limit the 
validity of consent to participate in the study or the compliance with protocol 
requirements; ability to cooperate adequately; ability to understand and observe 
the instructions of the physician or designee 
 
3. Healthy adult volunteer 
 
4. A female volunteer must meet one of the following criteria: 
a) Participant is of childbearing potential and agrees to use one of the accepted 
contraceptive regimens from at least 28 days prior to the first administration 
of the study drug, during the study and for at least 30 days after the last dose 
of the study drug. An acceptable method of contraception includes one of the 
following: 
 Abstinence from heterosexual intercourse 
 Systemic contraceptives (birth control pills, 
injectable/implant/insertable hormonal birth control products, 
transdermal patch) 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 Intrauterine device (with or without hormones) 
 Condom with spermicide 
or 
b) Participant is of non-childbearing potential, defined as surgically sterile 
(i.e. has undergone complete hysterectomy, bilateral oophorectomy, or tubal 
ligation) or in a menopausal state (at least 1 year without menses) 
 
5. Volunteer aged ≥ 18 and ≤ 60 years (inclusive) 
 
6. Volunteer with a BMI greater than or equal to 19.00 kg/m2 and below or equal to 
32.00 kg/m2  
 
7. Volunteer with a body weight ≥ 55 kg 
 
8. Non- or ex-smokers; an ex-smoker being defined as someone who completely 
stopped smoking for at least 3 months before study day 1 
 
9. Clinical laboratory values within the laboratory's stated normal range; if not within 
this range, they must be without any clinical significance as determined by the 
medical investigator 
 
10. Have no clinically significant diseases captured in the medical history or evidence 
of clinically significant findings on physical examination and/or clinical laboratory 
evaluations (hematology, general biochemistry, and urinalysis) as determined by 
the medical investigator 
 
11. Willingness to adhere to the protocol requirements as evidenced by the informed 
consent form (ICF) duly read, signed and dated by the volunteer 
 
The informed consent form must be signed by all volunteers prior to their participation 
in the study. 
5.3. EXCLUSION CRITERIA 
Volunteers presenting any of the following will not be included in the study: 
1. Females who are pregnant or are lactating 
 
2. Seated pulse rate less than 45 Beats per Minute (bpm) or more than 100 bpm at 
screening, unless deemed non-significant by the medical investigator. 
 
3. Seated blood pressure below 100/60 mmHg or higher than 140/90 mmHg at 
screening, unless deemed non- significant by the medical investigator 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4. History of significant hypersensitivity to chlorhexidine or any related products 
(including excipients of the formulations) as well as severe hypersensitivity 
reactions (like angioedema) to any drugs 
 
5. Presence of significant gastrointestinal, liver or kidney disease, or any other 
conditions known to interfere with the absorption, distribution, metabolism or 
excretion of drugs or known to potentiate or predispose to undesired effects 
 
6. History of significant gastrointestinal, liver or kidney disease that may affect drug 
bioavailability 
 
7. Presence of significant cardiovascular, pulmonary, hematologic, neurological, 
psychiatric, endocrine, immunologic or dermatologic disease 
 
8. Volunteers who have presence of a skin condition, excessive hair, scar tissue, 
tattoo, piercing, skin coloration, open sores or sunburn at the application site  that 
would interfere with application, or reactions to drug 
 
9. Any method of hair removal (e.g. waxing, shaving, epilating, laser) at the 
application site 7 days prior to the first application as well as hair removal with 
tweezers at the application site 58 hours prior to the first application 
 
10. Sunbathing and using tanning beds at the application site 7 days prior to the first 
application 
 
11. Use of topical product containing medication for application (including creams, 
lotions, ointments, gels, topical solutions, patches; including salicylate-based 
topical creams or ointments) at the application site 14 days prior to the first 
application 
 
12. Use of topical product without medication (including make-up, sunscreen, creams, 
lotions, powders, alcohol) at the application site 7 days prior the first application 
 
13. Use of oral acetylsalicylic acid (ASA) and salicylic acid or any oral product 
containing ASA or salicylic acid, in the previous 7 days before study day 1 
 
14. History of or disposition to seizures, state of confusion, clinically relevant 
psychiatric diseases 
 
15. Maintenance therapy with any drug or significant history of drug dependency or 
alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or 
chronic) 
 
16. Any clinically significant illness in the previous 28 days before study day 1 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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17. Use 
of 
any 
enzyme-modifying 
drugs, 
including 
strong 
inhibitors 
of 
cytochrome P450 (CYP) enzymes (such as cimetidine, fluoxetine, quinidine, 
erythromycin, 
ciprofloxacin, 
fluconazole, 
ketoconazole, 
diltiazem 
and 
HIV antivirals) and strong inducers of CYP enzymes (such as barbiturates, 
carbamazepine, glucocorticoids, phenytoin, rifampin and St John’s Wort), in the 
previous 28 days before study day 1 
 
18. Any history of tuberculosis and/or prophylaxis for tuberculosis 
 
19. Positive screening of alcohol, and/or drugs of abuse 
 
20. Positive results from the hepatitis serology, except for vaccinated subjects or 
subjects with past but resolved hepatitis, at screening. 
 
21. Positive results from the HIV serology at screening 
 
22. Volunteers who have already been included in one group of this clinical study.  
23. Volunteers who took chlorhexidine in the previous 28 days before study day 1 
 
24. Volunteers who took an Investigational Product in the previous 28 days before 
study day 1 
 
25. Volunteers who donated plasma in the previous 14 days before study day 1 
 
26. Donation of 1 blood donation unit (American Red Cross, etc.) in the previous 
56 days before study day 1 
5.4. CRITERIA FOR REMOVAL OF A SUBJECT 
Subjects will be allowed to discontinue their participation in the study at any time. 
Subjects will be discontinued from the clinical study and/or period for any of the 
following reasons: 
1. Use of oral ASA and salicylic acid or any oral product containing ASA or 
salicylic acid during the study 
2. Sunburn, sunbathing and/or use of topical medication/product at the application 
site during the study 
3. Hair removal at the application site during the study 
4. Presence of any skin condition that would interfere with the application of the 
study medication 
5. Females who are pregnant according to a positive pregnancy test 
6. Clinically significant laboratory values before each period, as judged by the 
Principal Investigator or designee  
7. Positive screening of alcohol and/or drugs of abuse 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Furthermore, participation in the clinical study and/or period could be discontinued by 
the physician in charge of the study or by the sponsor for any of the following reasons: 
1. Adverse events; 
2. Significant protocol violation; 
3. Difficulties with blood collection; 
4. The subject is uncooperative during the study 
The PK facility can, with sponsor’s approval, also remove a subject from the study 
due to an unanticipated event that could result in an inadequately characterized 
pharmacokinetic profile, such as a missed blood draw, an adverse event, meal 
deviations or concomitant medications. 
Details of reasons for removal of subjects will be recorded, reported to the sponsor and 
documented in the clinical study report. 
5.5. RESTRICTIONS 
Each subject will be questioned on the specific points listed below prior to each 
treatment. If a subject admits non-compliance with any of these restrictions, the 
Principal Investigator (or designee) and/or the sponsor will decide whether the subject 
will be permitted to remain in the study. Non-compliance with these restrictions will 
be noted. 
5.5.1. Medications 
In addition to the drugs prohibited as per the exclusion criteria, subjects will be 
requested to abstain from taking any other prescription medications used with the 
intention to treat a condition for 28 days prior to the first treatment and during the 
study, unless judged differently by the Principal Investigator or designee.  
Systemic contraceptives and hormone replacement therapy will be permitted. 
Subjects will also be requested to abstain from taking any over-the-counter (OTC) 
products for 7 days prior to the first treatment and during the study. They will be 
specifically reminded that this includes cold preparations, non-steroidal anti-
inflammatory drugs (NSAIDs), vitamins and natural products used for therapeutic 
benefits and antacid preparations.  
Vitamins used as nutritional supplements in non-therapeutic doses (as judged by 
the Principal Investigator or designee) may be accepted, but they must be stopped 
at least 48 hours prior to the first treatment and during the study. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Subjects will be instructed not to apply topical products without medication 
(including make-up, sunscreen, creams, lotions, powders, alcohol) to the skin area 
where the drug will be applied from 7 days prior to the first treatment until the 
end of the study. 
Subjects will be instructed not to apply topical product containing medication for 
application (including creams, lotions, ointments, gels, topical solutions, patches; 
including salicylate-based topical creams or ointments) to the skin area where the 
drug will be applied from 14 days prior to the first treatment until the end of the 
study. 
If a medication (including OTC) other than those specified in the protocol is used 
after the first treatment or at any time before the end of the study, the Principal 
Investigator or designee and/or the sponsor will decide whether the subject will be 
permitted to remain in the study, depending on the drug used, the time of drug 
intake, etc. The drug and dose will be noted. 
5.5.2. Alcohol 
Subjects will be requested to abstain from alcohol for 58 hours prior to each 
treatment and during each study period. Throughout the study in case of any 
doubt about alcohol consumption, a test for alcohol may be performed if 
requested by the physician. 
5.5.3. Xanthines 
Subjects will be requested to avoid food or beverages containing xanthines 
(i.e. tea, coffee, cola drinks, energy drinks or chocolate) for 58 hours prior to each 
treatment and during each study period. 
5.5.4. Fluids 
Fluid intake other than water will be controlled for each housing period and for all 
subjects. Water will be provided ad libitum during the housing periods.  
Non-carbonated, non-xanthine and non-grapefruit fluids will be provided during 
the housing periods. 
5.5.5. Food 
Food will be controlled and standardized for all subjects for each housing period. 
Meals and snacks will be served at appropriate times. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.5.6. Grapefruit, Seville Oranges, poppy-seed and pomelo-containing 
beverages and food 
Subjects will be instructed to avoid food or beverages containing grapefruit, 
Seville oranges and/or pomelo for 7 days prior to the first treatment and during 
the study.  
Food or beverages containing poppy-seeds should also be avoided for 36 hours 
prior to the first treatment and during the study. 
5.5.7. Posture and physical activities 
Subjects will remain seated for at least the first 4 hours following each treatment. 
However, should adverse events occur, subjects may be placed in an appropriate 
position. During this interval subjects will be permitted, under supervision, to 
leave their seats for brief periods, e.g. to use the washroom facilities or for blood 
sampling (if necessary). After this 4-hour period, subjects may get up, but only 
under supervision. Subjects will not engage in strenuous activity at any time 
during the housing periods. 
5.5.8. Contraceptive regimen throughout the study  
Female volunteers of childbearing potential will have to take appropriate 
measures to prevent pregnancy for at least 28 days prior to the first treatment, 
during the study and for at least 30 days after the last treatment, as described in 
section 5.2. 
5.5.9. Other Activities 
Subjects will be instructed that sunbathing and using tanning beds at the area 
intended for drug application is not allowed from 7 days prior to the first 
treatment and throughout the study in order to avoid sunburn at the application 
site.  
Subjects will be instructed not to shave, wax, epilate or laser (for hair removal) 
the skin area where the drug will be applied from 7 days prior to the first 
treatment until the end of the study. Moreover, subjects will be instructed not to 
remove hair with tweezers to the skin area where the drug will be applied for 
58 hours prior to the first treatment until the end of the study. 
In each study period, subjects will be required to not take a shower for 2 hours 
prior to the treatment until departure from the clinical site. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. CLINICAL PROCEDURES 
Unless otherwise stated in this protocol, SOPs of the clinical site, which are available for all 
activities relevant to the quality of the study, will be followed during this study. The different 
parts of this study are summarized in Table 1 and explained in the following sections. 
6.1. DESCRIPTION OF STUDY DAYS 
6.1.1. Pre-trial evaluation 
Potential study volunteers will be examined before the start of the study to 
determine their eligibility for participation. These tests are to be conducted no 
more than 28 days before the start of the study. The following examinations will 
be performed: 
6.1.1.1. Medical history 
The medical history will include evaluation of ears, nose, throat and any 
ophthalmological, 
cardiovascular, 
respiratory, 
musculoskeletal, 
gastrointestinal, 
genitourinary, 
neurological, 
endocrine, 
psychiatric, 
immunological or allergic, dermatological, hematological, family history 
disorder or disease. 
6.1.1.2. Physical examination 
The physical examination will include measurement of vital signs (blood 
pressure, pulse rate, respiratory rate and body temperature) and a review of the 
following: head and neck, heart, lungs, abdomen and general appearance. Skin 
examination at the application sites will be performed. 
Demographic data (age, gender, race, ethnicity, body weight adjusted for 
indoor clothing, height, BMI), and alcohol and smoking habits will be 
recorded. 
6.1.1.3. Laboratory tests 
General Biochemistry: 
Sodium, potassium, chloride, glucose, blood urea 
nitrogen (BUN), creatinine, bilirubin total, alkaline 
phosphatase, AST, ALT, albumin, calcium, carbon dioxide, 
inorganic phosphate, magnesium, total protein and uric acid 
Hematology: 
White cell count with differential (absolute values of 
neutrophil, 
lymphocyte, 
monocyte, 
eosinophil, 
and 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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basophil), red cell count, hemoglobin, hematocrit, mean 
corpuscular volume (MCV), and platelets count 
Urinalysis: 
Color, clarity, specific gravity, pH, leukocyte, protein, 
glucose, ketones, bilirubin, blood, nitrite, urobilinogen. 
Microscopic examination will only be performed if the 
dipstick test is outside of the reference range for leukocyte, 
blood, nitrite or protein 
6.1.1.4. Other laboratory tests 
Serology:  
HIV Ag/Ab Combo, Hepatitis B (HBsAg (B)) and 
Hepatitis C (HCV (C)) 
Drug Screen: 
Alcohol, 
amphetamines, 
barbiturates, 
cannabinoids, 
cocaine, opiates, oxycodone and benzodiazepine 
A pregnancy test will be performed on female subjects. 
6.1.1.5. Other tests 
Additional laboratory tests may be also performed by the medical laboratory as 
part of larger standard tests panels although not required for the subject’s 
safety. All test results will be assessed by physician for clinical significance. 
Only test results required by the protocol and/or abnormal results will be 
entered in the clinical database and reported in the Clinical Study Report, 
based on the report requirement. 
6.1.2. Study days 
The following procedures will be applied for each period of the study: 
Subjects will be admitted to the clinical site up until at least 10 hours prior to drug 
administration. 
Screening of alcohol and drugs of abuse will be performed at the subjects' arrival, 
prior to drug application. 
A pregnancy test will be performed at the female subject's arrival, prior to drug 
application. 
General biochemistry tests will be performed before each period of the study. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The first baseline blood sample will be collected 10 hours prior to each treatment 
(T = -10.00). After a supervised overnight fast, the subjects will be awakened, 
vital signs (blood pressure, pulse rate, respiratory rate and body temperature) will 
be measured, visual skin evaluation at the application site will be performed and 
the 2 other baseline blood samples (T= -2.00 and -0.50) will be collected. Pre-
dose vital signs should be done within 120 minutes of drug application. 
Serial blood sampling will follow drug administration (details in section 6.2.1). 
Vital signs (blood pressure and pulse rate) will be assessed twice after treatment 
(details in section 6.3). 
Visual skin evaluation at the application site will be performed several times after 
treatment (details in section 6.3). 
Subjects may leave the clinical site at least 24 hours after treatment. However, 
they will be advised to stay at the clinical site, if judged necessary by the 
physician in charge, for safety reasons. A card identifying the medication 
‘Chlorhexidine Gluconate’ will be distributed to all subjects prior to departure 
from the clinical site in period 1. This card is given to subjects in order for them 
to inform the hospital / doctors they are participating in a clinical trial in case of a 
medical emergency. 
6.1.2.1. Drug administration procedure 
ReadyPrep® CHG Application (Treatment-1 and Treatment-2): 
In two Treatment-1 and -2, a single topical application of ReadyPrep® CHG 
will be done on either the abdomen (surface area of approximately 5 x 5 
inches) or the groin (surface area of approximately 5 x 2 inches) according to 
the randomization scheme. 
The drug will be applied to a clean, dry, non-irritated, normal skin area. 
Possible hairs will be removed by means of scissors (no shaving) on the 
morning of dosing.  
Approximately 30 minutes prior to any application, the site should be gently 
washed with room temperature water and dried without rubbing or heavy 
pressure with a gauze or similar cotton soft material. The application site must 
be allowed to dry for at least 15 minutes before drug application. After drying, 
the application site will be marked for dose location.   
The topical application of ReadyPrep® CHG will consist of a 3-minute 
vigorous rub followed by a 1 minute dry time at the application site. The 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1-minute dry time will be air drying without dabbing or rubbing. The time of 
dosing will be defined as the start time of the drug application on the skin. 
Control Treatment (Treatment-3): 
In Treatment-3, the same procedures as Treatment-1 and -2 will be performed, 
but without the topical application of ReadyPrep® CHG or placebo (no 
placebo ReadyPrep® cloth will be provided or used). Therefore, approximately 
30 minutes prior, the site should be gently washed with room temperature 
water and dried without rubbing or heavy pressure with a gauze or similar 
cotton soft material. The application site must be allowed to dry for at least 
15 minutes and after drying, the skin site will be marked. Subjects should be 
placed in the same position, for the same length of time, in the same area as 
they would be dosed.    
The physician will remain at the clinical site for at least the first 
4 hours following each treatment and will remain available at all times during 
the entire period of the study. 
6.1.3. End of the study 
The following poststudy tests will be performed at the end of the study.  
For subjects whose participation in this clinical study is discontinued during the 
course of the trial, every effort will be made to perform the poststudy tests as soon 
as possible after discontinuation. 
6.1.3.1. Physical Examination 
The physical examination will include measurement of vital signs (blood 
pressure, pulse rate, respiratory rate and body temperature) and a review of the 
following: head and neck, heart, lungs, abdomen and general appearance 
6.1.3.2. Laboratory tests 
General Biochemistry: 
Sodium, potassium, chloride, glucose (random), 
blood urea nitrogen (BUN), creatinine, bilirubin 
total, alkaline phosphatase, AST, ALT, albumin, 
calcium, carbon dioxide, inorganic phosphate, 
magnesium, total protein and uric acid 
Hematology: 
White cell count with differential (absolute values of 
neutrophil, 
lymphocyte, 
monocyte, 
eosinophil, 
and 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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basophil), red cell count, hemoglobin, hematocrit, MCV, 
and platelets count 
Urinalysis: 
Color, clarity, specific gravity, pH, leukocyte, protein, 
glucose, ketones, bilirubin, blood, nitrite, urobilinogen. 
Microscopic examination will only be performed if dipstick 
test is outside the reference range for leukocyte, blood, 
nitrite or protein 
Additional laboratory tests may be also performed by the medical laboratory as 
part of larger standard tests panels although not required for the subject’s 
safety. All test results will be assessed by physician for clinical significance. 
Only test results required by the protocol and/or abnormal results will be 
entered in the clinical database and reported in the Clinical Study Report, 
based on the report requirement. 
6.1.3.3. Other laboratory tests 
A pregnancy test will be performed on female subjects at the end of the study. 
6.1.3.4. Other tests 
No other tests will be performed at the end of the study. 
6.2. SAMPLING DURING THE STUDY 
6.2.1. Blood sampling 
In order to better understand and control for the presence of chlorhexidine in the 
environment, baseline levels will be assessed in each study period.  
For baseline assessment, 3 blood draws will be performed prior to each treatment. 
A total of 12 blood samples will be collected (one tube of 6 mL each) in each 
study period. Samples will be collected into labeled tubes containing the 
appropriate anticoagulant as specified by the bioanalytical facility.  
The complete schedule for each study period is presented in Table 2. The time of 
blood sample collection will be calculated according to the drug application 
schedule. The clock time of all blood draws will be recorded and reported for all 
subjects. For postdose samples, all deviations from the scheduled sampling time 
of 2 minutes or more will be reported in the final report.  


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The total volume of blood withdrawn, including ~20 mL required for screening, 
pre-dose and poststudy tests, should be approximately 236 mL per subjects. The 
total blood donation may be higher if repeat blood samples are required for safety 
assessments. 
6.2.2. Urine sampling 
No urine samples will be collected during the course of this study, other than for 
screening prior to each drug administration, as well as for safety reasons at the 
end of the study. 
6.2.3. Sample processing, storage and shipping 
Blood samples will be processed, split, stored, and shipped according to the 
sample processing instructions supplied by the bioanalytical facility. 
6.3. SAFETY MONITORING 
6.3.1. Vital signs 
Blood pressure, pulse rate, respiratory rate and body temperature will be recorded 
within 120 minutes prior to each treatment, and at approximately 12 and 24 hours 
after each treatment. Vital signs will be monitored subsequently, if judged 
necessary by the medical investigator or designee. 
6.3.2. ECG records 
ECG will be recorded if judged necessary by the physician in charge. 
6.3.3. Visual skin evaluation 
Visual skin evaluation of the application site will be performed by the physician 
in charge or designee as follows: 
 
Application site verification (for redness, markings, scars, etc.) will be 
documented prior to and approximately 4, 8 and 24 hours after each treatment. 
6.3.4. Other measurements 
General biochemistry tests will be performed before each period of the study. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7. ADVERSE EVENTS 
7.1. DEFINITIONS 
An adverse event (AE) is defined as any untoward medical occurrence in a subject 
administered an investigational product and which does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and 
unintended sign (including a clinically significant abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of an 
investigational product, whether or not related to the investigational product. 
A suspected adverse reaction (SAR) is any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. ‘Reasonable possibility’ 
means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction, which means any adverse event caused by a drug. 
An adverse event may be: 
 
A new illness 
 
Worsening of a concomitant illness 
 
An effect of the study medication including comparator; it could be an abnormal 
laboratory value as well as a significant shift from baseline within normal range 
which the Medical Investigator considers to be clinically important 
Abnormalities in laboratory tests, in the measurements of vital signs, in visual skin 
evaluation or in other measurements performed after drug application or at the end of 
the study are to be recorded as adverse events only if they are medically relevant: 
symptomatic, requiring corrective treatment, leading to study discontinuation and/or 
fulfilling a seriousness criterion. If asymptomatic, but with a suspected underlying 
process, the Medical Investigator may consider the abnormalities to be medically 
relevant. 
Surgical procedures themselves are not adverse events. They are therapeutic measures 
for conditions that required surgery. The condition for which the surgery is required is 
an adverse event, if it occurs or is detected during the study period. Planned surgical 
measures permitted by the clinical study protocol and the conditions(s) leading to 
these measures are not adverse events, if the condition(s) was (were) known before the 
start of study treatment. In the latter case, the condition should be reported as medical 
history. 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at 
any dose: 
 
Results in death 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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 
Is life-threatening 
 
Requires in-patient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity (defined as a substantial 
disruption of a person’s ability to conduct normal life functions) 
 
Is a congenital anomaly or birth defect 
 
Is an important medical event that may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above (according to 
medical judgment of the Medical Investigator) 
7.2. SEVERITY ASSESSMENT 
All adverse events will be graded as mild, moderate, or severe according to the 
following definitions: 
Mild: 
 Causing no limitation of usual activities; the subject may experience slight 
discomfort. 
Moderate: Causing some limitation of usual activities; the subject may experience 
annoying discomfort. 
Severe: 
Causing inability to carry out usual activities; the subject may experience 
intolerable discomfort or pain. 
Every effort will be made to obtain an adequate evaluation of the severity. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.3. CAUSALITY ASSESSMENT 
The Medical Investigator will determine the relationship of any adverse event to the 
Investigation Product according to the following criteria: 
TERM 
DEFINITION 
Reasonable 
Possibility 
A temporal relationship exists between the AE onset and 
administration of the investigational product that cannot be readily 
explained by the subject’s clinical state or concomitant therapies. 
Furthermore, the AE appears with some degree of certainty to be 
related, based on the known therapeutic and pharmacologic actions or 
adverse event profile of the investigational product. 
In case of cessation or reduction of the dose the AE may abate or 
resolve and it may reappear upon rechallenge. 
No Reasonable 
Possibility 
Evidence exists that the adverse event has an etiology other than the 
investigational product. 
For SAEs, an alternative causality must be provided (eg, pre-existing 
condition, underlying disease, intercurrent illness, or concomitant 
medication). 
7.4. DOCUMENTATION AND REPORTING OF ADVERSE EVENTS 
For the purposes of this study, the period of observation of adverse events extends 
from the pre-trial evaluation until the end of the study. From screening to the first dose 
of the study, they will be recorded as screening events or as part of the medical 
history, as applicable. When AEs occur after initiation of study medication, they will 
be indicated as treatment-emergent AEs in the clinical study report. During the study, 
all adverse events spontaneously reported by the subject, observed by the clinical staff 
or elicited by general questioning will be recorded for all subjects and reported in the 
CRF. 
If necessary, every effort will be made to obtain an adequate follow-up of the subjects. 
Should any subject choose to withdraw early from the study, they will be advised of 
the safety precautions to be taken. 
Subjects will be questioned on their health status at the beginning of each study period 
and before each departure from the clinical site. Open-ended questions will be asked. 
Classification will be performed by System Organ Class (SOC) and Preferred Term 
(PT) using the Medical Dictionary for Regulatory Activities (MedDRA), version 19.0 
or higher. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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7.5. SERIOUS ADVERSE EVENT REPORTING REQUIREMENTS 
The clinical site will notify any SAE to the sponsor, without regard to causality, within 
24 hours after becoming aware of its occurrence. This notification will contain a 
description of the observed symptoms and an assessment of causality. A detailed 
report will be sent in the following days. 
The notification, in English, should be directed to the following sponsor 
representative: 
Alannah Minarcik, Clinical Research Associate II 
Medline Industries, Inc. 
Tel. (847)  643-3515                 (Working hours) 
Tel. (630)  327-0532                 (nights, weekends, and holidays) 
Fax. (866) 758-4660 
Email:aminarcik@medline.com 
A SAE will be considered as "unexpected" when the nature or severity is not 
consistent with information in the relevant source document(s).  
Algorithme Pharma will determine whether any serious unexpected related adverse 
event must be reported to the IRB. If so, the event will be reported via fax or email 
within 15 calendar days of the investigator or staff becoming aware of the event. 
The sponsor will be responsible for notifying FDA and all participating investigators 
of any SAE observed during conduct of the study, regardless of whether the event is 
considered drug related, as soon as possible but in no case later than 15 calendar days 
after becoming aware of its occurrence. If the adverse event is fatal or life-threatening, 
the sponsor must also notify the Clinical Safety Coordinator in CDER’s Office of 
Generic Drugs as soon as possible but in no case later than 7 calendar days after 
becoming aware of its occurrence. 
7.6. PREGNANCY 
Pregnancy in a female subject in the study shall be reported to the sponsor within 
24 hours of the knowledge of its occurrence by the clinical site (for pregnancies 
occurring during the course of the study or immediately following the end of the 
study). Because of the possibility that the fetus/embryo could have been exposed to 
the study drug through the parent and for the subject’s safety, the pregnancy will be 
followed up to determine its outcome, including spontaneous or voluntary termination, 
details of birth, presence or absence of any birth defects, congenital anomalies, or 
maternal and/or newborn complications. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The pregnancy will be recorded and reported by the clinical site to the sponsor. 
Pregnancy follow-up will also be properly recorded to ensure quality and 
completeness of the data belonging to the study drug and will include an assessment of 
the possible causal relation between the study drug and any pregnancy outcome. Any 
SAE experienced during pregnancy will be reported on a SAE Report Form. 
8. METHODS OF EVALUATION 
8.1. DRUG CONCENTRATIONS 
8.1.1. Bioanalytical assays 
Chlorhexidine plasma concentrations will be measured according to a validated 
bioanalytical method.  
The validated range can be truncated when less than 5 calibration standards 
appear to be below the expected Cmax, provided that this new calibration curve 
range is validated prior to use. 
In the event that the study is conducted in multiple groups, sample analysis will 
begin only after completion of the clinical portion of the last group (i.e. after the 
last sample is collected). 
Where possible, all samples from each subject will be analyzed on the same 
standard curve. Quality control samples will be distributed through each batch of 
study samples assayed. Samples with drug concentrations greater than the upper 
limit of quantification (ULQ) of the assay range will be diluted with the 
appropriate drug-free biological fluid and re-assayed; those which are below the 
lower limit of this range will be reported as being below limit of quantitation 
concentrations (BLQ). The analysts will not have access to the randomization 
scheme. 
8.1.2. Aberrant values and retested samples 
Unacceptable values attributable to bioanalytical reasons will be determined by 
the bioanalytical facility. Such re-assayed samples will be termed “repeats”. All 
cases of re-assay will be reported in the final report. 
No samples will be repeated for pharmacokinetic reasons. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.3. Incurred sample reproducibility 
In order to establish the reproducibility of the assay with incurred samples, at least 
10% of the total analyzable study samples will be selected and re-assayed. The 
replicate measurement is not to be averaged with the original one, but both values 
will be presented in the bioanalytical report with the initial value being used for 
PK calculations. The concentrations of the original and replicate samples will be 
tabulated, along with the percent difference between the two values. 
 
8.2. SAFETY DATA 
The safety population will include all subjects who received at least one treatment 
under study. 
Descriptive statistics will be used to summarize adverse events, safety results and 
demographic variables (age, height, weight and BMI). 
The laboratory tests and the measurements of vital signs, visual skin evaluation and 
other safety parameters performed after treatment are mainly performed for safety 
reasons, and changes may occur without any clinical symptoms. Therefore, any 
significant changes will be recorded as adverse events only if they are judged 
clinically significant by the Medical Investigator. 
The laboratory tests will be carried out according to the standard operating procedures 
of the licensed medical laboratory. Abnormal results will be verified to rule out 
laboratory error. Persistent relevant abnormal values should be followed up until the 
cause is determined or until the values return to the pre-medication value. 
9. PHARMACOKINETICS AND STATISTICS 
9.1. SUBJECTS TO ANALYZE 
Samples from all subjects who received at least one treatment and for whom sufficient 
number of blood samples was taken for pharmacokinetic analysis will be assayed and 
included in the pharmacokinetic analysis.  
Subjects who do not complete the sampling schedule of one or more study periods 
may be included in the pharmacokinetic analysis for only the PK parameters that are 
judged not to be affected by the missing sample(s). This decision is to be documented 
by the SRA department and approved by the sponsor before the start of the sample 
analysis by the bioanalytical facility. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.2. PHARMACOKINETIC ANALYSIS 
No or negligible plasma levels of chlorhexidine are expected following a single topical 
application of ReadyPrep® CHG. Chlorhexidine plasma concentrations produced by 
each treatment will be determined in order to establish the pharmacokinetic profile of 
the drug product. Below limit of quantitation concentrations (coded BLQ) will be 
treated as zero for all statistical analyses. In the event that chlorhexidine levels are 
measurable, the pharmacokinetic parameters that will be derived from the plasma 
concentrations versus time profiles are listed in Table 3. All reported sampling time 
deviations (see Section 6.2.1) will be taken into consideration for evaluation of PK 
parameters. 
In the case where concentrations of chlorhexidine cannot be determined due to 
bioanalytical or clinical reasons, these values will be set to missing for the 
pharmacokinetic analysis. 
In the case where less than 3 consecutive measurable concentrations of chlorhexidine 
are observed, the AUC parameters will not be estimated for that specific study period. 
In order to better understand and control for the presence of chlorhexidine in the 
environment, baseline levels will be assessed in each study period. The 
pharmacokinetic parameters for chlorhexidine will be presented both adjusted for 
baseline and unadjusted.  The baseline adjustment will consist of the following: 
 Baseline concentrations will be measured approximately 10.00, 2.00 and 
0.50 hours prior to each treatment. The mean of these 3 pre-dose 
concentrations will be used for baseline adjustment.  
 Concentrations post-dose will be adjusted for each subject during each period 
by subtracting the mean baseline value corresponding to that subject. Baseline 
adjustment will therefore be subject- and period- specific. 
If subtraction leads to values of adjusted profile that would be below the LOQ, these 
values will be reported without any change and they will not be reported as BLQ. 
However, if a negative plasma concentration value results after baseline adjustment, 
this value will be set to 0 prior to calculating the baseline-adjusted AUC.  
For baseline adjusted calculations, concentrations at time T= -0.50 h will be set to zero 
given that no concentration provided by the given treatment is expected to be present 
at this time point. Unadjusted baseline PK estimation will use the observed 
concentration value at time T=-0.50 h. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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The main pharmacokinetic parameters of interest for this study will be Cmax, AUC0-T 
and AUC0-∞. Other parameters such as Tmax, AUC0-T/∞, λZ and Thalf will be provided 
for information purposes only. 
The main absorption and disposition parameters will be estimated using a 
non-compartmental approach with a log-linear terminal phase assumption. The 
trapezoidal rule will be used to estimate the area under the curve (linear trapezoidal 
linear interpolation) and the terminal phase will be estimated by maximizing the 
coefficient of determination estimated from the log-linear regression model. However, 
AUC0-∞, AUC0-T/∞, λZ and Thalf parameters will be estimated for individual 
concentration-time profiles only when the terminal log-linear phase can be reliably 
characterized using the following criteria: 
 Phoenix® WinNonlin® Best fit range selection 
 R2 of at least 80%  
 The corresponding terminal half-life value must be lower than or equal 
to 2 times the time interval over which λZ was estimated (i.e. Thalf ≤ twice the 
time interval difference between TLQC and TLIN). 
Descriptive statistics will be calculated for plasma concentrations at each individual 
time point and for all pharmacokinetic parameters. The individual plasma 
concentration/time profiles will be presented using the actual sampling times whereas 
the mean plasma concentration/time profiles will be presented using the theoretical 
sampling times. 
Pharmacokinetic analyses will be generated using validated pharmacokinetic software 
(i.e. Phoenix® WinNonlin® version 6.3 or higher, Phoenix® ConnectTM version 1.3.1 or 
higher). 
9.3. STATISTICAL ANALYSIS 
No statistical analysis will be performed. 
9.4. SAMPLE SIZE JUSTIFICATION 
The objective of this study is to demonstrate that no or negligible systemic exposure 
occurs after a single topical application of ReadyPrep® CHG. Based on the sponsor’s 
data, it is estimated that 12 subjects should be sufficient to meet this objective. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10. REGULATORY REQUIREMENTS 
10.1. LIABILITIES 
It is the sponsor’s responsibility to guarantee sufficient insurance coverage should any 
serious events or deaths result directly or not from the execution of the present 
protocol. 
The present article is not to be interpreted as engaging the sponsor’s responsibility in 
the event of fault or negligence of the subjects, investigators, or any persons or 
employees under the control of the clinical site. 
10.2. STATEMENT OF INVESTIGATOR 
The FDA 1572 form, Statement of Investigator [Title 21, CFR Part 312], will be 
signed by the Principal Investigator, and will be kept on file and will remain available 
upon request. 
10.3. DELEGATION OF INVESTIGATOR DUTIES 
The Principal Investigator will ensure all personnel involved in the trial are adequately 
qualified and informed about the protocol, any amendments to the protocol, the study 
treatments, and their trial-related duties and functions. 
The Principal Investigator will maintain a list of sub-investigator(s) and other 
appropriately-qualified persons to whom he delegates significant trial-related duties. 
Should the Principal Investigator delegate the supervision of the investigational 
product administration to a designated person, this individual must have the 
appropriate medical legal qualifications. The Principal Investigator should also ensure 
key staff personnel have the appropriate medical qualifications to effectively conduct 
or supervise any potential resuscitation procedures. 
10.4. INSTITUTIONAL REVIEW BOARD (IRB) 
This protocol and the ICF will be submitted to an IRB (or IEC) prior to initiation of 
the study and the study will not start until the Board has approved the documents. 
Notification of the Board’s approval will be appended to the final report. 
This study will be conducted in compliance with the study protocol, the ethical 
principles that have their origins in the Declaration of Helsinki, the ICH Guideline E6 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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for GCP, the FDA GCP Code of Federal Regulations (CFR) Title 21 (part 56), and the 
European regulation EU 536/2014. 
10.5. INFORMED CONSENT FORM (ICF) 
Before screening activities can commence, each volunteer will be given a copy of the 
consent to read, and a full explanation of the purpose of the study, the procedures to be 
carried out, and the potential adverse event(s). Once this essential information is 
provided to the volunteer and the medical investigator or designee has the conviction 
the volunteer understands the implications of participating in the study, if the 
volunteer(s) chooses to continue screening, they will be requested to sign and date a 
properly executed written informed consent document in compliance with the U.S. 
Code of Federal Regulations (Title 21, Part 50). Subjects will be assured they may 
withdraw from the study at any time without jeopardizing their medical care or future 
study participation (for which they qualify). They will be given a signed copy of the 
informed consent. 
If an amended or revised ICF is introduced during the study, each subject’s further 
consent should be obtained. 
10.6. CASE REPORT FORM 
Data required by the protocol will be accurately reported on the CRF for each subject 
included (i.e., who received an Investigational Product treatment) in a clinical trial. 
The complete CRF will be approved and signed by the Principal Investigator or 
designee, who will receive a signature delegation from the investigator. 
A copy of the CRFs will be provided to the sponsor with the final report. 
10.7. RECORD RETENTION 
All essential documents and records will be maintained by the clinical site in 
accordance with, and for the period specified in the applicable regulatory 
requirement(s) (FDA CFR 312.57 (C)). 
10.8. QUALITY ASSURANCE/QUALITY CONTROL 
Designated personnel from Algorithme Pharma will be responsible for maintaining 
quality assurance (QA) and quality control (QC) systems to ensure that the trial is 
conducted and data are generated, documented and reported in compliance with the 
protocol, ICH Guideline E6 for Good Clinical Practices, applicable requirements as 
outlined in the FDA and OECD Principles of GLP, and the Reflection paper for 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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laboratories that perform the analysis or evaluation of clinical trial samples 
(EMA/INS/GCP/532137/2010).  
10.9. MONITORING OF THE STUDY 
The sponsor or its representative may visit the study facilities at any time in order to 
maintain current and personal knowledge of the study through review of the records, 
comparison with source documents, observation and discussion of the conduct and 
progress of the study. The clinical site will permit trial-related monitoring, audits, 
IRB/IEC review, and regulatory inspection(s) by providing direct access to source 
data/documents. 
10.10. 
DATA MANAGEMENT AND PROCESSING 
Data management activities will be performed using either ClintrialTM or the Medrio 
electronic data capture software in accordance with Algorithme Pharma’s standard 
operating procedures.  
Data entered will be checked at the point of entry and through validations for 
accuracy. When the database is declared to be complete and accurate, it will be locked. 
10.11. 
PREMATURE TERMINATION OR SUSPENSION OF A STUDY 
The sponsor or its representative may terminate the study at any time for scientific or 
corporate reasons. 
If the trial is prematurely terminated or suspended for any reason, the clinical site or 
the Principal Investigator (or designee) should promptly inform the trial subjects, 
should assure appropriate therapy and follow-up for the subjects and should inform the 
regulatory authority(ies) when required. 
10.12. 
ADHERENCE TO PROTOCOL 
Excluding an emergency situation in which proper treatment is required for the 
protection, safety and well-being of the study subjects, the study will be conducted as 
described in the approved protocol and performed according to ICH/GCP and FDA 
guidelines. Any deviation from the protocol will be recorded and explained. 
If amendments to the protocol and/or amendments or revisions to the ICF are required, 
the modifications will be documented and submitted to an IRB for approval. 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11. REFERENCES 
1. 
Nicolay, A. et al., Rapid HPLC Method for Determination of Parachloroaniline in 
Chlorhexidine Antiseptic Agent in Mouthrinses, Ophthalmic and Skin Solution, 
American Journal of Analytical Chemistry, 2011, 2, 422-428 
2. 
2% Chlorhexidine gluconate cloth [Label] (06/24/2014). NDA 021669, Drugs@FDA, 
FDA Web site. http://www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed 
2017/05/17. 
3. 
Center for Drug Evaluation and Research, Application Number 21-669, 
Pharmacology Review 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 1. Study Design and Schedule of Assessments 
 
 
 
Pre-
Trial 
Period 1 
Wash- 
Out 
Period 2 
Wash- 
Out 
Period 3 
End of 
Study 
Days a 
-28 to 
-1 
-1 
1 
2 
1-7 
7 
8 
9 
8-14 
14 
15 
16 
16 
Informed Consent Form Signed b 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to Unit 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Tests 
X 
Xc 
 
 
 
Xc 
 
 
 
Xc 
 
 
X 
HIV Ag/Ab Combo, HBsAg (B) 
and HCV (C) Tests 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and Drugs of Abuse 
Screening 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Pregnancy Test 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
Vital Signs 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
Visual Skin Evaluation 
X 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
Drug Application 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Blood Sampling 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a 
The days assigned to each period may change according to the exact wash-out determined between the drug administrations 
b 
The last version must be signed prior to subject's inclusion (first drug administration) 
c 
General biochemistry only 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 2. Blood Sampling Schedule 
 
Sample No 
Sampling Time 
(hours) 
Clock time* 
01 
-10.00** 
21:00 
02 
-2.00** 
05:00 
03 
-0.50** 
06:30 
04 
1.00 
08:00 
05 
2.00 
09:00 
06 
3.00 
10:00 
07 
4.00 
11:00 
08 
5.00 
12:00 
09 
6.00 
13:00 
10 
8.00 
15:00 
11 
12:00 
19:00 
12 
24:00 
07:00 
 
* 
Clock time may change according to the exact time of drug administration. Study medications will be applied to each 
subject consecutively for the purpose of accurate sampling time. 
** 
Before treatment 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 3. Pharmacokinetic Parameters 
 
Cmax 
 
 
Maximum observed plasma concentration 
 
Tmax 
Time of maximum observed plasma concentration; if it occurs at 
more than one time point, Tmax is defined as the first time point 
with this value 
 
TLQC 
 
 
Time of last observed quantifiable plasma concentration 
 
AUC0-T 
Cumulative area under the plasma concentration time curve 
calculated from 0 to TLQC using the linear trapezoidal method 
 
AUC0-∞ 
Area under the plasma concentration time curve extrapolated to 
infinity, calculated as AUC0-T + CLQC/λZ, where CLQC is the 
measured concentration at time TLQC 
 
 
AUC0-T/ 
 
Relative percentage of AUC0-T with respect to AUC0-∞ 
 
TLIN 
 
 
Time point where the log-linear elimination phase begins 
 
λZ  
Apparent elimination rate constant, estimated by linear regression 
of the terminal linear portion of the log concentration versus time 
curve 
 
Thalf 
 
 
Terminal elimination half-life, calculated as ln(2)/λZ 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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APPENDIX 1: AMENDMENT 01 
 
RATIONALE: 
 
Reason for amendment: 
1)  
The study design was updated to control for the   
presence of chlorhexidine in the environment. 
2) 
To exclude the use of oral acetylsalicylic (and 
salicylic acid) at screening and on-study as these 
compounds may interact with the bioanalytical assay of 
chlorhexidine.  
3)  
To correct a discrepancy in Table 1 
 
Requested by:  
1) 
Algorithme Pharma and Medline 
2-3) Algorithme Pharma 
 
 
TEXT OF AMENDMENT: 
 
Amendment 01: 
 
1) A control treatment with no topical application of ReadyPrep® CHG or placebo was 
added to the study. The study design is now a single center, randomized, single dose, 
laboratory-blinded, 3-period, 3-sequence, crossover design. The protocol and ICF 
were updated accordingly. 
 
2) Baseline levels, consisting of 3 blood samples, will be assessed before each treatment. 
In the event that chlorhexidine levels are measurable, the pharmacokinetic parameters 
will be estimated with and without baseline adjustment. The protocol and ICF were 
updated accordingly. 
 
3) ‘Drug application’ was changed to ‘treatment’ throughout the protocol and ICF. 
 
4) Protocol and ICF were updated to exclude the use of oral acetylsalicylic acid (ASA) 
and salicylic acid or any oral product containing ASA or salicylic acid, in the 
previous 7 days before study day 1 and during the study 
 
5) The line for Drug Removal was deleted from Table 1 as this is not applicable 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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AUTHORED BY: 
 
 
 
___________________________________  
 
____________________ 
Julie Basque, M.Sc., 
Date (yyyy/mm/dd) 
Senior Clinical Research Scientist 
Altasciences Company Inc. (doing business as Algorithme Pharma)