Clinical trial NCT04321460
Conditions: Antibiotic-associated Diarrhea
Keywords: diarrhea
Sponsor: Sandoz
Start date: 2020-10-01; Completion date: 2021-01-04
Enrollment: 520 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this study was to investigate the efficacy and safety of LRG-002 investigational medicinal product, capsules (Lek d.d., Slovenia) in comparison with placebo, as an adjunct treatment for prophylaxis of antibiotic-associated diarrhea (AAD) in patients with acute respiratory diseases (ARDs) receiving a standard antimicrobial therapy.

Detailed description:
This study was the prospective, multi-centered, double-blinded, randomized, parallel-group clinical study. The study investigated the efficacy and safety of LRG-002 investigational medicinal product, capsules (Lek d.d., Slovenia) in comparison with placebo, as an adjunct treatment for prophylaxis of antibiotic-associated diarrhea (AAD) in patients with acute respiratory diseases (ARDs) receiving a standard antimicrobial therapy.

The study comprised the following periods:

Study Periods Visit 1 (Day 1): Screening + randomization + initiation of treatment

Patients started participating in the study after signing the Informed Consent Form. Having completed screening tests, eligible patients were randomized on the same day to receive either LRG-002 or matching placebo capsules, each as an adjunct to the prescribed antibiotic. The treatment group was determined by randomization at a center ratio. Study subjects were supplied with the patient diary and blinded investigational product (investigational medicinal product or placebo) depending on the assigned treatment group. Patients could start study treatment only after receiving appropriate training. On Day 1, the study started in both groups from randomization and administration of the first dose of the investigational product depending on the assigned group after randomization:

Group T, treated with LRG-002: a single dose of 1 oral hard capsule taken during meals with some water; the product was to be taken orally 2 times per day for 14 days.

Group R, provided with placebo:a single dose of 1 oral hard capsule taken during meals with some water; the product is to be taken orally 2 times per day for 14 days.

Visit 2 (Day 7): Intermediate Follow-up Visit

Visit 3 (Day 15) : Visit 3 was scheduled at Day 15 when a patient was to come to the study site bringing along the completed diary, unused laboratory kit, unused product and empty packages.

Arms: arm 1: LRG-002 once daily for 14 days arm 2: Placebo once daily for 14 days
Interventions: intervention 1: LRG-002 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules containing live lyophilized probiotic bacteria of Lactobacillus genus intervention 2: Capsules containing placebo

Protocol documents:
Prot_000.pdf: 
Official Title: 
Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group 
Efficacy and Safety Study of LRG-002 Hard Capsules (Lek d.d., Slovenia) 
Used in the Prophylaxis of Antibiotic-associated Diarrhea in Adults 
NCT Number: 
NCT04321460 
Document Date: 
Clinical Study Protocol Version 3.0: 23 June 2020 


Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
Page 1 of 253 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Study title: Multicentre, double-blind, randomized, placebo-controlled, parallel-group efficacy 
and safety study of LRG-002 hard capsules (Lek d.d., Slovenia) used in the prophylaxis of 
antibiotic-associated diarrhea in adults. 
 
Protocol No.  CT_002_LRG_CAP 
Protocol version: 3.0 dated June 23, 2020 
Investigational Medicinal Product: LRG-002 
International Nonproprietary Name: Lactobacillus rhamnosus GG 1 х 1010 CFU 
Dosage form and strength: capsules 
Phase of the Clinical Study: III 
Study Sponsor: ZAO Sandoz. 
Address: 72 Leningradsky prospect, bld. 3, Moscow, 125315, the Russian Federation 
 
 
 
Confidentiality statement 
This document is intended for use by the parties to which it was addressed, it contains non-disclosed, 
confidential information and / or trade secrets protected from disclosure in accordance with applicable law. 
By accepting such documentation, the party acknowledges that such material is confidential, and agrees not 
to disclose it to any third party without the prior written consent of ZAO Sandoz and not to use it for any 
purpose other than intended. 


Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
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The Protocol Approval List by the Study Sponsor: 
The Protocol Title: Multicentre, double-blind, randomized, placebo-controlled, parallel-group 
efficacy and safety study of LRG-002 hard capsules (Lek d.d., Slovenia) used in the prophylaxis 
of antibiotic-associated diarrhea in adults. 
Protocol No. CT_002_LRG_CAP 
Protocol version: 3.0 dated June 23, 2020 
Sponsor’s representative: 
ZAO Sandoz, The Russian Federation. 
Address: Leningradsky prospect 72, bld. 3, Moscow, 125317, The Russian Federation 
Tel. 
 - Fax 
 
 
                     
        (Employee’s name)  
 (Function) 
 
Tel.: 
 (Ext. 
) 
E-mail: 
 
 
_____________________________                                     "____"___________2020  
                    Signature                                                                        Date 


Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
Page 3 of 253 
 
Investigator Statement of Compliance with the Study Protocol 
I confirm having read and understood the present Protocol, the Investigator’s Brochure, including 
potential risks and side effects of the medicinal product and other product and study information 
provided by the Sponsor.  I agree to perform the present Study in compliance with the Protocol 
requirements as well as to protect rights, safety, confidentiality and well-being of patients in 
accordance with ethic requirements set out in the Helsinki Declaration of the World Medical 
Association (WMA), in the Federal Law dated April 12, 2010,  No. 61-ФЗ (FZ) “On Circulation 
of Medicines”; requirements of the RF Ministry of Health dated April 1, 2016, No. 200n “On Good 
Clinical Practice Approval”; principles of the National Standard of the Russian Federation GOST 
R (ГОСТ Р) 52379-2005 “Good Clinical Practice” (GLP) and other regulatory requirements of the 
Russian Federation. I agree to introduce any modifications to the Protocol only after notification 
of the Sponsor, unless it is necessary for safety, protection of rights and well-being of patients. I 
completely understand that any modifications provided by the Investigator(s) without prior 
discussion with the Sponsor’s representative shall constitute Protocol violation (apart from 
procedures necessary for patients’ health maintenance). I agree to conduct or manage the described 
study by myself. I agree to inform patients that medications are used for research purposes; I will 
ensure compliance with the requirements for obtaining the Informed Consent after the Ethics 
Committee’s and the Independent Ethics Committee’s approval and in accordance with the 
principles of Good Clinical Practice (GCP).  In accordance with the principles of GCP, I agree to 
inform the Sponsor about any adverse events developed during the study. I agree to ensure that all 
employees, colleagues, and individuals involved in the study are informed of their obligations to 
comply with the above agreements. I agree to keep adequate and precise recording as well as to 
submit these records for analyses in accordance with the principles of GCP. I’ll ensure that local 
IEC acting in accordance with GCP requirements, is responsible for the performance of Ethic 
review as well as for the approval of the Study. I also agree to report all changes in research 
activities and all unexpected issues, including any patients’ risks and other aspects to the local IEC 
as soon as possible. In addition, I will not introduce any modifications to the Study without an 
approval by the Ethics Board/local IEC, unless there is a need for the management of any obvious 
unexpected life- and health-threatening cases in patients. I’m ready to provide the direct access to 
source medical records and agree for a review that will be performed by auditors and Sponsor’s 
representatives and supervising agencies. I guarantee that the study drug provided by the Sponsor 
will only be used, as described in the present Protocol. I agree to comply with all other 
requirements regarding the responsibilities of clinical investigators, as well as all other important 
requirements of Good Clinical Practice.   
 


Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
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Investigator: 
Signature:      ________________________________________________________________  
Date:    "____"___________ 20__  
Full name: 
Function: 
Facility: 
Address: 


Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
Page 5 of 253 
 
LIST OF ABBREVIATIONS 
AAD 
antibiotic-associated diarrhea 
AB 
antibiotic 
AB therapy 
antibacterial therapy 
ALD 
alcoholic liver disease 
BP 
blood pressure 
GAC 
gastric adenocarcinoma 
ALT  
alanine aminotransferase 
АО 
join stock company 
ASH  
alcoholic steatohepatitis 
AST 
aspartate aminotransferase 
ATP 
adenosine triphosphate 
ATPase 
adenosine triphosphatase 
ATC 
Anatomical Therapeutic Chemical (classification) 
ROS  
reactive oxygen species 
DS 
dietary supplement 
BSFS 
Bristol Stool Form Scale 
i.m. 
intramuscular(ly) 
i.v. 
intravenous(ly) 
ULN 
upper limit of normal 
HIV 
Human immunodeficiency virus 
IBD 
inflammatory bowel disease 
WMA 
World Medical Association 
IUS 
intrauterine system 
IUD 
intrauterine device 


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RSC 
Russian Society of Cardiologists 
WHO 
World Health Organization 
HPLC 
High performance liquid chromatography 
g 
gram 
GOST (ГОСТ) 
State Standard 
GC 
gas chromatography 
d.d.  
“d.d.” or “delniška družba”, Slovenian, public limited 
company 
DBP 
diastolic blood pressure 
CI 
confidence interval 
DMH 
dimethyl hydrazine 
DNA 
deoxyribonucleic acid 
TD 
traveler's diarrhea 
PDE 
 
permitted daily exposure 
GIT 
 
gastrointestinal tract 
ZAO 
Closed Join Stock Company 
EU 
European Union 
IAAD 
idiopathic antibiotic-associated diarrhea 
RF 
Record Form 
IL 
interleukin 
PI 
prescribing information 
FPS 
forename, patronym, surname 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
IFN 
interferon 


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IFN-γ  
interferon-gamma 
CRO 
contract research organization 
kg 
kilogramm(s) 
NSD 
number of sick days  
cfu 
colony forming units 
CPS 
capsular polysaccharides 
CRC 
colorectal cancer 
L 
liter(s) 
LRGG  
Lactobacillus rhamnosus GG 
LD-50  
half-lethal dose 
LPS 
lipopolysaccharides 
CF 
cystic fibrosis 
mg 
milligram(s) 
MDA 
malonic dialdehyde 
MH  
Ministry of Health 
min 
minutes 
ICD 
international classification of diseases 
μg (mcg) 
micrograms 
mL 
milliliters 
mm 
millimeters 
PBMC 
peripheral blood mononuclear cells 
INN 
international non-proprietory name 
MNNG 
methyl-nitro-nitrosoguanidine 
MIC 
minimum inhibitory concentration 
PCRBC 
Quantity of polychromatophilic red blood cells 


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NAFLD 
Non-alcoholic fatty liver disease 
e.g.: 
for example 
IEC 
necrotizing enterocolitis 
AR 
adverse reaction 
IEC  
Independent Ethics Committee 
AE 
adverse event 
AWD  
acute watery diarrhea 
AGE 
acute gastroenteritis 
DCS 
depleted cultural supernatant 
LLC 
Limited Liability Company 
RR 
relative risk 
ARD 
acute respiratory disease 
ICU 
intensive care unit 
FEV 
forced expiration volume 
OR 
odds ratio 
PVC 
polyvinyl chloride 
TJ 
tight junctions 
PCTFE 
polytrifluorochloroethylene 
PCA 
pyrrole-2-carboxylic acid  
PCR 
polymerase chain reaction 
QD 
once a day 
WP 
working party 
RIBT 
radiation-induced bowel toxicity 
RCTs 
randomized clinical trials 
BC 
breast cancer 


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RMOAG (РМОАГ) 
Society of arterial hypertension of the Russian Federation  
RNA 
ribonucleic acid 
ORS 
oral rehydration solution 
RD 
risk difference 
MA 
Marketing authorization 
RF 
Russian Federation 
SBP 
systolic blood pressure 
SAR 
serious adverse reaction 
SAE 
serious adverse event 
et al. 
contributors 
SOP 
standard operating procedure 
ESR 
erythrocyte sedimentation rate 
MD 
mean difference 
IBS 
irritated bowel syndrome 
d 
day 
i.e. 
that is (id est) 
TCID 
tissue culture infective dose 
TER 
transepithelial electric resistance 
FAP 
functional abdominal pain 
FD 
functional dyspepsia 
FL 
Federal Law 
SFP 
surname, patronym, forename 
TNF 
tumor necrosis factor 
FSH 
follicle stimulating hormone 
CU 
carbohydrate unit 


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CIBT 
chemically-induced bowel toxicity 
h 
hours 
NNT 
number of patients in need of treatment 
RR  
respiration rate 
HR 
heart rate 
ECG 
electrocardiography, electrocardiogram 
EPS 
exopolysaccharides 
AFB 
Acid Fast Bacilli 
AGRICOLA 
AGRICultural On Line Access - bibliographic data base of 
the United States National Agricultural Library 
AMED 
Allied and Complementary Medicine Database  - the 
specialized bibliographic database of the British Library on 
natural sciences and allied disciplines 
ATCC 
ATCC 53103 - L. rhamnosus strain 
AUC 
Area under the curve 
AUC0-∞ 
Area under the curve from time zero to infinity 
BALB 
laboratory line of albino domestic mice being commonly 
used in clinical trials 
BG2FO 
one of Lactobacillus spp strains 
C 
degree Celsius 
C. difficile 
Clostridium difficile 
C57BJ 
an inbred line of laboratory mice being commonly used as 
human disease models 
C57BL 
an inbred line of laboratory mice being commonly used as 
human disease models 
CaH 
calcium hydride 


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CBA 
an inbred line of laboratory mice 
 
CCL C-C 
Motif Chemokine Ligand 11 -chemokine 11 comprising CC 
motif   
CD 
cluster of differentiation – Т-helper surface protein 
CD62p 
activated platelet markers 
CdAD  
Clostridium difficile associated diarrhea 
CdD 
Clostridium difficile associated diarrhea 
CHCC 
one of Lactobacillus spp strains 
CHO 
Chinese hamster ovary - cell line generated from Chinese 
hamster ovaries 
CINAHL 
Cumulative Index to Nursing and Allied Health Literature 
CMPG 5153 
L. rhamnosus GG mutant strain 
CP 
Phosphoorganic pesticides parathion and chlorpyrifos 
CTM 
clinical trial manager 
CXCL  
interleukin-8  
CYP 
cytochrome P450 
CYP2E 
cytochrome Р450 
GCP 
Good Clinical Practice 
DN-114001 
one of Lactobacillus casei strains 
DOI 
digital object (paper) identificator 
E. cloacae 
Escherichia cloacae 
E. coli 
Escherichia coli 
EFSA  
European Food Safety Authority 
EMBASE 
Database for Biomedical Research 
EPEC 
enteropathogenic Escherichia coli  


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ERK 
protein kinase signal pathway 
ESPGHAN 
European Society of Pediatric Gastroenterology, Hepatology 
and Nutrition 
et al. 
et alii  and others 
ETEC 
enterotoxigenic E.coli 
F0F1- 
structural ATP synthase complex 
FAO 
Food and Agriculture Organization 
FDA 
Food and Drug Administration 
GAPDH 
glyceraldehyde-3-phosphate dehydrogenase  
GR 
one of L. Rhamnosus strains 
GRAS 
Generally Regarded As Safe – FDA sttate 
GSH 
glutathione 
H.pylori 
Helicobacter pylori 
HCl 
hydrochloric acid 
HIF 
Hypoxia-inducible factors 
HIV 
human immunodeficiency virus 
HNOO 1-DR20 
one of Lactobacillus rhamnosus probiotics 
HN001 
one of L. Rhamnosus strains 
HN019 
one of L. Rhamnosus strains 
HNOO 
one of L. Rhamnosus strains 
HNOl  
one of L. Rhamnosus strains 
ICH 
International Conference for Harmonization 
ITT 
intention-to-treat, population dependent on treatment 
prescribed 
IgA 
Immunoglobulin A 


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IgG 
Immunoglobulin G 
IgM 
 
Immunoglobulin M 
IkB 
inhibitory protein  
JAMA 
Journal of the American Medical Association  
L. 
Lactobacteria 
LCR 
Lactobacillus casei subsp. rhamnosus  
LGG 
one of L. Rhamnosus strains 
LGR  
one of L. Rhamnosus strains 
LPPV 
local person for pharmacovigilance 
LPXTG 
binding protein 
MANTIS 
Manual, Alternative and Natural Therapy Index System (the 
database for chiropractice, osteopathy and manual medicine) 
MAMP 
microbial molecular patterns 
MAPK 
mitogen activated kinase 
MedDRA 
medical dictionary for regulatory affairs 
MRS 
Liquid medium for Lactobacilli isolation according to the 
receipt recommended by Man, Rogosa and Sharpe as well as 
ISO 
MTg 
mouse thyroglobulin  
NNT 
number needed to treat 
OTA 
Ochratoxin A 
PECD62p 
activated platelet marker 
PJS 
Propionibacterium freudenreichii ssp. shermanii JS – 
probiotic strain 
PP 
per-protocol, population according to the Protocol 
PROSAFE 
probiotic and human strain collection 


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PRR 
pattern-recognizing receptors 
QPS 
Qualified Presumption of Safety 
RC 
one of L. Rhamnosus strains 
RR 
risk ratio 
S. boulardii  
Saccharomyces boulardii 
SF68 
Enterococcus faecium strain SF68 
Spp. 
Species 
Subsp 
Subspecies 
SUSAR 
suspected unexpected serious adverse reaction 
TGF 
Transforming growth factor 
TLR 
Toll-like receptor 
TOXLINE 
Toxicology Literature Online  
TY21A 
Salmonella typhimurium strain  
ToxFILE 
bibliographic database for biochemical, pharmacological, 
physiological and toxicological effects of drugs and other 
chemical substances 
VRE 
vancomycin-resistant enterococci  
ZO-1 
zona occludens-1 – peripheric membrane protein 


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Table of contents 
1. 
Synopsis ................................................................................................................................. 19 
 
General information ............................................................................................................... 41 
 
Protocol title, identification number and date ............................................................... 41 
 
Study Sponsor ................................................................................................................ 41 
 
Study Monitor ................................................................................................................ 42 
 
Clinical laboratories and other relevant organizations of the Study .............................. 43 
 
Rationale of the study and the program of clinical trials of the medicinal product .............. 44 
 
Program of clinical trials of the medicinal product ....................................................... 44 
 
Investigational drug ............................................................................................... 44 
 
Comparator product ............................................................................................... 47 
 
Summary of relevant results of non-clinical and clinical studies for this study ............ 48 
 
Summary of non-clinical results ............................................................................ 48 
 
Main pharmacological properties .......................................................................... 49 
3.2.2.1 In vitro investigations ................................................................................................ 49 
3.2.2.2 Investigations in vivo ................................................................................................ 53 
3.2.2.3 Pharmacological safety studies .................................................................................. 56 
3.2.2.4  Secondary pharmacological properties ..................................................................... 58 
3.2.2.5 Pharmacodynamic drug Interactions ......................................................................... 60 
3.2.2.6 Pharmacokinetics ....................................................................................................... 60 
3.2.2.7 
Adhesion to intestinal epithelium .......................................................................... 60 
3.2.2.8  Survival in gastrointestinal tract and excretion ........................................................ 61 
3.2.2.9  Pharmacokinetic drug interactions ........................................................................... 63 
3.2.2.10 Antibiotic resistance genes and probability of their transfer ................................. 64 
3.2.2.11 Susceptibility and resistance to antibiotics ............................................................ 65 
3.2.2.12  Toxicity study ......................................................................................................... 66 
3.2.2.13 Local tolerance ...................................................................................................... 72 
 
Summary of clinical studies .......................................................................................... 73 
 
Overview of biopharmaceutics .............................................................................. 76 
3.3.2 
Overview of clinical and pharmacological research data ...................................... 76 
3.3.3. Review of efficiency data in children and adults .......................................................... 87 
3.3.3.1 
Treatment of acute diarrhea in adults .................................................................... 87 
3.3.3.2 
Antibiotic-associated diarrhea: data on prevention and treatment in adults and 
children  ............................................................................................................................... 89 
3.3.3.3 
Coadjuvant therapy for the eradication of Helicobacter pylori in adults .............. 96 
3.3.3.4 
Treatment of acute gastroenteritis in children ....................................................... 98 
3.3.3.5 
Functional disorders of the gastrointestinal tract associated with abdominal pain in 
children  ............................................................................................................................. 106 
3.3.3.6 
Traveler's diarrhea ............................................................................................... 107 
3.3.3.7 
Study of occurrence and severity of respiratory and gastrointestinal infections in 
children  ............................................................................................................................. 109 
3.3.4 Other effects studied in human .................................................................................... 111 
3.3.4.1 
Immunological effects ......................................................................................... 111 
3.3.4.2 Efficacy in inflammatory intestine diseases ............................................................ 113 
3.3.5 Overview of safety data ............................................................................................... 114 
3.3.5.1 
Systemic infections .............................................................................................. 117 
3.3.5.2 
Unfavorable metabolic effects ............................................................................. 123 
3.3.5.3 Immune hyperstimulation ........................................................................................ 124 
3.3.5.4 
Gene transfer........................................................................................................ 124 


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3.3.5.5 
Gastrointestinal adverse effects ........................................................................... 124 
3.4 
A brief description of the known and potential risks and benefits to research subjects, if 
there are any............................................................................................................................. 124 
3.5 
Description and justification of the method of administration, dosage, dosing regimen 
and course of treatment............................................................................................................ 125 
3.5.1 
Description and justification of the method of administration, dosage, dosage 
regimen and course of treatment with the investigational drug........................................... 125 
3.5.2 
Justification of placebo use.................................................................................. 126 
3.5.3 
Regulatory frameworks ....................................................................................... 126 
3.6 
Description of study population .................................................................................. 127 
4 
Study aims and objectives ................................................................................................... 127 
4.1 
Study goal .................................................................................................................... 127 
4.2 
Study objectives ........................................................................................................... 127 
5. 
Study Design ....................................................................................................................... 128 
5.1 
Main and additional studied parameters ...................................................................... 128 
5.1.1 
Efficacy parameters ............................................................................................. 128 
5.1.2 
Safety parameters ................................................................................................ 129 
5.2 
Description of study design ......................................................................................... 130 
5.2.1 
Study type ............................................................................................................ 130 
5.2.2 
Flowchart of study design ................................................................................... 130 
5.2.3 
Study procedures ................................................................................................. 131 
5.2.4 
Study Periods ....................................................................................................... 136 
5.2.5 
Early study termination ....................................................................................... 139 
5.3 
Handling of investigational medicinal products .......................................................... 139 
5.3.1 
Supply of the medicinal products to the study site .............................................. 139 
5.3.2 
Quality complaints ............................................................................................... 140 
5.3.3 
Dispensing and collection of medical products ................................................... 140 
5.3.4 
Product Accountability ........................................................................................ 141 
5.3.5 
Collection and destruction of the medicinal products ......................................... 141 
5.4 
Measures aimed at minimizing/eliminating subjectivity ............................................. 141 
5.4.1 
Randomization ..................................................................................................... 141 
5.4.2 
Blinding methods ................................................................................................. 142 
5.5 
Dosage regimen of the study medicinal products ........................................................ 142 
5.6 
Dosage form, packaging and labeling of investigational medicinal products ............. 143 
5.6.1 
Dosage form ........................................................................................................ 143 
5.6.2 
Packaging ............................................................................................................ 144 
5.6.3 
Labeling of investigational medicinal product .................................................... 144 
5.7 
Duration of patient participation in the study .............................................................. 144 
5.8 
Rules for stopping the parts of clinical study and/or the clinical study in general ...... 144 
5.9 
Accounting procedures of the investigational medicinal products .............................. 144 
5.10 
Storage of randomized codes and procedure for their disclosure ................................ 145 
5.11 
List of data recorded in Individual Case Record Form (without prior written or electronic 
recording) and considered as primary data .............................................................................. 145 
6. 
Patient inclusion and exclusion ........................................................................................... 145 
6.1 
Inclusion criteria .......................................................................................................... 145 
6.2 
Non-inclusion criteria .................................................................................................. 147 
6.3 
Exclusion Criteria ........................................................................................................ 148 
6.3.1 
Timing and terms of subject exclusion from the study ....................................... 148 
6.3.2 
Terms and conditions of stopping/termination by the subject of treatment with the 
medicinal product under study ............................................................................................ 149 
6.3.3 
Replacing the discontinued patients .................................................................... 149 
7. 
Information about the medicinal products used in the clinical study .................................. 150 


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7.1 
Investigational medicinal product and reference product............................................ 150 
7.2 
Compliance control ..................................................................................................... 150 
7.3 
Allowed concomitant treatments ................................................................................. 150 
7.4 
Prohibited concomitant therapy ................................................................................... 151 
8. 
Efficacy Evaluation ............................................................................................................. 151 
8.1 
List of efficacy parameters .......................................................................................... 151 
8.2 
Methods and timing for evaluating, recording and analyzing efficacy parameters .... 152 
9. 
Safety Evaluation ................................................................................................................. 154 
9.1 
List of safety parameters.............................................................................................. 154 
9.2 
Methods and timing for evaluating, recording and analyzing safety parameters ........ 154 
9.3 
Requirements for reports, procedures on recording and reporting of adverse events and 
intercurrent diseases ................................................................................................................ 155 
9.3.1 
Terminology of adverse events and serious adverse events ................................ 155 
9.3.2 
Severity of adverse events ................................................................................... 157 
9.3.3 
Causality to the investigational medicinal product: ............................................ 157 
9.3.4 
Documentation of adverse events ........................................................................ 158 
9.3.5 
SAE Reporting ..................................................................................................... 159 
9.3.6 
Emergency SAE Unblinding ............................................................................... 161 
9.3.7 
Pregnancies .......................................................................................................... 161 
9.3.8 
Claims related to IMP / medical device............................................................... 162 
9.3.9 
Special cases ........................................................................................................ 162 
9.3.10 
Reconciliation ...................................................................................................... 163 
9.3.11 
Training of investigators ...................................................................................... 163 
10. Statistic ................................................................................................................................ 164 
10.1 
Description of statistical methods to be used, including the timing of each planned 
interim analysis ........................................................................................................................ 164 
10.1.1 
Demographic and other source data (comparability of groups for analysis) ....... 164 
10.1.2 
Primary efficacy parameter analysis.................................................................... 165 
10.1.3 
Analysis of secondary efficacy parameters ......................................................... 166 
10.1.4 
Analysis of safety parameters .............................................................................. 167 
10.3 
Sample size calculation ............................................................................................... 168 
10.4 
Applicable significance level of the clinical study ...................................................... 170 
10.5 
Clinical study termination criteria ............................................................................... 170 
10.6 
Missing, Suspect and Non-Amendable-To-Analysis Data Procedures ....................... 170 
10.7 
Procedures for reporting any deviations from the original statistical plan .................. 171 
10.8 
Selection of subjects for analysis................................................................................. 171 
11. Description of activities concerning Quality Control and Quality Assurance .................... 171 
11.1 
Study Monitoring and Quality Control ........................................................................ 171 
11.2 
Protocol amendments .................................................................................................. 172 
11.3 
Protocol Deviations ..................................................................................................... 173 
12. Description of the clinical trial ethical aspects .................................................................... 174 
12.1 
General provisions ....................................................................................................... 174 
12.2 
Procedure of obtaining informed consent .................................................................... 175 
12.3 
Confidentiality and identification of study subjects .................................................... 176 
12.4 
Selection of subjects from vulnerable and special groups ........................................... 176 
13. Description of working with data and recording ................................................................. 177 
14. Funding and Insurance ........................................................................................................ 179 
14.1 
Funding ........................................................................................................................ 179 
14.2 
Insurance ...................................................................................................................... 179 
15. Publications ......................................................................................................................... 181 
16. References ........................................................................................................................... 182 
17. Appendices .......................................................................................................................... 199 


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17.1 
Appendix 1. Prohibited Therapy List .......................................................................... 199 
17.2. Appendix 2. Prescribing on stool sample collection for patient .................................. 201 
17.3. Appendix 3. Patient diary ............................................................................................ 202 
17.4. Appendix 4. Bristol Stool Form Scale (according to Lewis S. J. Et al, 1997, adapt. by 
Kharchenko et al . 2007).......................................................................................................... 253 
 
 
 
 


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1. 
Synopsis 
Study Title 
Multi-center, double-blind, randomized, placebo-controlled, parallel-
group study of the efficacy and safety of LRG-002 hard capsules (Lek 
d.d., Slovenia) in the prophylaxis of antibiotic-associated diarrhea in 
adults. 
Study Code 
CT_002_LRG_CAP 
Sponsor 
Sandoz CJSC 
Investigational 
Medicinal Product 
LRG-002 = hard capsules with Lactobacillus rhamnosus GG not less 
than 1 x 1010 CFU per capsule (Lek d.d., Slovenia) 
Reference product 
Matching placebo, capsules 
Background 
Antibacterial Therapy 
Oral beta-lactam antibiotics, e.g. amoxicillin, Augmentin (amoxicillin 
clavulanate), cefixime, etc. (7-day course). The start of antibiotic 
therapy coincides with the first day of the study.  
Diagnosis of the underlying disease and the prescription of antibiotic 
therapy are not part of the study. 
Phase of the Clinical 
Study 
III 
Study Population 
It is planned to include (randomize) 520 patients (260 patients in each 
treatment group) taking into account a patient withdrawal rate of 20% 
or less. The minimal number of patients needed for statistical analysis 
is 416 patients with 208 patients of the per-protocol population in each 
treatment group.  
Planned Study 
Duration 
Maximum 17 days:  
Day 1: Screening/randomization/study treatment initiation  
Day 7 ± 2: Intermediate Follow-up Visit  
Day 15 ± 2: Treatment Completion / Study Termination Visit (after 
completion of LRG-002/Placebo regimen)  
 
The overall enrollment period is about 8 months. 
Planned Number of 
Investigational Sites 
Up to 40 sites in the RF  


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Study Goal 
To demonstrate the efficacy and safety of the investigational 
medicinal product LRG-002 as compared with placebo, as an adjunct 
treatment for prophylaxis of antibiotic-associated diarrhea (AAD) in 
patients with acute respiratory diseases (ARDs) receiving a standard 
antimicrobial regimen. 
Study Objectives 
Main objective: 
To evaluate the incidence of AAD while taking LRG-002, hard 
capsules (Lek d.d., Slovenia) as compared to placebo in antibiotic-
treated patients with ARDs. 
 
Secondary objective: 
To evaluate the safety of LRG-002, hard capsules (Lek d.d, Slovenia), 
as compared with placebo in antibiotic-treated patients with ARDs. 
 
Study Methodology 
Study Design 
A prospective, multi-center, double-blind, randomized, parallel-group 
clinical study. 
The study will comprise the following periods: 
Study Periods 
I. Screening + randomization + treatment initiation: Visit 1 (Day 1)  
II. Blinded treatment with LRG-002 in antibiotic-treated patients.  
Or 
Blinded treatment with matching placebo capsules in antibiotic-
treated patients.  
Note: Duration of LRG-002 / Placebo administration should cover AB 
treatment period + 7 days after the AB treatment is completed = a total 
of 14 days.  
Visit 2 (Day 7 ± 2): Intermediate Follow-up Visit  
Visit 3 (Day 15 ± 2): Treatment Completion / Study Termination Visit. 


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Domiciliary Visits by a doctor and a nurse at the patient’s home are 
allowed. 
Visit 1 (Day 1) 
Patients start participating in the study after signing the Informed 
Consent Form. Procedures at Visit 1 for patients in each study group: 
• Collection of demographic data (year of birth, sex, age);  
•  Body weight and height measurements;  
• Medical history;  
• Reporting concomitant treatment (including medications, medical 
devices and food supplements);  
• Complaints reporting;  
• Physical examination; 
• Vital signs assessment (heart rate [HR], blood pressure [BP]), body 
temperature [BT], respiratory rate [RR]); 
• Complete blood count;  
• Blood chemistry profile;  
• COVID-19 Antibody (IgM / IgG) combined express-test; 
• Urine pregnancy test;  
• A 12-lead electrocardiogram;  
• Evaluation of the inclusion/non-inclusion criteria;  
• Randomization; 
• Dispensing of the investigational medicinal product (IMP) / 
placebo; 
• Dispensing of patient diary, mercury thermometer and respective 
training; 
• Dispensing of laboratory kit with the necessary supplies to collect 
stool samples;  
• Adverse event assessment.  
Having completed the screening tests, eligible patients will be 
randomized on the same day to receive either LRG-002 or matching 
placebo capsules, each as an adjunct to the prescribed antibiotic (see 
inclusion criteria). The treatment group will be determined by 
randomization at a 1:1 ratio. Study subjects will be supplied with the 


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patient diary and blinded investigational product (investigational 
medicinal product or placebo) depending on the assigned treatment 
group. Patients will be able to start study treatment only after receiving 
appropriate training. On Day 1, the study will be started in both groups 
from randomization and administration of the first dose of the 
investigational product depending on the assigned group after 
randomization: 
Group T, treatment with LRG-002: a single dose of 1 oral hard 
capsule taken during meals with some water; the product is to be taken 
orally 2 times per day for 14 days. 
Group R, treatment with placebo: a single dose of 1 oral hard 
capsule taken during meals with some water; the product is to be taken 
orally 2 times per day for 14 days.  
If the appointment is received in the afternoon, the administration of 
one capsule is allowed on the first day. The interval between taking 
the oral antibiotic and IMP/Placebo should be at least 3 hours in both 
groups. 
IMP/Placebo capsules must not be taken concomitantly with alcohol, 
fruit juices or hot beverages. 
 In both groups, patients will be receiving an oral beta-lactam 
antibiotic (for instance, amoxicillin, amoxicillin + clavulanic acid, 
cefixime, etc.) (see Background Antibacterial Therapy).  
Patients will be able to start documentation in the patient diary only 
after receiving appropriate training.  
In the diary, the subjects should daily document:  
• Occurrence of bowel movements, specifying date/time for each 
bowel movement; 
• Stool consistency (Bristol Stool Form Scale, BSFS) for each bowel 
movement; 
• Intake of blinded IP (IMP/placebo); 
• Intake of antibiotic; 


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• Occurrence of gastrointestinal complaints (assessment of the 
severity of symptoms using a 5-point verbal scale [0 to 4]); 
• Occurrence of pyrexia; 
• Use of any drugs, other than the prescribed antibiotic therapy 
(indicating the name, strength and time of administration). 
Visit 2 (Day 7 ± 2) 
Intermediate Follow-up Visit  
Procedures at Visit 2 for patients in each study group:  
• Complaints reporting, medical history update; 
• Reporting concomitant medications; 
• Body weight measurements; 
• Physical examination; 
• Vital signs assessment; 
• Complete blood count;  
• Blood chemistry profile; 
• Adverse event assessment; 
• Evaluation of exclusion criteria; 
• Review of patient diary; 
• Dispensing of laboratory kit with the necessary supplies to collect 
stool samples (if necessary); 
• Assessment of the adherence to study procedures (compliance with 
diary completion and study treatment); 
• Assessment of diarrhea, if documented in the diary regarding its 
classification as AAD or non-AAD (according to investigator’s 
judgment). If the results of stool samples analysis are not available 
during visit, the assessment will be done after the investigator receives 
the results from the laboratory. 
Visit 3 (Day 15 ± 2)  


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Visit 3 is scheduled at Day 15±2 when a patient is to come to the study 
site bringing along the completed diary, unused laboratory kit, unused 
product and empty packages. Procedures at Visit 3 for patients in each 
study group:  
• Complaints reporting, medical history update; 
• Body weight measurements; 
• Reporting concomitant medications; 
• Physical examination; 
 • Vital signs assessment; 
• Adverse event assessment; 
• Evaluation of exclusion criteria; 
• Assessment of the adherence to study procedures (compliance with 
diary completion and study treatment); 
• Complete blood count; 
• Blood chemistry profile; 
• A 12-lead electrocardiogram; 
• Collection of unused laboratory kit; 
• Collection of unused medication; 
• Review and collection of patient diary; 
• Assessment of diarrhea, if documented in the diary regarding its 
classification as AAD or not (according to investigator’s judgment). 
If the results of stool samples analysis are not available during visit, 
the assessment will be done after the investigator receives the results 
from the laboratory. 
 
Collection of stool samples in case of diarrhea 
Visit 1  
• Dispensing of laboratory kit with the necessary supplies to collect 
stool samples:  
Stool sample collection in case of diarrhea (between V1 and V2):  
• 1 container – stool sample for presence of common diarrheal 
pathogens (rotavirus, adenovirus, norovirus, Campylobacter spp, 
Salmonella spp, Shigella spp,); 


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• 1 container – stool sample for presence of C. difficile toxins A and 
B; 
• 1 container – stool sample for culture for opportunistic flora: 
Klebsiella pneumoniae, Staphylococcus aureus, Proteus mirabilis, 
Candida spp, E. Coli and for culture Yersinia spp (special container).  
Visit 2  
• Dispensing of laboratory kit with the necessary supplies to collect 
stool samples (if necessary):  
Stool sample collection in case of diarrhea (between V2 and V3):  
• 1 container – stool sample for presence of common diarrheal 
pathogens (rotavirus, adenovirus, norovirus, Campylobacter spp, 
Salmonella spp, Shigella spp,); 
• 1 container – stool sample for presence of C. difficile toxins A and 
B; 
• 1 container – stool sample for culture for opportunistic flora: 
Klebsiella pneumoniae, Staphylococcus aureus, Proteus mirabilis, 
Candida spp, E. Coli and for culture Yersinia spp (special container).  
Visit 3  
• Collection of unused laboratory kit (in case there was no diarrhea 
between V1 and V3). 
In case of diarrhea between visits, the patient must contact the site and 
collect stool samples in three containers (containers are received at V1 
and V2). The site employee arrives at the patient to collect containers 
in thermo package and transport them to the laboratory.  
In the case of acute diarrhea (loose, watery stool [BSFS Type 6, 7] 
with an occurrence of 3 or more times within 24 hours), the patient 
should contact the investigator for advice on therapy. 
Unscheduled Visits 
The unscheduled visits will be conducted when necessary, e.g., in case 
of the index disease deterioration, AEs, or intolerability of IMPs 
(LRG-002 or placebo). 


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Every unscheduled visit, irrespective of its cause, must include the 
procedures listed below with completion of the relevant eCRF pages 
(Unscheduled Visit): 
• 
Physical examination; 
• 
Measurement of vital signs (BP, HR, RR, BT); 
• 
A 12-lead ECG; 
• 
Evaluation of adverse events; 
• 
Evaluation of the concomitant therapy; 
• 
If indicated, any of the study procedures may be additionally 
performed upon the decision of the Principal Investigator. 
Taking into account frequency of visits, unscheduled visits may be 
conducted on the same days as the scheduled ones but at a different 
time (e.g., in case of worsening the patient may visit the site in the 
afternoon).  
Procedures for planned clinical study visits are the same in each 
treatment group during each study period.  
Major 
Efficacy 
and 
Safety Parameters  
Primary efficacy parameter 
To evaluate the incidence of AAD while taking LRG-002, hard 
capsules (Lek d.d., Slovenia) as compared to placebo in antibiotic-
treated patients with ARDs; 
AAD is defined as diarrhea associated with the AB use caused by C. 
difficile or of otherwise not identified etiology, upon analysis of stool 
samples and differential diagnostics according to investigator's 
judgment.  
Diarrhea is defined as loose or watery stool (BSFS Type 5-7) three 
times a day (frequent bowel movements with formed stool is not 
considered diarrhea) in accordance with WHO criteria; based on the 
diary data (BSFS) and confirmation of AAD by the investigator. 
Secondary efficacy parameter 
• The occurrence of bowel movements per day (according to the 
diary data) in the treatment group compared with the placebo group 


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• The incidence of any diarrhea in the treatment group compared with 
the placebo group  
• The incidence of C. Difficile-associated AAD in the treatment 
group compared with the placebo group;  
• The incidence of non-C. Difficile-associated AAD in the treatment 
group compared with the placebo group;  
• The duration of AAD (the time from the onset of AAD to the 
normalization of stool form according to BSFS (types 1, 2, 3 and 4) 
and the presence of normal stool within 48 hours) in the treatment 
group as compared to the placebo group;  
• The duration of any diarrhea (the time from the onset of diarrhea to 
the normalization of stool form according to BSFS (types 1, 2, 3 
and 4) and the presence of normal stool within 48 hours) in the 
treatment group as compared to the placebo group;  
• Occurrence of changes in stool consistency (BSFS) (according to 
the diary data) in the treatment group as compared to the placebo 
group  
• The occurrence and severity of gastrointestinal symptoms, 
including nausea, vomiting, flatulence, abdominal pain and 
decreased appetite (according to the diary data) in the treatment 
group as compared to the placebo group;  
• Change in body weight at Visit 3 compared with Visit 1 in the 
placebo group as compared to the treatment group;  
• Hospitalization rate in the treatment group compared with the 
placebo group  
• The number of days of using standard symptomatic therapy (as 
“rescue medication”) to relieve symptoms of acute diarrhea in the 
treatment group as compared to the placebo group; 
• The number of patients using standard symptomatic therapy (as 
“rescue medication”) to relieve symptoms of acute diarrhea in the 
treatment group as compared to the placebo group. 
 
Safety assessment parameters 


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Safety evaluation is based on the following parameters (between V1 
and V3) compared between therapy and placebo groups. 
Frequency of adverse events (AEs) and/or serious adverse events 
(SAEs) in the treatment groups, including:  
- 
Overall AE rate as compared to placebo; 
- 
Frequency of AEs according to the results of physical 
examinations during each visit compared with placebo; 
- 
AE incidence according to the results of the vital signs 
assessment (HR, BP, BT, RR) at each visit in comparison 
with placebo; 
- 
AE incidence according to the ECG results on Day 15 (± 2) 
in comparison with placebo; 
- 
Frequency of AEs incidence according to the results of 
laboratory examinations on Days 7(± 2) and 15(± 2) 
compared with placebo; 
- 
Frequency of AEs  according to the patients’ records in the 
diary 
  
Diary records will be reviewed by the Investigator and for those 
records presumed to meet criteria of an AE, the patient will be 
questioned. If the investigator judges that the AE criteria have been 
met, all information relevant for an AE (including an evaluation of 
causality to the investigational product) will be documented. 
The AEs will be described according to the scheme given below: 
- 
AE description; 
- 
AE severity; 
- 
AE duration; 
- 
Causal relationship with the investigational product; 
- 
Outcome. 
All AEs will be coded according to MedDRA terms. 
Inclusion Criteria 
Patients will be considered eligible if they meet the following 
inclusion criteria:  


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1. An Informed Consent Form for study participation voluntarily 
signed by a patient;  
2. Male and female subjects, 18 to 65 years of age inclusive; 
3. Antibacterial treatment for active ARD started/to be started on the 
first day of the study (7-day course of oral beta-lactam antibiotic). 
Only one AB should be used per subject, in an outpatient setting. 
Diagnosis of acute respiratory infections and the prescription of 
antibiotic therapy should be completed before signing of the 
Informed Consent Form. 
4. Female patients are eligible for the study if they are: 
• Unable to become pregnant (i.e. postmenopausal women or those 
after surgical sterilization). Surgically sterile women are defined as 
patients 
with 
documented 
hysterectomy, 
and/or 
bilateral 
oophorectomy, and/or tubal ligation. Postmenopausal women are 
defined as women with amenorrhea for more than 1 year with the 
relevant clinical profile (e.g., age > 45 years, and absence of 
hormone replacement therapy). However, in controversial cases, it 
is recommended to confirm menopause by drawing a blood sample 
which would show an FSH level of > 40 IU/mL and estradiol level 
of < 40 pg/mL (< 140 pmol/L).   
• OR  
Capable of childbirth, but with negative pregnancy test at the 
screening visit, and the patient agrees to continuously and properly 
use one of the following suitable methods of contraception (i.e., in 
accordance with the approved Package Insert for the medicinal 
product and physician instructions) during the participation period: 
a. Complete abstinence; 
b. Oral 
contraceptives 
(combination 
drugs 
containing 
progestogen, or progestogen alone); 
c. Injectable progestogen; 
d. Levonorgestrel implants; 
e. Estrogen-containing vaginal ring; 
f. Transdermal contraceptive patches; 


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g. Intrauterine device or intrauterine system; 
h. A male partner has been sterile (vasectomy with documented 
azoospermia) prior to inclusion of a woman, provided that he 
is the only partner of the female patient. For the purpose of 
this definition, "documented" is related to the result of a 
subject's 
medical 
examination 
performed 
by 
Investigator/responsible person or a subject's past medical 
history review for assessment of eligibility for enrollment, 
obtained during the interview with a subject or from his/her 
medical records;  
i. 
Double barrier method: a condom or an occlusive cap 
(diaphragm or cervical/vault caps) with a spermicide 
(foam/gel/film/cream/suppository); 
5. Male participants are obliged to use appropriate contraception 
during the entire study period starting from signing of the 
Informed Consent Form and until the study end, and for 30 days 
after study completion; 
6. The ability to understand the information about the clinical study, 
readiness to comply with the study protocol requirements, ability 
to take IP and evaluate symptoms on his (or her) own using 
diary/questionnaires as per protocol; 
7. Ability to maintain the habitual lifestyle throughout the study, 
including diet. 
8.  Willing not to consume any products containing probiotics during 
participation in the clinical trial.  
9.    Willing not to take part in any other study during the present study. 
Non-inclusion Criteria Patients will not be eligible for study enrollment if they have one or 
more of the following criteria:  
1. Any treatment (including medications, medical devices and food 
supplements) that can influence the stool consistency according to 
the Investigator's opinion should not be used within 14 days prior 
to Visit 1. 
2. Use of anti-rejection medication after stem cell or solid organ 
transplant;  


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3. Use of glucocorticosteroids within the last 8 weeks prior to Visit 
1; 
4. Use of proton pump inhibitors within 3 months prior to Visit 1; 
5. Chemotherapy or radiation; 
6. History of recurrent diarrhea; 
7. Diarrhea or watery stool in the last 2 days prior to Visit 1; 
8. Severe ARD expected to require additional antibiotics or to 
require antibiotics therapy more than 7 days; 
9. Use of antimicrobials in the last 3 months prior to the study start; 
10. Use of yeast/probiotic/fermented products within the last 2 weeks 
prior to V1; 
11. Known allergy/sensitivity to the IMP; 
12. Immunocomopromised patients; 
13. Known digestion/absorption disorders of the gastrointestinal tract 
(e.g. inflammatory bowel disease, coeliac disease, pancreatitis, 
motility disorders etc.) and/or gastrointestinal surgery (with the 
exception of appendectomy more than 3 months before Visit 1); 
14. Known irritable bowel syndrome; 
15. Known small intestinal bacterial overgrowth; 
16. Pyrexia > 38 °C; 
17. Pregnant and/or breastfeeding women. 
18. Participation in other clinical trials of medicinal products or 
medical devices at the screening Visit or for 30 days before the 
screening Visit. 
19. Surgical intervention for 30 days before the screening visit or 
planned surgical treatment during the trial (before a follow-up 
visit is completed), including diagnostic procedures or hospital 
stay. 
20. Known or suspected alcohol and/or drug addiction; 
21. A suspected low compliance or incapability of the patient to 
perform the procedures and comply with restrictions according to 
the trial protocol (e.g., due to mental disorders); 
22. Potential for translocation of probiotic across bowel wall 
(Presence of an active bowel leak, acute abdomen, active 


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intestinal disease including colitis, or significant bowel 
dysfunction; presence of neutropenia or anticipation of 
neutropenia after chemotherapy; radiation therapy); 
23. Any disorders of cardiovascular, renal, hepatic, gastrointestinal, 
endocrine, or nervous disorders, and other conditions/diseases 
which, in the Investigator's opinion, may render study 
participation unsafe for a patient or may affect a test result. 
24. Positive result of express-test for detection of IgM antibodies for 
COVID-19. 
Exclusion Criteria 
Subject participation will be stopped in case any of the following 
reasons occur: 
1. Disease progression (including pyrexia above 38 °C for 3 days or 
longer); 
2. Positive culture or PCR results for Shigella and Salmonella spp, 
typhoid and paratyphoid species, pathogenic E. coli, and other 
pathogen species (including C. difficile), if supplementary 
antibacterial treatment is required during the study; 
3. Need to change tactics of antibiotic therapy (extension course of 
antibiotic therapy or change of antibiotic group); 
4. The Ethics Committee, regulatory authorities, or Sponsor 
terminate the trial or participation of the specific trial site for any 
reason; 
5. The Investigator’s decision to withdraw the patient from the trial 
in the interests of the patient; 
6. Withdrawal of the informed consent (unwillingness of the patient 
to continue his/her participation in the study); 
7. Individual intolerance of  Investigational products (according to 
Investigator’s judgment); 
8. Clinically significant adverse event or serious adverse event; 
9. Patient's non-compliance; 
10.  Error enrollment (e.g., the patient was included with violation of 
the inclusion/non-inclusion criteria); 
11. The patient complies with the non-inclusion criteria during the 
study; 


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12. The patient receives or requires an additional therapy which might 
influence the study results or patient's safety (see Prohibited 
concomitant therapy section); 
13. Other conditions or events which, in the Investigator's opinion, 
require the patient's exclusion from the study. 
Prohibited 
Concomitant 
Treatments 
1. Systemic glucocorticosteroids within 8 weeks prior to and during 
the study; 
2. Use of any antibacterials in the last 3 months prior to the study or 
of any antibacterials (except the AB per inclusion criterion 3) 
during the study;  
3. Use of any proton pump inhibitor within 3 months prior to the 
study;  
4. Other 
probiotics 
(bacteria 
or 
yeast, 
medications, food 
supplements, fermented products) and Broncho-munal® within 2 
weeks prior to and during the study;  
5. Any treatment (including medications, medical devices and food 
supplements) that can influence the stool consistency according to 
the Investigator's opinion within 14 days prior to and during the 
study (other than the drugs specified in items 3 and 4 of the 
Allowed Concomitant Treatments). 
See the list of prohibited drugs in Appendix No. 1. 
Allowed Concomitant 
Treatments 
1. Oral beta-lactam antibiotic (for instance, amoxicillin, amoxicillin + 
clavulanic acid, cefixime, etc.) (see Background Antibacterial 
Therapy) as per inclusion criterion 3, in the same dosage regimen 
as at study start. 
2. Continuation of the drug administration started prior to the 
inclusion into the study for treatment of concomitant diseases not 
covered by any of the exclusion criteria. Continuation of oral 
contraceptive administration by female participants during the 
study. 
3. Standard symptomatic treatment agents used to treat acute 
respiratory infections in case of medical need, including anilides, 
triazole derivatives, with the exception of drugs that can have a 
laxative effect (for example, throat lozenges with sugar substitutes)/ 


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4. Agents for relieving symptoms of acute diarrhea, in case of medical 
need, including electrolyte solutions, with the exception of 
sorbents. 
Prescribing therapy for acute diarrhea and acute respiratory infections 
is possible only by the decision of the investigator. 
Statistical Analysis 
The aim of the statistical analysis will be to prove the efficacy and 
safety of LRG-002 (Lactobacillus rhamnosus GG not less than 2 x 
1010 CFU) to be superior to placebo in antibiotic-treated patients with 
acute respiratory diseases, as an adjunct treatment for prophylaxis of 
antibiotic-associated diarrhea (AAD).  
The analysis will be performed for comparison of:   
- LRG-002 and matching placebo.  
The primary efficacy endpoint will be analyzed with a logistic 
regression model with fixed factors for treatment group and age group. 
The primary efficacy endpoint will be considered achieved if the odds 
ratio for the occurrence of AAD between placebo and LRG-002 is 
significantly higher than 1 (i.e. the occurrence of AAD is lower in the 
LRG-002 group).   
The secondary parameters will be compared with the following 
method:   
- continuous variables will be compared by Mann—Whitney-
Wilcoxon test.  
Binary and ordinal variables will be compared by chi- square test or 
Fisher's exact test (depending on the number of expected observations 
per cell: <5 or ≥5).   
The analysis of study subjects with AE (SAE) will be performed with 
chi-square test or Fisher's exact test.  
Poisson regression will be used for analysis of AE (SAE) frequency. 
The significance level is assumed as p < α, with α = 0.05.  
Sample size calculation 
Primary endpoint is the frequency of occurrence of AAD  from the 


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first to the last day of LRG-002 administration compared with placebo 
in antibiotic-treated patients with ARDs.  
A test based on odd ratio was used to calculate sample size. 
The following parameters were obtained from Figure 2 in a meta-
analysis [1] using only data for AAD:  
Using only data for AAD studies in adults from the cited publication, 
the rate for the control group is 0.24 and for the treatment group 0.14. 
Using only data for LGG studies in adults and children, the rate for 
the control group is 0.26 and for the treatment group 0.15.  
In meta-analysis [14] figures from Table 1 demonstrate a rate of 0.196 
for a treatment group and 0.29 for a placebo group (only trials for 
adults with LGG were taken into consideration). 
In meta-analysis [15] figures from Table 2 demonstrate a rate of 0.188 
for a treatment group and 0.269 for a placebo group (only trials for 
adults with LGG were taken into consideration). 
Consideration of AAD studies for LGG from [16], concerning 
infections at adults (including H. pylori), results in 0.14 for a probiotic 
group and 0.22 for a control group.  
Combining all the strains, we obtain an incidence of 0.26 for placebo 
and an incidence of 0.15 for treatment.  
The following indicators were used for calculations:  
 Difference of absolute risks of AAD in placebo group and in 
treatment group is expected to be positive. 
 Incidence of AAD 0.26 is assumed for a placebo and 0.15 for the 
treatment.  
 Probability of type I error: 0.05; 
 Power of the study is 80%, which corresponds to the type II error: 
0.20. 
 Statistical hypothesis is the evidence of superior efficacy: 
H0: OR=1  
H1: OR≠1, 


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where OR is the odds ratio between both groups. 
The ratio between the study and control group sizes is 1:1. 
The number of patients in each group could be calculated using the 
following formula [2]: 
 
(
)
(
)
2
1
/2
1
1
208
T
T
T
T
R
R
T
R
Z
Z
n
n
p
p
p
p
p
p
α
β
−
+


=
=
−
+
−
=





−


 
Thus, the minimum number of patients required for statistical analysis 
is 416 (208 patients in each group). Taking into account a 20% 
withdrawal rate, one needs to randomize 520 subjects (260 patients in 
each group). 
 
1. Efficacy of probiotics in prevention of acute diarrhea: a meta-
analysis of masked, randomized, placebo-controlled trials. Sazawal S, 
Hiremath G, Dhingra U, Malik P, Deb S, Black RE. Lancet Infect Dis. 
2006 
Jun; 
6(6):374-82. 
Review. 
PMID:16728323. 
DOI:10.1016/S1473-3099(06)70495-9 
2. Chow S, Shao J, Wang H. Sample Size Calculations in Clinical 
Research. 2nd Ed. Chapman & Hall/CRC Biostatistics Series, 2008 
3. Prophylaxis against ampicillin-associated diarrhea with a 
lactobacillus preparation. Gotz V., Romankiewicz J. A., Moss J. and 
Murray H. W. Am J Hosp Pharm. 1979 Jun; 36:754-757. PMID: 
12052801. DOI: 10.1136/bmj.324.7350.1361. 
 
4. Double-blind report on the efficacy of lactic acid-producing 
Enterococcus SF68 in the prevention of antibiotic-associated 
diarrhoea and in the treatment of acute diarrhoea. Wunderlich P.F., 
Braun L., Fumagalli I., D'Apuzzo V., Heim F., Karly M., Lodi R., 
Politta G., Vonbank F., Zeltner L. J Int Med Res. 1989 Jul-Aug; 
17(4):333-8. PMID: 2676650. DOI: 10.1177/030006058901700405 
 


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5. Prevention of beta-lactam-associated diarrhea by Saccharomyces 
boulardii compared to placebo. Lynne Mcfarland L., Surawicz C.M., 
Greenberg R.N., Elmer G.W., Moyer K.A., Melcher S.A., Bowen 
K.E., Cox J.L. The American Journal of Gastroenterology. 90(3):439-
48. PMID: 7872284. 
 
6. Randomised placebo-controlled double blind multicentric trial on 
efficacy and safety of Lactobacillus acidophilus LA-5 and 
Bifidobacterium BB-12 for prevention of antibiotic-associated 
diarrhoea. Chatterjee S, Kar P, Das T, Ray S, Gangulyt S, Rajendiran 
C, Mitra M. J Assoc Physicians India. 2013 Oct; 61(10):708-12. 
PMID: 24772726. 
 
7. Prophylactic Lactobacillus GG reduces antibiotic-associated 
diarrhea in children with respiratory infections: a randomized study. 
Arvola T., Laiho K, Torkkeli S, Mykkänen H, Salminen S, Maunula 
L, Isolauri E. Pediatrics. 1999 Nov;104(5):e64. PMID: 10545590 
DOI: 10.1542/peds.104.5.e64 
 
8. Effect of a multispecies probiotic on reducing the incidence of 
antibiotic-associated diarrhoea in children: a protocol for a 
randomised controlled trial. Łukasik J, Szajewska H. BMJ Open. 2018 
Jun 4;8(5):e021214. doi: 10.1136/bmjopen-2017-021214.  
 
9. Probiotics and antibiotic-associated diarrhea in children: A review 
and new evidence on Lactobacillus rhamnosus GG during and after 
antibiotic treatment. Mantegazza C., Molinari P., D'Auria E., Sonnino 
M., Morelli L., Zuccotti G.V. harmacol Res. 2018 Feb;128:63-72. 
PMID: 28827186. DOI: 10.1016/j.phrs.2017.08.001 Epub 2017 Aug 
19. 
 
10. Probiotics reduce symptoms of antibiotic use in a hospital setting: 
a randomized dose response study. Ouwehand A.C., DongLian C., 
Weijian X., Stewart M3, Ni J., Stewart T., Miller L.E. Vaccine. 2014 


Protocol No. CT_002_LRG_CAP 
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Jan 
16;32(4):458-63. 
PMID: 
24291194. 
DOI: 
10.1016/j.vaccine.2013.11.053. Epub 2013 Nov 26. 
 
11. Clinical trial: effectiveness of Lactobacillus rhamnosus (strains E 
⁄ N, Oxy and Pen) in the prevention of antibiotic-associated diarrhoea 
in children. Ruszczyn´ M., Radzikowski A.,Szajewska H. Aliment 
Pharmacol 
Ther 
28, 
154–161. 
2008. 
doi:10.1111/j.1365-
2036.2008.03714. 
 
12. Lactobacillus GG in the prevention of antibiotic-associated 
diarrhea in children. Vanderhoof J.A., Whitney D.B., Antonson D.L., 
Hanner T.L., Lupo J.V., Young R.J. J Pediatr. 1999 Nov; 135(5):564-
8. PMID: 10547243. 
 
13. World Gastroenterology Organisation Global Guidelines: 
probiotics and prebiotics Guarner F., Khan AG, Garisch J, Eliakim R, 
Gangl A, Thomson A, Krabshuis J, Lemair T, Kaufmann P, de Paula 
JA, Fedorak R, Shanahan F, Sanders ME, Szajewska H, Ramakrishna 
BS, Karakan T, Kim N; World Gastroenterology Organization. J Clin 
Gastroenterol. 2012 Jul;46(6):468-81. PMID: 22688142. DOI: 
10.1097/MCG.0b013e3182549092. 
 
14. McFarland LV. Meta-analysis of probiotics for the prevention of 
antibiotic associated diarrhea and the treatment of Clostridium 
difficile disease. Am J Gastroenterol. 2006 Apr;101(4):812-22. 
 
15. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-
associated 
diarrhoea. 
Aliment 
Pharmacol 
Ther. 
2012 
Jun;35(12):1355-69. doi: 10.1111/j.1365-2036.2012.05104.x. Epub 
2012 Apr 24. 
 
16. H. Szajewska, M. Kołodziej. Systematic review with meta‐
analysis: Lactobacillus rhamnosus GG in the prevention of antibiotic‐


Protocol No. CT_002_LRG_CAP 
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associated diarrhoea in children and adults. AP&T, Volume 42, Issue 
10, November 2015, Pages 1149-1157. 
Additional literature used: 
1. Fox MJ, Ahuja KD, Robertson IK, Ball MJ, Eri RD. Can probiotic 
yogurt prevent diarrhoea in children on antibiotics? A double-
blind, randomised, placebo-controlled study. BMJ Open. 2015 Jan 
14;5(1):e006474. doi: 10.1136/bmjopen-2014-006474. 
2. Agamennone V, Krul CAM, Rijkers G, Kort R. A practical guide 
for probiotics applied to the case of antibiotic-associated diarrhea 
in The Netherlands. BMC Gastroenterol. 2018 Aug 6;18(1):103. 
doi: 10.1186/s12876-018-0831-x. 
3. Elseviers MM, Van Camp Y, Nayaert S, Duré K, Annemans L, 
Tanghe A, Vermeersch S. Prevalence and management of 
antibiotic associated diarrhea in general hospitals. BMC Infect 
Dis. 2015 Mar 17;15:129. doi: 10.1186/s12879-015-0869-0. 
4. McFarland LV. Evidence-based review of probiotics for 
antibiotic-associated diarrhea and Clostridium difficile infections. 
Anaerobe. 
2009 
Dec;15(6):274-80. 
doi: 
10.1016/j.anaerobe.2009.09.002. Epub 2009 Oct 13. 
5. Szymański H, Armańska M, Kowalska-Duplaga K, Szajewska H. 
Bifidobacterium longum PL03, Lactobacillus rhamnosus KL53A, 
and Lactobacillus plantarum PL02 in the prevention of antibiotic-
associated diarrhea in children: a randomized controlled pilot trial. 
Digestion. 2008;78(1):13-7. doi: 10.1159/000151300. Epub 2008 
Aug 14. 
6. McFarland LV. Antibiotic-associated diarrhea: epidemiology, 
trends and treatment. Future Microbiol. 2008 Oct;3(5):563-78. 
doi: 10.2217/17460913.3.5.563. 
7. McFarland LV. Meta-analysis of probiotics for the prevention of 
antibiotic associated diarrhea and the treatment of Clostridium 
difficile disease. Am J Gastroenterol. 2006 Apr;101(4):812-22. 
8. Blaabjerg S, Artzi DM, Aabenhus R. Probiotics for the Prevention 
of Antibiotic-Associated Diarrhea in Outpatients-A Systematic 


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Review and Meta-Analysis. Antibiotics (Basel). 2017 Oct 12;6(4). 
pii: E21. doi: 10.3390/antibiotics6040021. 
Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-
associated 
diarrhoea. 
Aliment 
Pharmacol 
Ther. 
2012 
Jun;35(12):1355-69. 
doi: 
10.1111/j.1365-2036.2012.05104.x. 
Epub 2012 Apr 24. 
Interim Analysis 
Interim data analysis is not planned.  
Blinding, 
Randomization  
It will be a double-blind, randomized study. 
Patients will be included by applying stratified randomization in two 
strata:  
• Age < 50 years; 
• Age ≥ 50 years. 
Each treatment group will be balanced at a ratio of 1:1 within each 
stratum. 
Stratified randomization is a two-stage procedure in which patients 
who enter a clinical trial are first grouped into strata. Within each 
stratum, patients are then assigned to a treatment according to separate 
randomization schedules. Randomization module of EDC system 
assigns patient unique randomization code base on group of treatment 
and stratum. Randomization schedules will be hidden from medical 
personnel and all other persons involved in the study (monitors, data 
management, biometry, sponsor etc.), except the specialists 
responsible for labeling of the IMP and emergency unblinding. 
 


Protocol No. CT_002_LRG_CAP 
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 General information 
 
Protocol title, identification number and date  
Title: Multicentre, double-blind, randomized, placebo-controlled, parallel-group efficacy and 
safety study of LRG-002 hard capsules (Lek d.d., Slovenia) used in the prophylaxis of antibiotic-
associated diarrhea in adults. 
Identification number: CT_002_LRG_CAP  
Protocol version: 3.0 
Date: June 23, 2020 
 
Study Sponsor 
Study Sponsor: 
Name of organization: 
ZAO “Sandoz”, Russia 
Address: 
72, Leningradsky prospect, bld. 3, Moscow, 125317, Russia. 
Telephone:  
 
E-mail: 
sandoz.russia@sandoz.com 
 
Sponsor’s representative: 
 
 
 
 
Name: 
 
Tel.: +
 Fax: 
  
E-mail:  
  
:  
 
 
 Novartis Pharma  
 
Name: 
 
Address: 
72 
Leningradsky prospect, bld.3, Moscow, Russia 
125315 Tel.: 
 Cell number: 
 (24 h) Fax: 
 
60 E-mail: 
 
 
 
 
 
 
 


Protocol No. CT_002_LRG_CAP 
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Sponsor Representative for medical issues: 
Name: 
 
Function: 
 
 
Name of organization: 
ZAO “Sandoz”, Russia 
Address: 
72, Leningradsky prospect, bld. 3, Moscow, 125317, Russia 
Telephone:  
Tel: 
  
Fax: 
 
E-mail: 
 
 
Alternate of Sponsor Representative for medical issues: 
Name: 
  
Function: 
  
Name of organization: 
ZAO “Sandoz”, Russia 
Address: 
72, Leningradsky prospect, bld. 3, Moscow, 125317, Russia 
Telephone:  
Tel.: 
 ext.
  
Fax: 
 
Cell number: 
 
E-mail: 
 
 
Study Monitor 
Contract research organization (CRO)/organization responsible for the Study  
  
Legal address: 
 
Tel.: 
, Fax: 
 
E-mail: 
 


Protocol No. CT_002_LRG_CAP 
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Clinical laboratories and other relevant organizations of the Study 
Name of organization: 
 
 
Address:  
 
 Moscow 
Telephone:  
 
  
E-mail: 
 
 
 
  
  
  
 


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 Rationale of the study and the program of clinical trials of the medicinal product 
 
Program of clinical trials of the medicinal product 
In accordance with the clinical development program of the LRG-002 medicinal product, capsules 
(Lek. d.d., Slovenia), Sandoz is planning to perform the clinical trial on the territory of the Russian 
Federation: 
Multicentre, double-blind, randomized, placebo-controlled, parallel-group efficacy and safety 
study of LRG-002, capsules (Lek d.d., Slovenia) used in the prophylaxis of antibiotic-associated 
diarrhea in adults. According to Federal Law No. 61-ФЗ (FZ) as of April 12, 2010 On Circulation 
of Medicines (as amended), the clinical trial with participation of Russia is required for medicinal 
product authorization on the territory of the RF. Therefore, this clinical trial is designed to 
investigate LRG-002 tested medicinal product efficacy and safety, capsules as compared with 
LRG-002 placebo, for prophylaxis of antibiotic-associated diarrhea (AAD) in patients with acute 
respiratory diseases (ARDs) receiving a standard antimicrobial therapy. 
According to the results of the present clinical trial Sandoz is planning to have the LRG-002, 
capsules medicinal product, authorized. 
 Investigational drug 
Name of the medicinal product: LRG-002, capsules. 
Manufacturer: Lek d.d., Verovskova 57, 1526 Ljubljana, Slovenia. 
Dosage form, dosage: capsules 
Description: Each capsule contains live lyophilized probiotic bacteria of Lactobacillus genus. 
Composition per 1 capsule: each capsule contains at least 1 х 1010 CFU of Lactobacillus 
rhamnosus GG as a lyophilizate.  
Excipients: sucrose, maltodextrin, silicon dioxide, magnesium stearate, sodium ascorbate 
Capsule shell: hypromellose, titanium dioxide (E171), gellan gum, water. 
Pharmacotherapeutic 
group: 
anti-diarrhea 
microorganisms, 
lactic 
acid 
producing 
microorganisms.  
ATC code: A07FA01 
Pharmacodynamic properties 


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Lactobacillus rhamnosus GG comprised in LRG-002 is a well-known probiotic strain and a well-
established probiotic bacterium which reconstitutes and maintains the reconciliation of gut 
microbiota in adults and children. 
Along with other bacteria, Lactobacteria (benefit bacteria) are commonly present in human gut 
microbiota. These bacteria maintain the structure of intestinal cells and their contacts, healthy acid-
alkaline reconciliation necessary for normal functioning of digestive enzymes, prevent harmful 
bacteria overgrowth, influence the intestinal motility (peristalsis) and stimulate the immune 
system. 
Disturbance of the gut microbiota reconciliation (e. g. in viral and bacterial gastrointestinal 
infections, in therapy with wide spectrum antibiotics and chemotherapy drugs, in irradiation of 
abdominal and pelvic organs, and when travelling abroad) may cause digestion disorders (such as 
flatulence, diarrhea and constipation). 
The use of Lactobacillus rhamnosus GG positively influences the reconstitution and control of 
physiologic balance of intestinal microbiota. A wide range of research literature and clinical trials 
of Lactobacillus rhamnosus GG indicate that this probiotic strain can positively affect 
gastrointestinal and immune functions. Furthermore, its safety and good tolerability have been 
demonstrated. 
Pharmacokinetic properties 
Probiotic bacteria as well as Lactobacillus rhamnosus GG provide a local effect on the 
gastrointestinal tract. There is no systemic absorption with oral administration. Routine 
pharmacokinetic studies are thus not applicable. The resistance of Lactobacillus rhamnosus GG to 
gastric acid and bile allows most of these bacteria to survive during the passage of stomach and 
duodenum. Bacteria adhere to the intestinal mucous membrane. Like all other microorganisms 
contained in the gastrointestinal tract, they are gradually excreted by peristalsis and defecation. 
 
Intended indications 
The LRG-002 medicinal product may be used as a part of complex therapy of antibiotic-associated 
diarrhea in adults. 
Contraindications 
Drug active substance or excipients hypersensitivity. 


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Special warnings and precautions for use 
Before starting the therapy, the patient should consult a doctor when: 
• the body temperature is above 38 °C, 
• presence of blood or mucus in feces, 
• diarrhea duration of more than two days, 
• severe pattern of diarrhea accompanied by dehydration and body weight loss, 
• diarrhea is accompanied with severe abdominal pain, 
• the presence of other chronic diseases (e. g., diabetes mellitus, cardiovascular diseases) or 
immune deficit (e. g., HIV infection). 
• a patient has diarrhea and other serious health problems (severe disease, cardiac diseases, 
central venous catheter installed), 
• a patient has immune deficit (e. g., HIV infection or immunosupressive therapy), 
• a patient has an intestinal barrier function disordered (e. g., short gut syndrome). 
It’s very important to compensate for water and electrolyte loss in diarrhea. 
The product contains glucose and sucrose. Persons with rare hereditary pathologies, such as 
fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should 
not take this medicinal product. 
This product contains less than 1 mmol of sodium (23 mg) per capsule, i.e. it is essentially sodium-
free. 
Pediatric population 
Diarrheas in children younger than six years should be treated under medical supervision. 
Use in gestation and breast feeding period 
The particular caution is required in acute diarrhea during pregnancy and breastfeeding to prevent 
any occurrence of water and electrolyte deficit and other adverse reactions which would be 
dangerous for a child or a pregnant woman. The use in diarrhea during pregnancy and 
breastfeeding should be under medical supervision. 
Posology and method of administration 
Adults and children: one capsule once or twice a day (dependent on severity of symptoms). 
The LRG-002 medicinal product capsules may be taken until symptoms disappeared. If diarrhea 
lasts for more than two days it’s necessary to seek medical attention.  


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It’s very important to compensate for water and electrolyte loss in diarrhea treatment. 
Method of administration 
To provide the maximum efficacy, LRG-002 capsules should be taken with meals. 
LRG-002 capsules must not be taken concomitantly with alcohol, fruit juices or hot beverages. 
For those who are not able or cannot swallow a capsule it should be opened, and its content should 
be poured out into a spoon and mix with some liquid. It is recommended to take LRG-002 capsules 
not earlier than 3 hours after the antibiotic intake. 
Adverse Reactions 
Adverse reactions are extremely rare in use of probiotic products. 
Mild gastrointestinal disorders such as nausea, abdominal cramping, flatulence or abdominal 
distension have been reported. 
Overdose 
No case of overdose has been reported. 
 
Interaction with other medicinal products and other forms of interaction 
Drug-to-drug interaction studies have not been performed. 
As other bacteria, the probiotic bacteria are sensitive to antibiotics. For this reason, it is 
recommended to take the LRG-002 product not earlier than 3 hours after the antibiotic intake. 
Special warnings 
Do not store above 25 °C. 
Store in the original package in order to protect from moisture. 
Effects on the ability to drive or use machines  
Studies of the drug effect on the ability to drive vehicles and work with mechanisms have not been 
performed  
 Comparator product 
LRG-002 placebo capsules. 


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Summary of relevant results of non-clinical and clinical studies for this study 
 Summary of non-clinical results 
The Lactobacillus rhamnosus «GG» strain was first isolated in 1983 and well-studied for 
pharmacokinetics, pharmacodynamics, safety and toxicity. The capability of this LGG strain to 
adhere to intestinal mucous membrane, to inhibit different pathogenic bacterial growth, to 
reconstitute the integrity of intestinal epithelium and to regulate the immune response by means 
of the effect on pro-inflammatory cytokine release was demonstrated in in vitro and in vivo studies. 
All listed characteristics positively influence the normal intestinal microflora reconstitution and 
the gastrointestinal functional state usually affected in infection and antibiotic-associated diarrhea. 
Furthermore, benefits of the LGG strain are not limited by the intestine. Thus, in many studies the 
possibility to use the LGG strain as an adjunctive therapy of different diseases including cancer 
had been proposed.  
It had been shown in safety studies that the LGG strain did not cause any adverse reactions in 
animals despite administration in extremely high dosages.  
Studies for Lactobacilles microbiological properties evaluation including antibiotic sensitivity and 
the potential for uptake and transferring of antibiotic-resistance genes were also performed. In 
these studies, it was established that despite of natural resistance of many lactobacilli to various 
antibiotics (including vancomycin) the possibility to transfer antibiotic-resistance genes to other 
species is minimal.  
So, LGG is a non-pathogenic strain for both healthy and immunocompromised animals. After 
administration at high dosages this strain can’t induce any systemic infections in rodents. Further 
more, no undesirable metabolic activity was established. As for antibiotic resistance, the 
L. rhamnosus strain may be considered to be genetically stable. The information from non-clinical 
studies performed for the LGG strain is provided below. 


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 Main pharmacological properties 
3.2.2.1 In vitro investigations 
Forrestier et al. (2001) performed the investigation evaluating the probiotic activity of the human 
isolate of theLactobacillus casei subsp. rhamnosus (Lcr35).strain. The presence of adhesive 
properties of this strain had been demonstrated In the in vitro model based on the Caco-2 cell line. 
The 
inhibitory 
effect 
of 
Lcr35 
on 
three 
pathogenic 
species, 
particularly 
enteropathogenic Escherichia coli (EPEC), enterotoxigenic E. coli (ETEC), and Klebsiella 
pneumoniae, was demonstrated. The reduction in number of adhesive pathogens as a result of pre-
incubation, post-incubation and co-incubation with the Lcr35 strain was established. In addition, 
the Lcr35 cell-free supernatant antibacterial activity was studied for nine different human 
pathogenic 
bacteria: 
ETEC, 
EPEC, Klebsiella pneumoniae, Shigella 
flexneri, Salmonella 
typhimurium, Enterobacter 
cloacae, Pseudomonas 
aeruginosa, Enterococcus 
faecalis, and 
Clostridium difficile. According to the results of the assessment of viable bacterial cells dynamics, 
growth inhibition of all strains’ was determined, however no bactericidal activity was found in this 
in vitro test. Based on the results of the observations, it can be assumed that the studied probiotic 
strain can be used to prevent colonization of the gastrointestinal tract by various pathogens. 
Jacobsen et al. (1999) carried out a study evaluating the probiotic potential of 47 strains of 
Lactobacillus spp. Selected strains were studied for resistance to pH 2.5 and 0.3% bovine bile, 
adhesion to Caco-2 cells, and antimicrobial activity against pathogenic intestinal bacteria in model 
systems. 29 of the 44 strains remained viable after 4 hours of incubation in a medium with pH 2.5, 
but none of them retained the ability to replicate. A significant variability of the characteristics of 
the studied bacterial strains was determined. 299, 299v, DSM 12246, LGG, 18911-2, 19020-10, 
19070-2, CHCC 2329, CHCC 3137 and BG2FO4 strains showed high adhesive ability, unlike 
other strains with moderate or low adhesive ability. The strains also differed in antimicrobial 
activity. The LGG strain caused severe growth inhibition of Bacillus cereus, moderate growth 
inhibition of Listeria monocytogenes, Escherichia coli, Shigella flexneri, Yersinia enterocolitica, 
and did not inhibit the growth of Staphylococcus aureus and Salmonella typhimurium.  
The authors also evaluated the antimicrobial activity of 8 individual strains (including LGG) in 
relation to the resident microflora of the gastrointestinal tract. A moderate inhibitory effect of LGG 
strain on Klebsiella oxytoca and Enterobacter cloacae was determined, but it did not affect other 
commensal bacteria, including other lactobacilli. These results indicate a favorable effect of the 
LGG strain on the intestinal microflora, the inhibitory effect of this strain on the growth of many 
pathogenic bacteria and its very limited inhibitory effect on the growth of normal microflora.  


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Nemcova et al. (1993) also studied 14 strains of lactobacilli in order to determine their sensitivity 
to antimicrobial dietary supplements, acid resistance, adhesion to porcine intestinal epithelial cells 
and antimicrobial activity. Four strains were identified as Lactobacillus casei subsp. casei, two 
strains — as Lactobacillus rhamnosus and Lactobacillus reuteri, and three strains — as 
Lactobacillus salivarius. In antibiotic sensitivity tests, the sensitivity of lactobacilli to many of the 
antimicrobial supplements commonly used for pigs was established. A large numbers of strains 
resistant to ciadox and nourseothricin were found. The studied strains of lactobacilli showed acid 
resistance in a medium with pH 3. A high adhesion ability to pig intestinal epithelial cells was 
established for 13 lactobacilli strains, while one strain showed weak adhesion ability. All 
lactobacilli inhibited test bacteria in the presence of glucose. The main end products of glucose 
fermentation in all strains were lactate and acetate. 
Zhang et al. (2005) studied the effects of L.GG strain, viable and non-viable, on TNF-α-mediated 
induction of the interleukin response. Caco-2 cell line was exposed to viable or thermally 
inactivated bacteria of the LGG strain at doses of 104 to 1010 CFU/L in a medium with additives 
of antibiotics and TNF-α or without additives. The LGG strain regulated TNF-α-induced 
production of IL-8 by Caco-2 cells in all three conditions. However, influence of viable bacteria 
of the LGG strain at higher doses in a medium without TNF-α with or without the addition of 
antibiotics in vitro induced the synthesis of IL-8 (P<0.001). The thermally inactivated bacteria of 
the LGG strain also reduced TNF-induced synthesis of IL-8 (P = 0.01), but at higher doses did not 
increase the synthesis of IL-8 to the same high level as viable bacteria (P = 0.05). Bacteria of the 
LGG strain reduced TNFα-induced NFB translocation to the nucleus and decreased the degree of 
IB reduction in the cytoplasm (P = 0,05). Bacteria of the LGG strain reduced TNF-α-induced 
synthesis of IL-8 by affecting the NFB/IB signaling pathway in Caco-2 cell line. The viable 
bacteria of the LGG strain at high doses significantly increased IL-8 synthesis, however, thermally 
inactivated bacteria of the LGG strain caused only a slight increase in IL-8 synthesis. The authors 
did not explain why exposure to bacteria of the LGG strain at very high doses (1010 CFU/ml) led 
to an increase in IL-8 synthesis.  This indicates the potential for induction of inflammation in the 
intestine when taking very high doses of probiotics due to excessive bacterial growth. However, 
the results presented are observations taking from in vitro study, that is why they must be 
reproduced in vivo before making any reliable conclusions based on them. It is important to note 
that a potential of LGG strain to reduce the inflammatory response was also demonstrated in this 
study even against the background of antibiotic therapy. 


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Lebeer et al. (2007) studied the ability of bacteria of the LGG strain to form biofilms on abiotic 
surfaces compared with other lactobacilli, studied under the same conditions. According to the 
results of the analysis of biofilms on a microtiter plate, the ability of LGG strain bacteria to form 
biofilms in vitro is highly regulated by nutrient factors and conditions in the gastrointestinal tract, 
including low pH, high osmolarity and the presence of bile, mucins and indigestible 
polysaccharides. In addition, the phenotypic test of exopolysaccharides indicated their relative 
importance in the formation of biofilms. Assessing the formation of biofilms in different media is 
an additional approach to a better understanding of the mechanisms by which bacteria adapt to 
stressful environment and colonize different niches. Based on the results obtained, important 
characteristics of LGG strains were determined, increasing their higher adhesive ability and 
stability in the gastrointestinal tract, compared with other strains of lactobacilli.  
By Donato et al. assumption (2010), probiotics support barrier function by influencing the 
signaling pathways mediated by pro-inflammatory cytokines. Caco-2 cells were inoculated in 
Transwell chambers to produce polarized monolayers with intercellular tight junctions (TJ). The 
bacteria of LGG probiotic strain were inoculated onto the apical side of the monolayers, and after 
3 hours IFN-C (100 ng/ml) was added on the basolateral side and the culture was left overnight. 
Then the monolayers were transferred onto freshly prepared basal medium with TNF-α additive 
(10 ng/ml) or without the additive, and transepithelial electrical resistance (TER) was measured 
during the period of stimulation by TNF-α. In order to supplement TER data, the cells were 
prepared for immunofluorescence staining with zona occludens-1 (ZO-1). In order to measure the 
downstream signaling pathway, TNF-α cells were exposed to immunofluorescent staining for the 
NF-kB p65 subunit and then quantitative analysis of CXCL-8 mRNA was performed by qRT-PCR 
method. Basal culture medium was collected after overnight incubation with TNF-α to measure 
the level of chemokine secretion, including CXCL-8 (interleukin 8) and CCL-11 (eotaxin). After 
inoculation of the LGG strain bacteria, priming with IFN-C and 24-hour stimulation with TNF-α, 
epithelial cells retained TER and the distribution profile of ZO-1. The LGG strain bacteria reduced 
p65 nuclear translocation, which was demonstrated by immunofluorescence assay and evaluation 
of CXCL-8 mRNA expression level. After inoculation of LGG strain bacteria and cytokine load, 
a decrease in the level of CXCL-8 and CCL-11 proteins in the cells was determined. Signalling 
interactions between LGG strain bacteria and the epithelium of the model are mediated by two 
mechanisms. Firstly, LGG strain bacteria inhibit TNF-α-induced activation of NF-kB, as 
evidenced by the preservation of the epithelial barrier integrity for pro-inflammatory cytokines. 
Secondly, the effects of this probiotic are mediated, at least in part, by the response from ERK-


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1/2, upon inhibition of which the protective effect of LGG on the integrity of the polarized 
epithelial monolayer disappears. 
These observations indicate that the LGG strain bacteria facilitate the manifestation of the effects 
of pro-inflammatory cytokines on the integrity of the epithelial barrier and the inflammatory 
response, which are mediated, at least in part, by inhibition of NF-kB signaling pathway. 
De Keersmaecker et al. conducted a survey study of antimicrobial substances synthesized by L. 
rhamnosus GG strain (2006). It was found that the bacteria of Lactobacillus rhamnosus GG strain 
synthesize a low molecular weight thermostable non-protein bactericidal substance, which is 
active against various species of bacteria in an acidic environment. The spent culture supernatant 
(SCS) of LGG strain bacteria cultured in MRS medium contained five substances that 
corresponded to the above description, if present in a given concentration. According to the results 
of HPLC analysis, these five components were identified in the antimicrobial fraction of LGG SCS 
as the following substances: unidentified substance with a retention time of 5.7, acetic acid, 
pyrrole-2-carboxylic acid (PCA), formic acid and lactic acid. Since the first three components were 
also present in sterile MRS medium, and formic acid did not show bactericidal activity against 
salmonella at the concentration in which it is present in LGG-ACS, lactic acid was identified as 
the main antimicrobial substance produced by LGG strain bacteria. Based on the results of various 
experimental approaches, it was concluded that under the studied culture conditions the high 
antimicrobial activity of LGG strain bacteria against salmonella was mediated by lactic acid. 
Kankainen et al. (2009) compared the genomic sequence of the studied strain with a length of 3.0 
MB and a similar genomic sequence of L. rhamnosus LC705 strain, an additional starter culture 
with a lower degree of binding to the mucous membrane. A high identity and sequence synteny 
were established for these genomes. However, the genome collinearity of both strains was 
interrupted by genomic islets, five for GG strain and four for LC705 strain. A significant number 
of strain-specific genes was assumed for these islets (80 for GG strain and 72 for LC705 strain). 
Islets specific for GG strain included genes encoding bacteriophage components, sugar 
metabolism and transport, and exopolysaccharide biosynthesis. Only one genomic islet of L. 
rhamnosus GG strain contained genes for 3 secreted LPXTG-like pilins (spaCBA) and pilin-
specific sortase. The presence of fimbriae on the cell wall was determined by immunoblotting 
assay with antibodies to SpaC. Electron microscopy analysis with immunogold staining showed 
that the pilin of SpaC type is located at the top of the fimbriae, but is also sometimes determined 
along their entire length. Moreover, adhesion of GG strain to intestinal mucus in humans was 
blocked by serum to SpaC and did not occur in the mutant with inactivated SpaC gene. By analogy, 
the ability to bind to intestinal mucus was demonstrated for purified SpaC protein. According to 


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the authors, the presence of SpaC is necessary for the interaction of LGG strain with intestinal 
mucus and can explain the ability of this strain to stay longer in the human gastrointestinal tract as 
part of an intervention study, compared with LC705 strain. The presence of fimbriae that bind 
mucus on the surface of a non-pathogenic gram-positive bacterial strain explains the previously 
unclear mechanism of interaction of individual probiotic lactobacilli with the tissues of the host 
body. 
3.2.2.2 Investigations in vivo  
Lebeer et al. (2011) conducted in vivo study in mice to evaluate the role of long-chain 
exopolysaccharides with high galactose content  (EPS) of the prototypic probiotic strain of 
Lactobacillus rhamnosus GG (LGG). Survival and stability of EPS-deficient LGG mutant in GIT 
of mice were studied as part of the competition assessment. A mixture of wild-type LGG strain 
(control) and CMPG5351 strain (EPS-deficient mutant) with 1:1 ratio was administered by oral 
probe to five female BALB/c mice for three consecutive days. From 6 to 72 hours after the first 
administration by probe, fecal samples were collected. A pronounced proportional decrease in the 
mutant population with a competitiveness index (CI) of less than 1 was determined in all fecal 
samples collected. To collect more detailed information on the relative contribution of adhesion to 
the external characteristics of LGG strains in feces, mice were sacrificed in 24 hours after the last 
probe administration and tissue samples (mucous membrane scrapings) were collected from 
different sections of the gastrointestinal tract (stomach, duodenum, cecum and colon). According 
to replica plating analysis, the relative percentage of the EPS-deficient mutant CMPG5351 strain 
was especially reduced in the mucus and mucous layer of cecum and colon. The observations 
obtained indicate an important protective function of long EPS molecules with a high galactose 
content for bacteria of LGG strain in GIT. Thus, EPS are a factor in the adaptation of LGG strain 
bacteria, which contributes to their survival and stability in the host organism. It should be noted 
that similar biological functions of EPS and CPS were described in pathogenic and symbiotic 
bacteria.  
Lin et al. (2009) carried out a study in immature mice that were administered with LGG strain 
using a probe. The test animals were sacrificed and the intestinal mucosa was analyzed. An 
increase in the level of GSH oxidation and cullin-1 deneddylation was determined in intestinal 
tissue samples, which reflects the local formation of reactive oxygen species (ROS) and the final 
inactivation with the participation of Ubc12, respectively. Moreover, preliminary administration 
of LGG strain bacteria prevented TNF-α-induced activation of NF-κB in the intestine. These 
studies suggest that LGG strain bacteria can reduce the level of inflammatory signaling in the 
immature intestine by inducing local ROS formation, which may underlie the mechanism of the 


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preventive action of probiotic bacteria against necrotizing enterocolitis (NEC) in premature infants 
and reducing the severity of inflammatory bowel disease (IBD) in children. 
Ritze et al. (2014) studied the possible protective effect of LGG strain bacteria against 
experimental non-alcoholic fatty liver disease (NAFLD) in a mouse model. Experimental NAFLD 
was induced by administering high fructose feed for eight weeks to C57BL/J6 mice. Fructose was 
administered with drinking water containing 30% fructose solution with LGG supplement at a 
concentration of 5.6 × 107 CFU/g bm or without the supplement. Mice were studied for changes 
in the microflora of the small intestine, intestinal barrier function, concentration of 
lipopolysaccharides (LPS) in the portal vein, inflammatory changes in the liver, and accumulation 
of fat in the liver. The administration of LGG strain bacteria was accompanied by the growth of 
beneficial bacteria in the distal small intestine. Moreover, LGG strain bacteria reduced the level 
of IkB protein in the duodenum and restored the concentration of proteins at the level of tight 
junctions in the duodenum. There was a decrease in the level of LPS in the portal vein (P ≤ 0.05) 
and a tendency towards a decrease in the expression level of TNF-α, IL-8R, and IL-1b mRNA in 
the liver of animals receiving the high fructose feed with LGG supplement. Moreover, mice fed a 
high fructose feed with LGG supplement showed less pronounced fat accumulation in the liver 
and lower concentration of alanine aminotransferase in the portal vein (P ≤ 0.05). 
The obtained results indicate the potential benefit of LGG strain bacteria in the case of NAFLD, 
as well as, in general, for the balance of intestinal microflora. The mechanisms of this protective 
effect may include an increase in the population of beneficial bacteria, recovery of the intestinal 
barrier function, and a subsequent decrease in inflammation and liver steatosis.  
The anti-inflammatory properties of LGG strain bacteria were also studied by Sawada et al. (2007) 
in the model of human atopic dermatitis in NC/Nga mice. Female mice and their offspring were 
given a feed with or without the supplement of thermally inactivated LGG strain during pregnancy 
and breastfeeding, as well as after ablactation. A spontaneous appearance of typical skin lesions, 
very similar to those in patients with atopic dermatitis, was noted in control animals of NC/Nga 
line, which were kept under conditions without control of air pollution. On the other hand, the 
introduction of feed with the supplement of thermally inactivated LGG strain inhibited the 
appearance and development of atopic skin manifestations, which was accompanied by a lower 
number of mast cells and eosinophils in the skin lesion sites. A significant increase in IL-10 plasma 
level was determined in mice receiving the feed with LGG strain supplement, compared with the 
control animals, while the proportion of CD4+CD25+ regulatory T-cells in the spleen did not 
significantly differ between the group of LGG strain administration and the control group. A higher 
level of IL-10 mRNA expression was determined in Peyer's glands and mesenteric lymph nodes 


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of mice fed with LGG supplement. These observations suggest that some components of the 
thermally inactivated bacteria of LGG strain are able to delay the onset and prevent the 
development of atopic dermatitis, probably by means of the mechanism of pronounced induction 
of IL-10 in lymphoid organs and systemic blood flow. 
Isolauri et al. (1993) studied the effect of lactobacilli on the intestinal mucosa in suckling rats aged 
14 days. In addition to ordinary mother’s milk, animals from "milk" group received cow milk daily 
by means of a probe, animals from "milk-GG" group received cow milk with the supplement of 
Lactobacillus casei GG strain, and the animals from the control group were administered with the 
same volume water by means of the probe. After 21 days, the absorption of horseradish peroxidase 
was evaluated in the segments of jejunum without Peyer's glands and in the segments with Peyer's 
glands using Ussing chambers. A significant intergroup difference in the average level of 
absorption of intact horseradish peroxidase, expressed in ng • h-1• • cm-2, was found both in the 
segments without Peyer's glands (control group: 9 [95% confidence interval: 7–12]; «milk» group: 
72 [60–87]; «milk-GG» group: 15 [4–52]), and in the segments with Peyer's glands (control group: 
3 [1–17]; «milk» group: 80 [43–151]; «milk-GG» group: 15 [4–56]). There was a significant 
increase in the frequency of cells secreting antibodies to beta-lactoglobulin (according to the data 
of enzyme-linked immunospot assay) in "milk-GG" group. Prolonged administration of cow milk 
to the suckling rats led to an increase in permeability of intestinal wall for intact proteins, while 
Lactobacillus GG strain counteracted the permeability increase. The obtained results indicate a 
relationship between the intensity of the antigen-specific immune response and stabilization of the 
mucous barrier. 
Lee et al. (2000) studied the bacterial translocation of the ampicillin-resistant Escherichia coli K1 
strain and the effects of L. rhamnosus GG (LGG) strain in 77 newborn New Zealand albino rabbits. 
On the day of birth, the newborn rabbits were separated from the females and distributed into the 
groups of probe feeding with placebo, 108 КОЕ LGG (n = 8), 108 КОЕ K1 (n = 26) or a 
combination of both bacterial strains at a dose of 108 CFU (n = 33) twice a day for two days. These 
newborn rabbits were sacrificed on the 3rd day and tissue samples were taken, which were 
incubated under aerobic conditions for 48 hours, and then the number of colonies of LGG and K1 
strains was counted. In newborn rabbits fed with the LGG strain supplement, significantly lower 
intestinal colonization with the K1 strain (25%) was determined compared to animals not receiving 
LGG strain. Also, a significantly lower degree of bacterial translocation of strain K1 to the 
mesenteric lymph nodes, spleen, and liver was noted in this group. Damages of the small intestine 
mucous membrane were detected in none of the rabbits. Bacterial translocation of the LGG strain 
to these extraintestinal foci was detected in 1 of 8 animals in the LGG group and in 4 of 33 animals 


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in the LGG + K1 group. According to the authors, LGG strain inhibited the colonization of E. coli 
K1 strain bacteria and their translocation into extraintestinal foci. However, despite the fact that 
for newborns rabbits had a tendency to immaturity of the immune function and underdevelopment 
of the mucous membrane, mucous layer and intestinal epithelium, as well as, despite the absence 
of visible clinical manifestations of infecting by LGG strain, the authors expressed concern about 
the even rarer problem of LGG strain translocation. 
Naaber et al. (1998) studied the effects of the L. rhamnosus GG (LGG) strain in 10 adult Syrian 
hamsters who were given with ampicillin at a single dose of 3 mg, and after 24 hours — an 
infecting dose of Clostridium difficile. Starting 20 hours before the introduction of C. difficile and 
up to 5 days after the sacrifice, 0 or 0.5 ml of LGG strain in the broth culture (the CFU value was 
not specified) was introduced once a day into the test animals. According to the results of stool 
culture, LGG strain bacteria were isolated from all animals receiving active therapy, however, they 
did not prevail in the intestinal microflora and were not observed among translocating lactobacilli. 
Four of the five hamsters treated with the probiotic LGG strain remained healthy and had milder 
inflammatory changes in the intestinal mucosa compared with animals from the control group. No 
adverse effects were reported. 
3.2.2.3 Pharmacological safety studies 
There were no reports in preclinical studies about safety hazards associated with the use of LGG 
strain. In toxicity tests of extremely high doses of the Lactobacillus rhamnosus GG strain and other 
strains, no adverse effects on overall health, general clinical and biochemical blood values, 
histological parameters of the intestinal mucosa, or bacterial translocation frequency were 
determined.  There were several reports about bacterial translocation (Link et al., 1995, Wagner et 
al., 1997, Lee et al., 2000). Although we considered it was normal and even beneficial (Bengmark 
and Jeppsson, 1995), there is a probability of developing septicemia and generalized infections in 
subjects with impaired immunity. However, this effect was rarely observed, and clear clinical 
evidence was not found. According to Herzberg et al. (1992), infecting New Zealand albino rabbits 
with lactic acid bacterium (LAB) strains that can induce platelet aggregation (Agg+) invariably 
caused infectious endocarditis with a more severe course and higher mortality compared to 
infection with Agg- strains. As a result, the lack of platelet aggregation potential is indicated as 
one of the most important criteria for choosing a probiotic strain (Harty et al., 1993, Kirjavainen 
et al., 1999.). Based on this, Zhou et al. (2005) studied the ability of strains of L. rhamnosus 
HN001, GG and B. animalis ssp. lactis HN019 to the induction of platelet aggregation in humans 
in vitro. Three probiotic strains and Streptococcus sanguis 133-79 strain, used as a positive control, 
were cultured, purified and concentrated into a suspension containing approximately 109 CFU/ml. 


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Blood samples were took from six healthy volunteers aged 24 to 45 years old, then the samples 
were centrifuged, exposed to bacterial cells with 1:1 ratio of platelets to bacterial cells (the optimal 
ratio for inducing platelet aggregation) and incubated at room temperature for 30 minutes. Platelet 
samples were analyzed by flow cytometry for the average fluorescence intensity and the 
percentage of cells twice positive for mC-CD41a and PECD62p (markers of normal and activated 
platelets, respectively). Additionally, the following clinical blood values were measured: the total 
red blood cell and platelet counts, hemoglobin concentration, hematocrit, mean corpuscular 
volume, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration. None of 
the listed clinical blood values changed under the influence of bacterial cells. S. sanguis strain  
induced platelet activity to a higher degree; more than 91% of the cells were CD62p positive. On 
the other hand, probiotic bacterial strains did not affect platelet activity; the degree of platelet 
activation did not significantly differ between platelets exposed to probiotic strains and intact 
platelets. By analogy, the evaluation of platelets exposed to the S. sanguis strain showed a 
significant increase in the size of thrombocytic particles and aggregates. Probiotic bacteria did not 
affect the size of thrombocytic particles, which indicates that L. rhamnosus HN001 strain and other 
studied probiotic strains did not induce or enhance platelet aggregation. In addition, 
Vankerckhoven et al. (2007) studied the potential infectivity of 10 isolates of L. rhamnosus and 7 
isolates of L. paracasei in a model of experimental infectious endocarditis in rats. All test 
organisms were obtained from PROSAFE strain collection. Four strains of L.  rhamnosus were 
commonly used probiotics, other four strains were isolated in patients with endocarditis, one strain 
was used in fermentation processes, and another strain was under consideration as a potential 
probiotic. As part of the study, experimental lesion was induced in female Wistar rats with a body 
mass of 180–200 g by leading a catheter through aortic valve. After 24 hours, rats were injected 
intravenously with 104–108 CFU of each test microorganism in groups of 7–11 animals per strain 
and inoculum. After 72 hours, the rats were sacrificed, after which the heart and infected valves 
were removed to count microorganisms. Strains of Staphylococcus aureus Newman, Streptococcus 
gordonii Challis and Lactococcus lactis 1363 were used as a positive and negative control of 
infectivity. Additionally, adhesion of lactobacilli to immobilized matrix proteins of host organism 
and their sensitivity to thrombocytic proteins with microbiocidal activity were evaluated. 90% 
infectious doses of S. aureus and S. gordonii for tissue culture (SCID90) were 104 and 105 CFU, 
respectively, indicating a high infectivity of the true pathogens of endocarditis, whereas SCID90 
of the control strain of Lactococcus lactis was 107 CFU.  The SCID90 value of L. rhamnosus 
isolates varied from 106 to 107 CFU.  SCID90 of LGG strain was 106–107. According to the 
authors, investigational probiotic, nutritional and probiotic isolates of lactobacilli are less able to 
induce experimental endocarditis compared to isolates, which are common causative agents of 


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endocarditis in humans. The number of lactobacilli necessary for infection of 290% of individuals 
was from 100 to 1000 times higher than the number of S. aureus or S. gordonii bacteria. They 
additionally suggested that lactobacilli can act as the causative agent of endocarditis under certain 
factors on the part of the host organism, since the corresponding cases were recorded mainly in 
patients with severe background diseases or reduced immunocompetence. Shu et al. (1999) studied 
the safety of different strains of lactobacilli in BALB/c mice by introducing different doses of the 
corresponding bacteria (5 × 107, 109 or 5 × 1010CFU per individual a day) for 7 days. During the 
trial, abnormal clinical manifestations were observed in none of the groups. There were no 
significant differences in the feed and water intake levels or liveweight gain between mice 
receiving various probiotic strains and animals from the control group not receiving LAB. No 
bacteria were found in spleen tissues in any animals. Despite the fact that lactic acid bacteria were 
detected in the kidney tissues of one of animals in each of the groups receiving the strains of Lb. 
rhamnosus HN001 or B. lactis HN019, analysis by DNA fingerprinting showed the difference 
between the recovered isolates and tested probiotic strains. Histological and hematological 
indicators also showed the absence of adverse effects of lactic acid bacteria strains on mice health 
condition.  
3.2.2.4 Secondary pharmacological properties 
Lactobacillus rhamnosus strain was successfully used in the treatment of alcohol-induced liver 
injury in animals, for example in rats and mice.  These studies identified additional anti-
inflammatory effects that are also important for understanding the basic pharmacological 
properties of LGG strain.  
Forsyth et al. (2009) suggested that probiotics can maintain normal barrier function in the animal 
model of ALD by preventing alcohol-induced oxidative stress and, as a result, inhibiting the 
development of increased permeability and subsequent alcoholic steatohepatitis(ASH). Male 
Sprague-Dawley rats were gavaged alcohol twice a day (8 g/kg) for 10 weeks. Rats that received 
alcohol were also gavaged 2.5 × 107 live bacteria of the L. rhamnosus (Gorbach–Goldin) strain 
(LGG) or vehicle (V) once a day. Intestinal permeability (initially and after 10 weeks) was studied 
by bolus injection of sugar and subsequent analysis of sugar in the urine by GC. Intestinal and 
liver tissues were analyzed for oxidative stress and inflammation markers. A histological 
evaluation of the liver for the ASH severity and total fat content (steatosis) was also performed. 
Rats treated with alcohol and LGG strain (ALC+LGG) showed a significantly lower severity of 
ASH (P≤ 0.05) compared with rats from the ALC+V group. The L. rhamnosus (Gorbach–Goldin) 
strain also reduced alcohol-induced "leakage" of the intestine and significantly reduced alcohol-
induced oxidative stress and inflammation in the intestines and liver. Probe administration of the 


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probiotic L. rhamnosus (Gorbach–Goldin) strain significantly reduced the manifestations of ASH 
in rats. The observed improvement was accompanied with a decrease in the level of oxidative 
stress and inflammation markers in the intestines and liver and the intestinal barrier function 
preservation. 
Wange et al. (2011) carried out a study in C57BJ/6N mice, which received Lieber DeCarli feed 
with the 5% alcohol supplement for 8 weeks. The animals also received the supplement of 
Lactobacillus rhamnosus GG (LGG) strain for the last two weeks. The introduction of LGG 
supplement led to a significant reduction in alcohol-induced endotoxemia and liver steatosis and 
resulted in liver function improvement. LGG strain restored alcohol-induced decrease in the level 
of HIF-2α and intestinal trefoil factors. It was demonstrated in in vitro studies using a Caco-2 cell 
culture model that the addition of the supernatant of LGG strain prevented alcohol-induced 
dysfunction of the intestinal barrier formed by the epithelial monolayer. Moreover, HIF-1α/2α 
gene silencing eliminated the effects of LGG, which indicated the dependence of the protective 
effect of LGG strain on HIF. 
This study examined the mechanisms that underlie the probiotics effectiveness in the treatment of 
ALD, and suggests a critical role of intestinal hypoxia and decrease in the trefoil factor level for 
ALD development. 
Wang et al. (2013) studied the effect of probiotics on the tumor necrosis factor α (TNF-α) synthesis 
in the liver and inflammatory response to chronic alcohol consumption. The mice received Lieber 
DeCarli liquid feed with 5% alcohol supplement for 8 weeks, and additionally Lactobacillus 
rhamnosus GG strain (LGG) was introduced to them for the last 2 weeks. The introduction of 
alcohol for eight weeks led to a significant increase in the inflammatory response in the liver, as 
was shown in the results of histological evaluation and analysis of myeloperoxidase activity in 
liver tissues. The introduction of the LGG strain supplement for two weeks reduced the 
inflammatory response in the liver and the liver damage, and also significantly reduced TNF-α 
expression. The introduction of alcohol led to an increase in the expression level of mRNA of toll-
like receptors (TLR) and CYP2E1 in the liver and a decrease in the expression level of nuclear 
factor erythroid 2-related factor 2. Administration of LGG supplement reduced the extent of these 
changes. Using macrophages obtained from human peripheral blood monocytes, we also showed 
that incubation with ethanol triggers lipopolysaccharide- and flagellin-induced synthesis of TNF-
α, and the supernatant of LGG strain culture dose-dependently reduced this inducing effect. In 
addition, the introduction of the LGG strain also significantly reduced the degree of 
alcohol-induced phosphorylation of p38 MAP kinase. Thus, the probiotic strain LGG reduced 


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alcohol-induced liver inflammation by reducing the synthesis of TNF-α through inhibition of 
TLR4 and TLR5-mediated activation of endotoxins. 
3.2.2.5 Pharmacodynamic drug Interactions 
Data about pharmacodynamic drug interactions was not reported.  
It is known that the effectiveness of LGG strain may decrease on treatment of antibiotics 
(Radulovic et al., 2012).  
3.2.2.6 Pharmacokinetics  
The pharmacokinetics of probiotics mainly describes a change in their condition (survival and 
association with the host organism) in the gastrointestinal tract. Several in vitro models were 
developed to predict in vitro survival of probiotics or their adhesion to intestinal epithelium. Static 
models can provide information on the sensitivity of strains to a constant pH or bile concentration. 
Multicompartment dynamic models were also developed in which using a computer program the 
dynamics of secretion of gastric juice and bile, as well as the passage of chyme through the 
intestines can be reproduced. These models can more accurately predict in vivo situations, as well 
as examine the effects of various indicators, such as bile concentration or variability in gastric acid 
secretion (Marteau and Vesa 1998).  
3.2.2.7  Adhesion to intestinal epithelium 
The lactobacilli adhesion to the mucous membrane is considered one of the first components of 
the digestive tract colonization process in the host organism. 
Nishiyama et al. (2016) provided a comprehensive overview of the lactic acid bacteria adhesion 
properties. The main segment of the intestine colonized by the LAB, especially Lactobacillus 
genus bacteria, is the segment between the duodenum and the terminal part of the ileum, in which 
the intestinal wall is lined with a mucous layer consisting mainly of mucin-like glycoproteins. The 
mucous layer contributes to the protection of intestinal epithelial cells against damage but is also 
a critical factor in the lactobacilli adhesion in the gastrointestinal tract. Lactobacilli exhibit 
different adhesiveness to mucin and mucin carbohydrate chains due to the wide scatter of 
molecular structures. This means that lactobacilli adapt to the constantly changing intestinal 
environment of the host organism, and additionally indicates that the lactobacilli adhesion factors 
have a specific affinity for binding, which allows them to efficiently colonize the intestines of the 
host organism and at the same time avoid competition with other bacteria. 
Two main adhesion factors were determined for the Lactobacillus rhamnosus GG strain: 
mucus-specific adhesin (von Ossowski et al., 2011, Nishiyama et al., 2015) and fimbria 


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(Nishiyama et al., 2016, Kanakinen et al., 2009, Reunanen et al., 2012, Rintahaka et al., 2014, von 
Ossowski et al., 2010).  
Conway et al. (1987) studied the adhesion mechanism of different strains of lactobacilli. Based on 
the fact that all strains showed a certain adhesive ability to human and porcine intestinal cells, 
nonspecific attachment was suggested as a possible adhesion mechanism. This was further 
confirmed in a study by Sillanpää (2001). This study demonstrated that the ability to adhere to 
target human tissues, established for lactobacilli, is typical for LAB from different sources and 
different types of the Lactobacillus genus bacteria. 
3.2.2.8 Survival in gastrointestinal tract and excretion 
Goldin et al. (1992) carried out a study in which 76 volunteers took the Lactobacillus GG strain 
as a frozen concentrate or fermented preparation in milk or serum. The studied strain was isolated 
from feces of all volunteers who took fermented milk or serum, and 86% of volunteers who took 
the frozen concentrate, according to the results of inoculation on one feces sample from the 
volunteer. The studied microorganism was also present in the feces of subjects taking ampicillin 
at the time of the study. After stopping the administration of a probiotic supplement with food, the 
Lactobacillus GG strain continued to be excreted in feces in 87% of volunteers after four days and 
in 33% of participants after seven days. Lactobacillus GG strain reduced the activity of fecal 
bacterial beta-glucuronidase by about 80% in volunteers who received it with food for four weeks. 
It was shown in these studies that the Lactobacillus GG strain survives in the human 
gastrointestinal tract and temporarily colonizes it, as well as the fact that it affects the metabolic 
activity of resident microflora. 
Moreover, according to Marteau and Vesa (1998), the strains of L. acidophilus, L. reuteri, and L. 
rhamnosus GG show a higher survival ability in acidic medium compared to other strains of 
lactobacilli. After the L. rhamnosus GG supplement administration, the concentration of this strain 
in feces reached 106 CFU/g. After stopping the probiotic strains oral administration, their excretion 
kinetics approached the inert marker excretion kinetics, which indicates the absence of 
colonization.  
Charteris et al. (1998) developed an in vitro method for modeling a transit in the human upper 
gastrointestinal tract. The survival of potential probiotic strains of Lactobacillus and 
Bifidobacterium genera during transit through the gastrointestinal tract was studied by exposure 
to washed cell suspensions at 37 °C in artificial gastric juice (pH 2.0) containing pepsin (0.3% m/v) 
and sodium chloride (0,5% m/v), as well as artificial small intestinal juice (pH 8.0) containing 
USP pancreatine  (1 g/L) and sodium chloride (5 g/L), and periodic monitoring of changes in the 


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total viable bacteria count. This method was also used to evaluate the effect of adding milk proteins 
(1 g/L), gastric mucus of domestic pigs (1 g/L), and soybean trypsin and chymotrypsin inhibitor 
[SBTCI] (1 g/L) for survival during transit in gastrointestinal tract. A limited survival was 
established for the Lactobacillus rhamnosus GG strain during transit through simulated gastric 
juice, namely, after 1.5 hours, 0.1% of the exposed cells survived. This observation confirms the 
results of Goldin and Gorbach (1989), according to which the number of GG strain bacteria 
decreased from 109 to 103 after 2 hours in the human stomach at pH 1-2. The authors also 
determined a decrease in the number of bacteria of GG strain from 108 to 106 after holding them 
in normal human gastric juice for 1.5 hours at pH 2.5. Nevertheless, it was shown that 
Lactobacillus rhamnosus GG strain tolerates the transit through the stomach (Gorbach and Goldin, 
1989; Goldin et al., 1992; Charteris et al., 1994, 1996), the effects of biliary salts (Gorbach and 
Goldin, 1989) and has the ability to adhere to the cells of ileum adenocarcinoma (Silva et al., 1987) 
and human colon in the culture (Elo et al. 1991; Chauviere et al., 1992). The current study also 
demonstrated the natural resistance of the LGG strain to intestinal proteases, since its viability did 
not decrease during simulated transit through the small intestine.  
Corocan et al. (2005) studied the effect of glucose on the survival of L.rhamnosus GG strain in 
artificial gastric juice at pH 2.0. It was found that in the presence of 19.4 mmol glucose, the 
survival of the studied strain increased by 6 log10times after 90-minute exposure. An additional 
study in the diluted HCl confirmed that this effect is mediated exclusively by glucose. In the course 
of comparative analysis with other strains of Lactobacillus, it was determined that survival is 
increased in all strains, but at different pH values. In the presence of glucose in concentration from 
1 to 19.4 mmol/L, the survival of L. rhamnosus GG strain in artificial gastric juice increased by 
6.4–8 log10 CFU/ml. The mechanisms of this protective effect of glucose were studied. According 
to observations, the addition of N′,N-dicyclohexylcarbodiimide to artificial gastric juice deprived 
the bacterium of its ability to survive, which indicates a significant role of F0F1-ATPase inhibition. 
The results of an additional test with neomycin-resistant mutants, which had F0F1-ATPase activity 
from 38 to 48% of initial level, support this observation. The survival of these mutants decreased 
3 × 106- fold in the presence of glucose compared with the survival of the non-mutant strain (8.02 
log10 CFU/ml). Bacteria of L. rhamnosus GG strain survived in an acidic environment only in the 
presence of sugars, which they could efficiently metabolize. In order to confirm the role of the 
glycolysis process in the considered glucose effect, iodoacetic acid was used to inhibit the activity 
of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). The decrease in GAPDH activity was 
accompanied by a decrease in survival by 8.30 log10 CFU/ml in the presence of glucose. The 
obtained observations indicate that glucose serves as a source of ATP for F0F1-ATPase during 


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glycolysis, which ensures the process of proton exclusion and, thereby, increases survival during 
transit through the stomach. 
3.2.2.9 Pharmacokinetic drug interactions  
Bacteria of LGG strain are not absorbed after oral administration. However, they affect the 
absorption of other substances in the intestine. The most important consequence of this observation 
is the potential use of LGG strain and other probiotics as adjunctive therapy in cases of acute or 
chronic poisoning.  
Gratz et al. (2006) demonstrated that oral administration of LGG strain to rats leads to a change in 
the uptake of B1 oral aflatoxin. An increase in AFB1 excretion with feces due to binding to bacteria 
was noted. In turn, this therapy prevented a body mass loss and reduced the hepatotoxic effect of 
high doses of AFB1.  
Moreover, Deabes et al. (2012) also studied the effects of the oral LGG supplement on subacute 
exposure to aflatoxin in male albino mice. According to observations, the oral administration of 
LGG culture to mice led to a significant reduction in mycotoxin-induced toxicity by preventing 
oxidative stress, maintaining glutathione levels and stable activity of SOD, and also preventing 
mycotoxin-induced genotoxicity and toxic effects on sperm  
Trinder et al. (2016) studied the effect of bacteria of Lactobacillus rhamnosus species on the 
absorption of organophosphorus compounds (parathion and chlorpyrifos (CP)) in Drosophila 
melanogaster. According to observations, strains of Lactobacillus rhamnosus GG (LGG) and L. 
rhamnosus GR-1 (LGR-1) are capable of significant sequestration of organophosphorus pesticides 
from solution after 24-hour co-incubation. The indicated effect was independent on metabolic 
activity due to absence of hydrolytic activity against CP in the L. rhamnosus GG strain and the 
absence of differences in sequestration of organophosphorus compounds between live and 
thermally inactivated strains. Moreover, LGR-1 and LGG strains reduced the absorption of 
100 mol of parathion or CP in the Caco-2 Transwell model of small intestine epithelium. In order 
to determine the effect of sequestration on acute toxicity, recently caught Drosophila melanogaster 
flies were given with a feed containing 10 mol CP with or without the LGG strain live bacteria 
supplement. With the simultaneous introduction of LGG strain, but not simultaneously with the 
CP administered three days before (preventive therapy), a decrease in CP-induced mortality was 
observed. 


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3.2.2.10  Antibiotic resistance genes and probability of their transfer 
Salminen et al. (1998) performed a review of lactic acid bacteria safety, during which it was noted 
that these bacteria have a long history of safe use in food products. Lactic acid bacteria are naturally 
resistant to many antibiotics. However, in many cases, resistance is not transferred, and the studied 
species are also sensitive to many antibiotics used in clinical practice, even in case of opportunistic 
infections associated with lactic acid bacteria. Thus, the presence of natural resistance does not 
raise any particular concerns about safety. 
Like all bacteria, LAB are prone to gene exchange in order to increase survival in a medium 
containing antibiotics (Teuber et al. 1999). The main concern associated with ability of phenotypic 
antibiotic resistance in probiotic bacteria is their potential for in vivo transferring this resistance to 
pathogenic or potentially pathogenic microorganisms. 
Borriello et al. stated that (2003) many strains of lactobacilli are naturally resistant to vancomycin. 
Nevertheless, it is generally accepted that insensitivity or resistance to antibiotics alone does not 
cause concern if it does not prevent the treatment in rare cases of infections caused by a probiotic, 
or if it can not be transferred to potential pathogens, resistance to which may cause therapeutic 
consequences.  
By analogy, Temmerman et al. (2003) established resistance to kanamycin of all studied strains of 
L. rhamnosus and other strains of lactobacilli and bifidobacteria. Genetic grounds for resistance to 
kanamycin were not determined, and therefore this property is classified as natural. 
In the framework a review of the antibiotic resistance of enterococci, Arthur and Courvalin (1993) 
noted that back in 1986, plasmid-mediated resistance to the glycopeptide antibiotics vancomycin 
and teicoplanin was found (Leclercq et al., 1988; Uttley et al., 1989), and also that the induced 
resistance to high doses of vancomycin and teicoplanin determines the manifestation of the vun(A) 
phenotype. According to the authors, the nucleotide sequences associated with the vun(A) gene 
were not found in gram-positive bacteria with natural resistance to glycopeptides, including 
Lactobacillus spp. Thus, resistance genes are not part of the chromosomes of these species and are 
not susceptible to gene transfer. 
Based on materials from Teuber et al. (1999): despite the theoretically possible transfer of 
antibiotic resistance genes between LAB and bacteriophages and prophages, this has not been 
proved to be practically relevant. Moreover, the scatter of such a transfer in theory should be 
limited to closely related strains of the same species. 


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3.2.2.11  Susceptibility and resistance to antibiotics 
Zhou et al. (2005b) assessed the resistance of lactobacilli to antimicrobial drugs. They studied 
resistance to 18 commonly used antibiotics by the disk diffusion method. The three studied 
lactobacilli strains had an antibiotic resistance profile similar to that of Lactobacillus plantarum 
HN045 strain and two commercial probiotic Lactobacillus strains, namely GG and LA-1. The 
antibiotic resistance profile of B. lactis HN019 was similar to that of three commercial probiotic 
B. lactis strains (Bb12, HN049 and HN098). All 10 strains were sensitive to antibiotics with 
activity against gram-positive bacteria, such as erythromycin and novobiocin, broad-spectrum 
antibiotics - rifampicin, spectinomycin, tetracycline and chloramphenicol, as well as beta-lactam 
antibiotics penicillin, ampicillin and cephalotin. At the same time, most strains were resistant to 
antibiotics active against gram-negative bacteria, such as fusidic acid, nalidixic acid and 
polymyxin B, and aminoglycosides neomycin, gentamicin, kanamycin and streptomycin. All three 
strains of L. rhamnosus (HN001, HN067 and GG) were resistant to vancomycin, and several 
strains also showed resistance to cloxacillin. 
Klein et al. (2000) compared the genetic basis of lactobacilli and enterococci resistance to 
glycopeptides in order to determine their similarity. L. rhamnosus GG (ATCC 53103) strain, as 
well as five L. reuteri strains and 4 control Enterococcus strains were analyzed for the presence of 
the van(A) gene cluster, van(B) gene, and van(C) gene by PCR, Southern blot-hybridization, and 
DNA-DNA hybridization. Their antibiotic resistance and plasmid profiles were also determined. 
All strains of lactobacilli showed a certain resistance to vancomycin, oxacillin, gentamicin, 
ciprofloxacin, and trimethoprim/sulfamethoxazole, but were sensitive to a wide range of 
antibiotics, including clindamycin, imipenem, chloramphenicol, and rifampin. The authors noted 
that resistance of L. rhamnosus and L. reuteri strains to glycopeptide antibiotics is a natural 
property, and that there was no evidence of a possible transfer of this property of lactobacilli to 
other bacterial strains. The genomes of the studied lactobacilli strains did not contain the van(A), 
van(B) or van(C) genes. 
According to these observations, the mechanism of resistance to glycopeptide antibiotics of the 
examined strains of lactobacilli differs from that of enterococci. The authors concluded that the 
study supports the safety of the presence of resistance to vancomycin in lactobacilli strains.  
Kastner et al. (2006) in Switzerland, conducted a review of starter and probiotic cultures in order 
to study the current status of antibiotic resistance of nutritional supplements of bacterial nature. 
They screened 200 isolates from 90 different sources for phenotypic resistance to 20 antibiotics 
using the disk diffusion method. According to observations, the L. rhamnosus GG strain (the only 


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studied strain of L. rhamnosus species) showed resistance to 8 antibiotics (fusidic acid, kanamycin, 
nalidixic acid, tobramycin, nitrofurantoin, oxacillin, streptomycin and vancomycin), but not to the 
other studied antibiotics (cefotaxime , clindamycin, ofloxacin, penicillin G, tetracycline, 
lincomycin, meticillin, erythromycin, chloramphenicol, rifampicin, novobiocin and gentamicin). 
The last observation, namely the sensitivity of LGG strain to gentamicin, differs from the 
mentioned above Zhou et al. results. (2005b). 
Twenty-seven isolates with an identified antibiotic resistance, which is not a natural characteristic 
of the corresponding genera, were further studied by microarray hybridization in order to identify 
phenotypic resistance to certain genetic determinants. No antibiotic resistance genes were found 
in the genome of the L. rhamnosus GG strain. Klare et al. (2007) evaluated 131 isolates of L. 
rhamnosus strains for resistance to 16 antimicrobials, which covered almost all important classes, 
in order to determine the distribution of minimum inhibitory concentration (MIC) for each isolate. 
This study revealed a surprisingly small proportion of cases of acquired antibiotic resistance. 
According to the authors, this could be due to the fact that all studied isolates were well-known 
and recognized completely harmless strains. Acquired resistance was observed only to 
streptomycin, erythromycin, clindamycin (3 isolates for each antibiotic) and oxytetracycline 
(12 isolates). Five of 131 isolates of L. rhamnosus showed acquired resistance, but no known 
antibiotic resistance genes were found in the genome of any of them. 
3.2.2.12 Toxicity study  
3.2.2.12.1 Acute toxicity 
 In acute toxicity studies, the same procedures as in chemicals toxicity tests were used. In these 
trials, high doses of probiotic strains are orally administered to animals, usually mice, for a short 
period of time. One of the important studied indicators is the translocation of the probiotic strain 
from the intestine to other tissues, especially intestinal lymph nodes, since this is one of the 
necessary conditions for the development of potential opportunistic infections. Zhou et al. (2000a) 
evaluated the acute oral toxicity of three strains of lactobacilli (Lactobacillus rhamnosus HN001, 
Lb. acidophilus HN017 and Bifidobacterium lactis HN019) in BALB/c mice that were 
administered with HN019, HN001 or HN017 strains in a high dose of 1011 CFU per animal per 
day for 8 consecutive days. According to the obtained results, the listed probiotic strains did not 
have adverse effects in relation to overall health, food intake, weight gain and morphology of the 
intestinal mucosa (villus height, crypt depth, epithelial cell height and mucous membrane 
thickness). No viable bacteria were identified in the blood and tissue samples of mice (mesenteric 
lymph nodes, liver and spleen). Also, no development of any diseases or deaths associated with 


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treatment was reported. The results indicate that the oral LD50 of HN019, HN001 and HN017 
strains in mice exceeds 50 g/kg/day, which is 700 times higher than the usual dose of probiotic in 
humans.  
Donohue et al. (1993) studied the acute toxicity of several strains of lactobacilli, including LGG, 
in mice. LGG strain at a dose of 0, 1.5, 3, 6 or 9 × 1011 CFU/kg was administered by means of a 
probe to twenty-five adult male house mice. Significant changes in behavior, food intake and body 
mass were not observed. Treatment-related deaths and toxic effects were absent, as well as 
noticeable macroscopic changes in internal organs. According to the authors, the acute oral LD50 
of each of the studied bacterial strains is >9 × 1011 CFU/kg bm for male house mice. A dose of 
6 g/kg/day was established as LD50 for the LGG strain, which corresponds to the maximum dose 
that can technically be administered to mice. (Bioactive Foods in Promoting Health: Probiotics и 
Prebiotics 2010; Kabeir et al., 2008). 
3.2.2.12.2 Repeated dose toxicity studies 
Zhou et al. (2000b) studied the overall safety of immunostimulating strains of lactic acid bacteria 
(LAB) Lactobacillus rhamnosus HN001, Lb. acidophilus HN017 and Bifidobacterium lactis 
HN019. In groups of BALB/c mice, test strains of LAB or a commercial control Lb. acidophilus 
LA-1 strain were orally administered at a dose of 2.5 × 109, 5 × 1010 or 2.5 × 1012 colony forming 
units (CFU) per kg of body mass per day for 4 weeks. During the period of the supplement 
administration, the intake of food, water, and live weight was monitored. At the end of the 4-week-
long follow-up, samples of blood, liver, spleen, kidney, mesenteric lymph nodes and intestines 
(ileum, cecum and colon) were taken to determine the following indicators: hematological values 
(the total red blood cell and platelet counts, hemoglobin concentration, mean corpuscular volume, 
mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration), Arneth formula, 
blood chemistry values ((total protein, plasma albumin, plasma cholesterol and plasmatic glucose), 
histological characteristics of the mucous membrane (epithelial cell height, mucous membrane 
thickness, villus height), bacterial translocation into extraintestinal tissues (blood, spleen liver, 
kidneys and mesenteric lymph nodes). Identification of viable bacterial strains isolated from these 
tissues was performed by DNA fingerprinting. According to the obtained results, the introduction 
of these strains of LAB for 4 weeks was not accompanied by adverse effects on overall health, 
hematological values, blood chemistry values, histological characteristics of the intestinal mucosa 
and the frequency of bacterial translocation. 


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A small number of viable LAB were isolated from the tissues of the control and test group animals, 
but none of them was identified as inoculated strain based on the results of DNA fingerprinting 
analysis. According to the results obtained in this study, the LAB HN001, HN017 and HN019 
potentially probiotic strains are not toxic to mice.  
Zhou (2000) studied the potential adverse effects of a dietary supplement based on two LAB 
strains, HN001 and HN019, in a model of immunocompromised animals. For the purpose of 
immunosuppression induction, dexamethasone was administered subcutaneously to animals 
24 hours before the administration of probiotic (200 micrograms per individual for 48 hours). A 
freshly prepared strain of LAB was administered at a dose of 1.5-2.5 × 107 CFU per individual per 
day for 7 days. A pathogenic strain of Salmonella typhimurium was used as a positive control. At 
the end of the test, animal tissue and blood samples were taken to determine hematological 
parameters and bacterial translocation. None of the considered safety indicators was significantly 
changed. The introduction of the LAB supplement was not accompanied with adverse effect on 
animals, and there were no cases of bacterial translocation and systemic infections.  
To study the effects of LAB strains in individuals with initial immunological dysfunction in a 
group of female CBA/CaH mice with experimentally induced autoimmune thyroiditis, a freshly 
prepared LAB strain (HN001 4.2 × 108 CFU per individual per day; HN019 2.16 ×108 CFU per 
individual per day) was administered for 5-8 weeks. Probiotic administration was started a week 
before immunization with autoantigens (MTg; mouse thyroglobulin). According to the results 
obtained, the introduction of LAB did not cause increased proliferative responses of splenocytes 
to MTg or lymphocytic infiltration of thyroid tissue. The LAB strains did not have adverse effects 
on the induction or course of autoimmune reactions in mice.  
3.2.2.12.3 Genotoxicity 
No studies demonstrating the lactobacilli genotoxic potential have been performed. On the other 
hand, there is an evidence of a genoprotective effect of the LGG strain administered 
simultaneously with known genotoxic substances.  
Burns and Rowlan (2004) studied the effect of six strains of lactic acid bacteria (LAB) on 
genotoxicity against cells of fecal extract from the colon through a comet DNA analysis that 
measures single-strand DNA breaks. All the studied bacteria, with the exception of Streptococcus 
thermophilus, significantly reduced the DNA damage. The decrease in genotoxicity was associated 
with cell density, and it was found that viable probiotic cells did not affect the genotoxicity of fecal 
waters.  


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Pool-Zobel et al. (1996) evaluated the potential of different strains of lactobacilli to prevent DNA 
damage induced by N-methyl-N'- nitro-N-nitrosoguanidine (MNNG, 7.5 mg/kg of body weight) 
in rat colon cells. The results showed that most of the studied strains of LAB significantly inhibited 
genotoxicity against the GI tract of rats, and that only viable LAB can show a protective effect in 
vivo. The studies presented above were also summarized and reviewed in Rowlans’ article (2007). 
Farag et al. (2010) conducted a study to assess the possible protective effect of the Lactobacillus 
rhamnosus GG (LGG) strain on OTA-induced toxicity in mice. The study included four groups of 
30 mice each: the control group, the LGG administration group (1 × 1010 CFU), the OTA 
administration group (1.8 mg/kg body weight), and the group of LGG administration two hours 
before the OTA probe. The study measured the activity of malondialdehyde (MDA), glutathione 
(GSH), and superoxide dismutase (SOD) in the liver and kidneys. Genotoxicity was studied by 
means of a micronuclear test on bone marrow cells, analysis of chromosomal aberrations in 
spermatocytes, as well as mitotic and meiotic activity; additionally, sperm parameters were 
evaluated. In mice treated with the LGG strain prior to OTA probe administration, there was a 
significant decrease in lipid peroxidation (POL) in the liver and kidneys due to increased GSH 
content and SOD activity. Cytogenetic analyses showed that the introduction of the LGG strain 
before the OTA probe led to a significant decrease in the incidence of MYAPCHE in the bone 
marrow and chromosomal aberrations in spermatocytes, as well as to the restoration of mitotic and 
meiotic activity. Moreover, when the LGG strain was gavaged before OTA, there was a significant 
recovery of all the studied sperm parameters.  
Chiu at al. (2013) studied the genotoxicity on lyophilized powder of cultured probiotic strains that 
included 
Lactobacillus 
rhamnosus LCR177, Bifidobacterium 
adolescentis BA286, 
and Pediococcus acidilactici PA318. The Ames test, in vitro analysis of chromosomal aberrations 
in mammalian cells, and micronuclear tests on mouse peripheral blood cells were performed. For 
five strains of Salmonella typhimurium, the Ames tests did not show an increase in the number of 
reverse mutations after exposure to the test substance. The frequency of chromosomal aberrations 
in CHO cells did not increase in response to the introduction of probiotics. Similarly, the 
occurrence of micronuclear reticulocytes in mice treated with probiotic did not differ from that in 
individuals from the negative control group. Generalized results of toxicity studies indicate that 
multi-species probiotic mixtures do not exhibit mutagenic activity against different species. 
3.2.2.12.4 Carcinogenicity 
There are no studies that demonstrate the carcinogenic potential of lactobacilli. On the contrary, 
there is evidence that the LGG strain has anti-carcinogenic potential. However, some strains of 


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LAB synthesize enzymes necessary for deconjugation or dehydroxylation of bile acid salts (Eyssen 
1973, Gilliland and Speck 1977), which is a concern because dehydroxylated bile acid salts exhibit 
cytotoxicity and cocancerogenicity (Marteau et al., 1995). However, more recent studies have 
concluded that the biological effect of probiotics is minimal and therefore not considered 
dangerous or clinically significant (Marteau and Salminen 1999, Zhou 2000c). 
Banna et al. (2017) summarized the available evidence for the anti-carcinogenic effect of the LGG 
strain. The authors claim a positive effect of the LGG strain on inflammatory responses, epithelial 
damage, invasiveness, and proliferation of malignancies, based on the results of in vitro and in 
vivo studies. 


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Table 1. Effects of the Lactobacillus rhamnosus GG (LGG) strain on intestinal disorders 
associated with cancer (based on Banna et al., 2017) 
Medical 
condition 
Model of the study 
LGG strain effect 
Control 
In vitro 
In vivo 
Gastric 
cancer 
HGC-27 
 
Displacement of the 
polyamine ionization 
profile to the acidic 
side 
Linsalata et al., 2010 
GAC 
 
Immunoregulation IL-
8 
H. 
pylori-dependent 
action 
Rokka at al., 2008 
Colon cancer 
Caco-2, 
HT29, 
SW480 
 
Proapoptotic agent in 
combination 
with 
vitamin K 
Orlando et al., 2016 
Caco-2 
 
Immunoregulation IL-
8 
Flagellin-induced 
action 
Lopez et al., 2008 
 
Male rats of 
the 
Fischer-
344 line 
Antiproliferative 
action 
Goldin et al., 1996 
 
Sprague 
Dawley rats 
Inhibition 
of 
angiogenesis 
and 
inflammation 
Gamallat et al., 2016 
Metastatic 
CRC 
HCT-116 
 
Inhibition 
of 
invasiveness 
Escamilla et al., 2012 


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Female mice 
of 
the 
C57BL/6 line 
Tumor regression 
Seow et al., 2010 
Loss 
of 
intestinal 
crypts 
 
The mouse of 
line C57BL/6 
Reduction 
of 
epithelial 
cell 
apoptosis 
Ciorba et al., 2012 
Inflammation  
The mouse of 
line C57BL/6 
Activation 
of 
the 
mucosal 
immune 
response 
Wang et al., 2017 
RIIT 
and 
CIIT 
 
Human 
Reducing 
the 
frequency of diarrhea 
by 15 % 
Osterlund et al., 2007 
 
GAC — gastric adenocarcinoma; H. pylori — Helicobacter pylori; DMG — dimethylhydrazine; 
CRC — colorectal cancer; RIIT — radiation-induced intestinal toxicity; CIIT — chemo-induced 
intestinal toxicity. 
3.2.2.12.5 Reproductive Toxicity 
There have been no preclinical studies of the effect of the LGG strain or other probiotic strains on 
reproductive functions. 
3.2.2.13  Local tolerance 
Zhou et al. (2000) studied pathological changes in the intestinal mucosa in BALB/c mice 
inoculated with three probiotic strains (Lactobacillus rhamnosus HNOO 1-DR20™, Lactobacillus 
acidophilus HNOl 7 and Bifidobacterium lactis HN019-DR10®). According to observations, the 
introduction of Lb. rhamnosus HN001, Lb. acidophilus HN017 or B. lactis HN019 LAB strains to 
mice in a high dose (2 times 1012 CFU/ml in skimmed milk [50 µl] per day [equivalent to 1011 
CFU per individual per day]) for 8 days did not result in histologically distinguishable damage of 
the intestinal mucosa. No adverse effects were observed on the morphology of the intestinal 
mucosa (villi height, crypt depth, epithelial cell height and mucosal thickness), as well as on the 
orientation and location of the mucosal epithelial cells. According to the conclusion, the HN019, 


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HN001 and HN017 strains do not violate the integrity of the gastrointestinal mucosa when taken 
in an acceptable daily dose (ADD) of 35 g of dried bacteria per day for a person weighing 70 kg. 
Kozakova et al. (2016) evaluated the effect of a mixture of three Lactobacillus strains 
(Lactobacillus (L.) rhamnosus LOCK0900, L. rhamnosus LOCK0908, and L. casei LOCK0919) 
on the integrity of the intestinal mucosa and allergic sensitization. The results showed that oral 
administration of a mixture of three strains of lactobacilli improved the intestinal epithelial barrier 
and reduced allergic sensitization in a model of gnotobiotic mice. These observations clearly 
indicate the positive effect of certain strains of lactobacilli on the process of allergic sensitization 
and even support their use for early prevention of allergies. 
 
Summary of clinical studies 
The beneficial effect of probiotic bacteria on human health is presumably based on three main 
mechanisms of action (Lebeer et al. 2008, Segers and Lebeer 2014). First, certain probiotic bacteria 
can displace or inhibit pathogens through direct action or influence on synanthropic 
microorganisms (Lebeer et al. 2008, Corr and Hill 2009). Second, some probiotic strains are able 
to strengthen the epithelial barrier by modulating signaling pathways, for example, mediated by 
nuclear factor-kB (NF-kB), Akt, and mitogen-activated protein kinase (MAPK), which result in 
mucus production induction (Mack et al. 2003) or strengthening close contacts (Rao et al. 2013). 
Third, most probiotic strains are also able to modulate the host's immune response, which is 
manifested by strain-specific local and systemic effects (Wells 2011). Most interactions between 
probiotic bacteria and intestinal epithelial and immune cells are presumably mediated by molecular 
structures known as microbial molecular patterns (MAMP), which can be recognized by specific 
image-identifying receptors (PRR), such as Toll-like receptors (TLR) (Abreu 2010). 
A strain can be recognized as probiotic if it meets a number of criteria (Dunne et al. 2001; Zuccotti 
et al. 2008):  
1. 
has a human origin; 
2. 
is non-pathogenic; 
3. 
is not destroyed during processing; 
4. 
is not destroyed with gastric juice and bile; 
5. 
is capable of adhesion to the intestinal epithelium; 
6. 
is capable of colonizing the gastrointestinal tract, even in a short time; 
7. 
produces antimicrobial substances; 
8. 
modulates the immune response; 


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9. 
affects metabolic processes in the human body (cholesterol assimilation, lactase activity, 
vitamin production). 
 
The Lactobacillus genus is represented by non-pathogenic rod-shaped LAB and consists of more 
than one hundred species. The November 2007 report of the European food safety authority (EFSA 
2007) lists 112 species, whereas according to Bernardeau et al. (2008), this genus includes about 
135 species and 27 subspecies. Bacteria of the Lactobacillus genus have heterogeneous 
phenotypic, biochemical and physiological characteristics; the extreme diversity of genomes of 
bacteria of the Lactobacillus genus is proposed to be used as a justification for the allocation of 
new subgenus divisions (Bernardeau et al. 2008). Lactobacilli are rod-shaped fixed non-spore-
forming microorganisms. Growth of lactobacilli is possible in an environment with a reduced 
oxygen content, provided that there is sufficient nutrient content. This genus includes both homo-
and heterofermentative bacteria. The first ones convert carbohydrates into lactic acid via the 
glycolytic pathway, and the second, with the participation of phosphoketolase, convert 
carbohydrates into lactic acid, acetic acid, ethyl alcohol and carbon dioxide. L. rhamnosus bacteria 
are optional heterofermenters of hexose (GRAS status notification # 288). 
The strain of L. rhamnosus GG (ATCC 53103) has acid and bile resistance, which is a mandatory 
characteristic of functionally probiotic strains (Pant et al. 1996). In addition, this strain shows a 
high affinity for the cells of the human intestinal mucosa and produces lactic acid. The GG strain 
of lactobacilli has been studied as a probiotic in mice and humans, and its probiotic properties 
determine its effectiveness in the treatment of various forms of gastrointestinal and respiratory 
disorders and diseases (Papizadeh et al. 2016). The Lactobacillus GG strain showed no 
invasiveness, despite a high degree of adhesion to human intestinal cells (Elo et al. 1991, English 
and Dean 2013). According to a safety study, the Lactobacillus GG strain slowed the development 
of dimethylhydrazine-induced colon tumors in rats fed a high-fat diet (Goldin et al. 1996).  
Since recently, it has been known that Lactobacillus, like L.cmei, is a synanthropic microorganism 
that colonizes the intestines, vagina, and distal ureters of a healthy person (Anukam et al. 2006; 
Voravuthikunchai et al. 2006). This type is often used for foodstuff preparation (for example, in 
the production of cheese, milk fermentation). Since Lactobacillus is found in the digestive tract of 
humans and mammals, it is obvious that the bacteria of this species enter the body during normal 
meals for a long period. As a result, it can be concluded that a person has swallowed bacteria of 
the species L.rhamnosus with food for a long time, which does not cause any visible undesirable 
effects. 


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The Lactobacillus rhamnosus GG strain has been used everywhere since 1990 as a component of 
food and dietary supplements (Salminen et al. 2002). The US food and drug administration (FDA) 
assigned the LGG strain the "generally recognized as safe" status (GRAS) (FDA notifications of 
GRAS status # 281 and 288) in Europe, and the European food safety administration (EFSA) 
assigned Lactobacillus rhamnosus the QPS status ("qualified presumption of safety") in 2007 at 
the species level (EFSA 2007).  
Based on the available data, the following significant aspects can be identified that justify the need 
and feasibility of studying the effectiveness and safety of Lactobacillus rhamnosus in relation to 
AAD (antibiotic-associated diarrhea):  
1. 
The increase in the prevalence of AAD in recent decades and the particular acuteness of 
the problem in the Russian Federation. 
2. 
The predominant use of a large number of beta-lactam antibiotics, which have a proven 
depressing effect on the intestinal microbiota. 
3. 
The risk of developing CdAD is one of the most severe manifestations of AAD. 
4. 
A well-founded therapeutic tactic for prescribing probiotics for the prevention and 
treatment of AAD, with proven efficacy and safety of Lactobacillus GG (ATCC 53103). 
Probiotics are living microorganisms that, when used in adequate quantities, are beneficial to the 
health of the host organism (report of the United Nations Food and Agriculture Organization 
(FAO)/World Health Organization (WHO), 2001). Therefore, to achieve a positive effect, they 
should be taken in fairly high doses. The proposed dose of Lactobacillus rhamnosus GG is within 
the range of doses that have been proven effective in well-planned and randomized controlled 
trials, and also corresponds to the doses recommended in the published guidelines of the world 
gastroenterological organization (WGO, 2017) and the European society of pediatric 
gastroenterologists, hepatologists and nutritionists (ESPGHAN, 2016).  
According to the recommendations of the World Gastroenterological Organization, given in the 
international guidelines on probiotics and prebiotics (WGO, 2017) considering dosage in the case 
of antibiotic-induced diarrhea, the recommended dose of Lactobacillus rhamnosus GG for children 
is 1–2 × 1010 CFU, and for adults −1010 CFU twice daily. The developed product contains at least 
1010 CFU of Lactobacillus rhamnosus GG per capsule. The recommended dosage is one or two 
capsules per day, depending on indications.  
The choice of this dosage is also consistent with the data obtained during the acute toxicity study 
by Donohue et al. (1993), in which it was shown that the acute oral LD50 for the LGG strain is 
6 g/kg/day, which corresponds to the maximum dose that can technically be administered to mice. 


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  Overview of biopharmaceutics 
Klu et al. (2012) studied the effect of storage conditions and the drug matrix on the survival of the 
L.rhamnosus GG strain. L. rhamnosus GG cells in an amount of 107CFU/g were inoculated on a 
layer of full- or reduced-fat peanut oil. Inoculated peanut oil was stored at 4, 25, and 37 °C for 
48 weeks. Samples were collected periodically to count populations of L.rhamnosus GG. The 
results indicated that there was no significant reduction in the number of viable L. rhamnosus GG 
cells in preparations stored at 4°C. The survival rate of L. rhamnosus GG decreased with increasing 
temperature and storage time. The drug matrix had no significant effect on the survival of 
L.rhamnosus GG, except for storage conditions at 37 °C. Populations of L. rhamnosus GG were 
maintained at > 6 log in preparations stored at 4 °C for 48 weeks and at 25 °C for 23-27 weeks. At 
a storage temperature of 37 °C, populations of 6 log size were not preserved even for 6 weeks.  
In a 6-month human study, Tannock et al. (2000) performed the repeated analysis of the 
concentration of viable L.rhamnosus HN001 cells in a lyophilized powder stored in a nitrogen 
atmosphere at room temperature. The powder contained 5.3 × 107 CFU at the beginning of the 
study and maintained this concentration after 6 months of storage; other bacteria other than 
lactobacilli were absent, and the viability of lactobacilli did not change for 6 months. In a study of 
the stability of the L. rhamnosus HN001 strain in infant formula stored at 30 °C, a decrease in 
bacterial viability was determined at a rate of 0.4 log per year. 
3.3.2 Overview of clinical and pharmacological research data 
3.3.2.1 Pharmacokinetic characteristics 
The pharmacokinetic characteristics of probiotics can be broadly divided into three main groups:  
- survival in the gastric environment; 
- ability to adhere to the intestinal wall (colonization); 
- metabolic pathway of active ingredients. 
The active ingredients of probiotics are not always well known, so most studies are aimed at 
assessing the survival of probiotics in the human gastrointestinal tract (Marteau and Vesa 1998).  
One of the main conditions for assigning a bacterial strain to probiotics is its ability to survive in 
the gastrointestinal tract. The role of probiotic strain survival for its effectiveness is not absolute, 
since even inactivated and dead cells exhibit immunological and health-promoting effects (Linares 
et al. 2017, Zhang et al. 2005). Despite this, viability is still considered a prerequisite for optimal 
functioning of the probiotic strain (Lahtinen 2012). 
Goldin et al. (1992) studied the Lactobacillus rhamnosus GG strain for survival in the human 
gastrointestinal tract. In this trial, 76 volunteers took the Lactobacillus GG strain as a frozen 


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concentrate or fermented preparation in milk or serum. The strain was isolated from feces of all 
volunteers who took fermented milk or serum, and 86% of volunteers who took the frozen 
concentrate, according to the results of inoculation on one sample of feces from the volunteer. The 
studied microorganism was also present in the feces of subjects taking ampicillin at the time of the 
study. After stopping the introduction of this microorganism with food, Lactobacillus GG was 
preserved in the feces of 87% of volunteers after four days and 33% of participants after seven 
days. Lactobacillus GG strain reduced the activity of fecal bacterial beta-glucuronidase by about 
80% in volunteers who received this strain with food for four weeks. This indicates that the 
Lactobacillus GG strain survives in the human gastrointestinal tract and temporarily colonizes it, 
as well as the fact that it affects the metabolic activity of resident microflora. 
Saxelin et al. (1995) studied discharge of the L.rhamnosus GG strain with feces after oral 
administration. Twenty healthy volunteers received the Lactobacillus GG strain as gelatin capsules 
for 7 days in daily doses of 1.6 × 108 CFU and 1.2 × 1010 CFU. All volunteers in the high-dose 
group had a distinguishable amount of Lactobacillus GG in their feces during the trial period. The 
studied strain was detected in the feces of all volunteers 3 days after administration. The effect on 
the total number of lactobacilli in the feces was not determined.  
Stool was sampled before L.rhamnosus GG administration and on days 3, 5 and 7. Fecal samples 
were immediately frozen and stored in the refrigerator at -45 °C. Samples were analyzed for the 
presence of Lactobacillus and Lactobacillus GG on cups with MRS agar at pH 6.2. The plates were 
incubated anaerobically for 3 days at 37 °C and the total number of Lactobacillus and typical 
Lactobacilus GG colonies was evaluated.  
Lactobacillus GG was detected in the feces of all 10 volunteers in the higher dose group (1.2 × 
1010 CFU) during the test period (table 2). A slight decrease in Lactobacillus GG was observed on 
the seventh day, but the change was not statistically significant. In the lower-dose group, 
Lactobacilus GG was registered in feces of only one volunteer at the end of the treatment period 
(table 2). The introduction of Lactobacillus GG did not appear to affect the total number of 
lactobacilli in the feces (see the table below). It is worth mentioning that none of the volunteers 
had typical Lactobacillus GG colonies or any morphologically similar colonies in the fecal samples 
prior to the test (day 0, table 2).  
The number of lactobacilli in stool samples (in CFU/g of feces) in healthy volunteers after oral 
administration of Lactobacillus GG for 7 days at doses of 1.6 × 108 CFU/day or 1.2 × 1010 
CFU/day. 
 


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Table 2. The number of Lactobacillus GG and the total number of lactobacilli in fecal samples of 
20 healthy volunteers received the Lactobacillus GG strain as gelatin capsules for 7 days in daily 
doses of 1.6 × 108 CFU and 1.2 × 1010 CFU. 
Dose 
The number of Lactobacillus GG and the total number of lactobacilli in stool 
samples 
CFU/ 
day 
Day 0 
Day 3 
Day 5 
Day 7 
Lb 
Lb 
GG 
Lb 
Lb GG 
Lb 
Lb GG 
Lb 
Lb GG 
1.6×108  
1.5×108  
ND 
1.7×107  
ND 
2.8×108  
ND 
8.0×107  103 
1.2×1010  9.2×107  
ND 
2.1×108  
2.0×106  2.5×108  
1.5×106  9.8×107  1.2×105  
Note: Lb – Lactobacili, ND – not detected. 
The study showed that orally administered Lactobacillus GG in gelatin capsules can be detected 
in the feces of healthy human volunteers when taken at higher doses (1.2 × 1010 CFU).  
Hibberd et al. (2014) conducted a study of a drug containing Lactobacillus rhamnosus GG in 
elderly healthy volunteers.  
Fifteen elderly volunteers aged 66-80 received Lactobacillus rhamnosus GG capsules containing 
1 × 1010 CFU twice a day for 28 days, and were monitored for 56 days. 
The main goal of this open-label clinical study was to evaluate the safety and tolerability of 1 × 
1010 CFU of Lactobacillus rhamnosus GG taken orally twice a day in elderly volunteers for 
28 days. The study also determined the concentration of Lactobacillus rhamnosus GG excreted in 
the feces by day 28 and 56 of the study. 
Lactobacillus rhamnosus GG was found in the feces of 11 out of 15 (73%) volunteers at the end 
of the treatment period (study day 28), although the number of colonies in the feces varied 
significantly from 1.4 × 103 to 1.3 × 108. None of the volunteers was found to have Lactobacillus 
rhamnosus GG in the feces at the beginning of the study or by day 56 of the study. 
No serious adverse events were reported in healthy volunteers during the study. A total of 
47 adverse events were reported in 15 volunteers (1 to 7 per volunteer), 39 (83%) of which were 
assessed as mild, and 40% were assessed as possibly related to the use of Lactobacillus 
rhamnosus GG. The most common adverse events were recorded from the gastrointestinal tract 
(bloating, gas, and nausea), 27 of which were assessed as mild adverse events, and 3 as moderate. 
In the first week of taking LGG, mild and passing gastrointestinal symptoms were recorded, which 
did not affect the daily activity of the volunteers. After the first week, most of the gastrointestinal 
symptoms appeared periodically during treatment and during the follow-up period with no 
identified Association with LGG. 


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All AEs registered in this study are described in detail in table 3. 
Table 3. AE description in healthy volunteers after taking Lactobacillus rhamnosus GG capsules 
containing 1 × 1010 CFU twice a day for 28 days 
Study day 
1−3 
4−7 
8−14 
15−28 
29−64 
All 
time 
Symptoms 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
N (%) 
Expected AE 
5 (11) 
4 (9) 
6 (13) 
7 (15) 
9 (19) 
31 (66) 
Gastrointestinal disorders 
Abdomen distention 
0 (0) 
1 (2) 
1 (2) 
0 (0) 
0 (0) 
2 (4) 
Flatus 
3 (6) 
1 (2) 
2 (4) 
2 (4) 
2 (4) 
10 (21) 
Borborygmus 
1 (2) 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (2) 
Diarrhea 
0 (0) 
0 (0) 
1 (2) 
1 (2) 
1 (2) 
3 (6) 
Abdominal spasms or pain 
0 (0) 
0 (0) 
0 (0) 
1 (2) 
0 (0) 
1 (2) 
Nausea 
1 (2) 
0 (0) 
2 (4) 
0 (0) 
2 (4) 
5 (11) 
Vomiting 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
2 (4) 
2 (4) 
Loss of appetite 
0 (0) 
0 (0) 
0 (0) 
1 (2) 
0 (0) 
1 (2) 
Epigastric burning  
0 (0) 
1 (2) 
0 (0) 
1 (2) 
1 (2) 
3 (6) 
Constipation 
0 (0) 
1 (2) 
0 (0) 
1 (2) 
0 (0) 
2 (4) 
Others 
Rash 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (2) 
1 (2) 
Unexpected AE 
0 (0) 
1 (2) 
1 (2) 
2 (4) 
2 (4) 
6 (13) 
Actinic keratosis 
0 (0) 
0 (0) 
0 (0) 
1 (2) 
0 (0) 
1 (2) 
Fever 
0 (0) 
0 (0) 
0 (0) 
0 (0) 
1 (2) 
1 (2) 
Headache 
0 (0) 
0 (0) 
1 (2) 
0 (0) 
0 (0) 
1 (2) 
Knee pain 
0 (0) 
1 (2) 
0 (0) 
0 (0) 
1 (2) 
2 (4) 
Kidney stones 
0 (0) 
0 (0) 
0 (0) 
1 (2) 
0 (0) 
1 (2) 
 
28 
56 
All 
time 
Unexpected AE (based on the results of physical examination or 
laboratory tests) 
7 (15) 
3 (6) 
10 (21) 
Vital signs 
High blood pressure 
0 (0) 
1 (2) 
1 (2) 
Low blood pressure 
1 (2) 
0 (0) 
1 (2) 


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Laboratory parameters 
Decrease in hemoglobin concentration 
2 (4) 
0 (0) 
2 (4) 
Increased white blood cell concentration 
0 (0) 
1 (2) 
1 (2) 
Increased blood urea nitrogen 
2 (4) 
1 (2) 
3 (6) 
Decrease in glucose concentration 
1 (2) 
0 (0) 
1 (2) 
Increase of glucose concentration 
1 (2) 
0 (0) 
1 (2) 
Ninety-four percent (116) of the symptoms were disappearing, lasted for a short time, and did not 
require additional therapy. The study showed that Lactobacillus rhamnosus GG is safe and well 
tolerated by healthy adult volunteers aged 65 and older. 
Pitino et al. (2010) studied six strains of Lactobacillus rhamnosus for their ability to survive in the 
upper parts of the human gastrointestinal tract. MRS broth was used as a carrier, and survival was 
evaluated in vitro by gastric digestion separately and in combination with duodenal digestion. The 
results indicated a high survival rate of all studied strains during both gastric and duodenal 
digestion. In particular, a very high survival rate was determined for three strains, which was 
evidenced by the degree of extraction in the range from 117 to 276 %. In accordance with the data 
on survival, a high level of lactic acid production was determined for all strains, which confirms 
the preservation of their metabolic activity during digestion. 
Jacobsen et al. (1999) conducted an in vitro study on 47 strains of lactobacilli and additionally 
studied 5 selected strains in vivo. Selected strains were studied for resistance to pH 2.5 and 0.3% 
bovine bile, adhesion to Caco-2 cells, and antimicrobial activity against pathogenic intestinal 
bacteria in model systems. For LGG, the high adhesion capacity was determined, as well as 
resistance to gastric acid and bile salts (simulated by a medium with a pH of 2.5 and 0.3 % bovine 
bile). Under these conditions, the bacteria survived, but lost the ability to replicate. LGG was one 
of the strains selected for in vivo testing. Twelve healthy volunteers took two doses daily of 1010 
lyophilized bacteria of the selected strains for 18 days, followed by a washout period of 17 days. 
Fecal samples were collected on days 0 and 18, as well as on days 5 and 11 of the washout period. 
Bacteria were re-isolated mainly during the administration period (day 18; 7 cases out of 12). On 
day 23, only 2 of 12 cases were re-isolated with the LGG strain. No bacteria were re-isolated on 
day 29. The LGG strain also inhibited a number of pathogenic bacteria and had minimal effect on 
the normal intestinal microflora.  
According to the results obtained in this study, the bacteria of the LGG strain survive during 
passage through the gastrointestinal tract and can be re-isolated during the introduction period. 
However, there was no long-term colonization of any of the studied bacterial strains. 


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Dommels at al. (2009) conducted a double-blind randomized placebo-controlled interventional 
clinical trial to assess the survival of Lactobacillus reuteri DSM 17938 and Lactobacillus 
rhamnosus GG strains in the human gastrointestinal tract after daily use of low-fat probiotic spread 
using traditional cultivation methods as well as molecular methods. Forty-two healthy volunteers 
were randomly assigned to one of three treatment groups in which they received 20 g of placebo 
spread (n = 13), 20 g of spread with L. reuteri DSM 17938 at a target dose of 109 CFU (n = 13), 
and 20 g of spread with L. rhamnosus GG at a target dose of 5 × 109 CFU (n = 16) daily for 
3 weeks. Fecal samples were collected before and after the intervention period. After three weeks 
of daily use of the spread containing the strain L. reuteri DSM 17938 or L. rhamnosus GG, a 
significant increase in the degree of recovery of viable probiotic lactobacilli in stool samples 
relative to the baseline level was determined according to selective counting. No such increase 
was observed in the placebo group. The results obtained indicate the ability of the LGG strain to 
survive in the human gastrointestinal tract. The number of viable bacteria of the L. rhamnosus GG 
strain in fecal samples was at the level of 6.6 log10 CFU/g after 3 weeks of using the L. rhamnosus 
GG spread, which contained, on average, from 3.3 × 1010 to 5.6 × 1010 CFU of L. rhamnosus GG 
per 20 g of spread. These numbers are comparable to the results of the evaluation of the extraction 
degree of L. rhamnosus GG bacteria from feces after taking them with different foods, which were 
published earlier. 
Saxelin et al. (1993) studied the concentration of Lactobacillus GG bacteria in human feces after 
the oral administration. In this study, 44 healthy volunteers received Lactobacillus GG bacteria for 
7 days in the form of enteric-coated tablets at a daily dose of 1 × 109, 4 × 109, and 8 × 109 CFU, 
as well as fermented milk at a daily dose of 2 × 109 and 1.2 × 1010 CFU. All volunteers were 
observed for the excretion of the studied strain with feces on the 3rd day of the test period. The 
average content of LGG bacteria in feces did not significantly differ between the groups receiving 
tablets. When using fermented milk, there was a clear statistically significant increase in the 
average content of Lactobacillus GG bacteria in the feces after taking a dose of 1.2 × 1010 CFU/day 
compared to a dose of 2 × 109 CFU/day. According to the results obtained, fermented milk and 
tablets with an enteric coating are effective carriers for the Lactobacillus GG bacteria strain used 
as a probiotic. 
Alander et al. (1999) studied colon biopsies to demonstrate the adhesion of lactobacilli of the GG 
strain to the human intestinal mucosa and the persistence of this connection after discontinuation 
of this probiotic. In this study, volunteers took 100 ml of a commercial drink based on whey with 
hydrolyzed lactose fermented with the GG strain twice a day for 12 days. The daily dose of GG 
strain bacteria was about 6 × 1010 CFU. After taking the GG strain bacteria, the volunteers were 


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divided into three groups: those who underwent a colonoscopy immediately after the 12-day intake 
period, 1 week after stopping taking it, and 2 weeks after stopping taking the probiotic, 
respectively. Patients collected stool samples, which were first stored in home freezers at -20 °C 
(for up to 3 weeks), and then in the laboratory at -20 °C before analysis. Biopsies of the descending 
colon were immediately placed in a thioglycolate medium and stored at 4 °C until analysis was 
performed (within one day). Confirmatory PCR analysis was also performed on L. rhamnosus 
isolates.  
There was a high level of matching (88%) between the results of the PCR analysis and the 
screening analysis based on the assessment of colony morphology and the lactose fermentation 
test, which confirms the overall reliability of strain identification. The number of colonies of the 
GG strain decreased as a function of time after stopping the probiotic to be taken.  
GG strain bacteria were found in biopsies and last stool samples of all volunteers in group A. In 
group B, colonies of the strain L. rhamnosus GG were found in seven of the eight biopsies. 
However, only two of the eight subjects had colonies of the GG strain at a discernible level in the 
last fecal samples. None of the seven subjects from group C had colonies of the GG strain in the 
last fecal samples. However, colonies of the GG strain were found in the biopsies of two of the 
seven volunteers. According to the results obtained, the bacteria of the strain L.rhamnosus GG are 
capable of adhesion to the colon mucosa in vivo, where they remain for a long period of time after 
stopping taking the GG strain bacteria. 
Saxelin et al. (1991) conducted a dose-response study to determine fecal colonization by bacteria 
of the LGG strain. Forty healthy adult volunteers took LGG strain bacteria in the form of 
lyophilized powder once a day for 7 days in doses 1,5 × 106, 1,5 × 107, 1,5 × 108, 1,5 × 109, 1,5 × 
1010 and 1.1 × 1011 CFU/day. Fecal samples collected on day 0 and on each day of the treatment 
period were analyzed for the total number of lactobacilli and LGG strain bacteria. Bacteria of the 
LGG strain were not detected in fecal samples before the probiotic period and were absent in the 
fecal samples of subjects from groups with dosages of 106–108 during the probiotic period. Two 
of seven subjects from the group with a dosage of 109 during the tests was periodically observed 
the colonization of feces with bacteria of LGG strain on distinguishable level, and all subjects of 
the groups with doses of 1010 and 1011 were observed colonization of stool with these bacteria at 
the level of 105–107 CFU/g. There was no influence of level of intake of the bacterial strain LGG 
on the total number of lactobacilli, as well as the dominance of strain LGG in the feces. No adverse 
effects were observed. 


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3.3.2.2  Pharmacokinetics in special groups 
Millar et al. (1999) studied the ability of a probiotic strain of Lactobacillus GG to colonize the 
immature intestines of premature infants and, if found, the possibility of reducing the size of the 
intestinal reservoir of nosocomial pathogens, such as enterobacteria, enterococci, yeast fungi or 
staphylococci, as well as the effect of colonization by bacteria of the Lactobacillus GG strain on 
clinical progress and outcome. Twenty premature babies at gestational age of no more than 
33 weeks, who had been in the neonatal unit for a long time, were monitored from the beginning 
of feeding with milk until discharge. Infants were randomized to groups of feeding with simple 
infant formula or with the addition of bacteria of strain Lactobacillus GG at a dose of 108 colony-
forming units twice a day for two weeks. The clinical characteristics of infants from the two groups 
were similar. The orally administered strain of Lactobacillus GG was well tolerated and did not 
colonize the intestines of premature babies. However, colonization by bacteria of the Lactobacillus 
GG strain did not reduce the fecal reservoir of potential pathogens, and there was no evidence of 
a positive clinical effect of colonization in this group of infants. 
Ling et al. (1992) evaluated the use of a whey beverage fermented with bacteria of LGG strain by 
elderly people from nursing homes, 
which noted difficulties with defecation for 2 weeks, which included a 2-week introduction period 
and a 2-week washout period. All participants had distinguishable levels of bacteria of LGG strain 
in fecal samples and significantly reduced levels of glycochol, hydrolase, and tryptic activity. A 
slight normalization 
of stool consistency was determined, but there was no effect on the frequency, mass, and pH of 
the stool. According to the authors, bacteria of the LGG strain can change the metabolism of 
bacteria, but do not have a significant effect on intestinal function. 
In a study evaluating the possible induction of colonization of the intestines of their infants against 
the background of intake of LGG strain bacteria by pregnant women (Schultz et al. 2004) 6 women 
were identified who took 2 × 109 CFU LGG/day in weeks 30-36 of pregnancy. Four pregnancies 
ended in vaginal delivery, and two in cesarean section. In all four children born by vaginal delivery, 
and one of the two children born by caesarean section, the LGG strain bacteria (according to DNA 
sequencing analysis) were isolated from the feces at the age of 1 and 6 months. Bacteria of the 
LGG strain were isolated in the feces of 3 children aged 12 months and 2 children aged 24 months. 
At the age of 36 months, the LGG strain of bacteria was not detected in the feces of children. 
According to the authors, temporary colonization of the intestines of infants with LGG bacteria is 
possible by colonizing the intestines of a pregnant woman before delivery. 


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3.3.2.3 Pharmacodynamics 
Siitonen et al. (1990) studied the effectiveness of introducing LGG strain bacteria into yogurt to 
reduce erythromycin-associated diarrhea in 16 healthy adult men. Participants took 400 mg of 
erythromycin acistrate 3 times a day for 7 days; half of them consumed 125 ml of regular yogurt 
twice a day (control group), and the test group received yogurt with LGG. Subjects who received 
yogurt with addition of LGG, had significantly less pronounced diarrhea, abdominal discomfort, 
stomach pain, and flatulence compared to those who consumed regular yogurt. Despite the fact 
that the total number of lactobacilli in the feces remained unchanged in the test and control groups, 
colonies with morphological characteristics of LGG were found in the feces of subjects from the 
LGG group and were absent in the feces of subjects from the control group. The authors did not 
report any adverse effects (GRAS status notification # 288). 
Fang et al. (2000) randomly assigned 30 healthy adults (15 of each sex, aged 20-50 years) to three 
groups: a group of oral administration of lyophilized LGG at a dose of 4 × 1010 CFU/day, B.lactis 
at a dose of 3.4 × 1011 CFU/day, or a placebo for 7 days. They took an oral vaccine based on a 
weakened strain of Salmonella typhimurium TY21A in capsule form on days 1, 3, and 5. On days 
-1 and +14, blood samples were taken and analyzed for immunoglobulin-secreting cells and cells 
that secrete antibodies to S.typhimurium. 
Significant differences in the amount of IgA, IgG, or IgM - secreting cells between groups 
were not detected. The authors did not report any adverse effects (GRAS status notification # 288). 
Reid et al. (2001) conducted a study of bacterial vaginosis. Forty-two healthy women were 
randomized to groups of oral intake of a combination of L.rhamnosus GR-1 and L.reuteri RC-14 
bacteria at a dose of up to 6 × 109 CFU/day, or only LGG bacteria at a dose of 1010 CFU/day for 
28 days. The data obtained was difficult to interpret, but it was clear that the combination of 
probiotic strains had a generally favorable effect on the vaginal microflora population. None of 
the patients had clinically expressed vaginitis or urinary tract infections, or any adverse side effects 
during or after the study. Discharge of all tested strains of bacteria with feces was stopped on the 
14th day after stopping taking the Supplement. 
Reid et al. (2003a) conducted a double-blind placebo-controlled trial to study the effect of oral 
probiotic administration on the vaginal microflora during and after antibiotic therapy. Twenty-four 
women diagnosed with respiratory or oral infections who received antibiotic therapy were 
randomly assigned to a placebo or a combination of L.rhamnosus GR-1 and L.reuteri RC-14 
bacteria at a dose of 2 × 109 CFU/day for 21 days starting from the first day of taking antibiotics. 


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Cases of vaginitis or diarrhea were absent in the probiotic group and were observed in 3 women 
from the placebo group. This difference was not statistically significant. No adverse effects of 
probiotic therapy were registered. 
The effect of taking probiotics on women with asymptomatic bacterial vaginitis was further 
studied by Reid et al. (2003b) in a randomized placebo-controlled trial in which 64 women aged 
35 on average received a placebo or a combination of probiotic strains of L.reuteri RC-14 and 
L.rhamnosus at a dose of 2 × 109 CFU/day for 60 days. Evaluation of vaginal smears on days 0, 7, 
28, 60 and 90 showed an improvement in the populations of lactobacilli in the vaginal microflora 
and a decrease in the content of pathogenic bacteria and yeast fungi. No adverse effects of probiotic 
therapy were registered. 
Elmadfa et al. in 2001, conducted a cross-sectional study with 12 healthy adults (6 men and 
6 women aged 25-36 years) who applied 500 g of yogurt per day, which corresponds to a dose of 
LGG 2.5 × 1010 CFU/day, for 4 weeks. The studied yogurt also contained strains of Streptococcus 
thermophilus and Lactobacillus acidophilus. In the first two weeks, yogurt cultures underwent 
thermal inactivation. Urine samples were collected daily, and blood samples were collected on 
days 1, 15, and 29; urine and blood samples were analyzed for group B vitamins content.  
There was a significant and continuous decrease in the level of vitamin B1 in blood plasma during 
the study, as well as a slight but relevant decrease in this vitamin in the urine. These changes were 
associated with a 25% decrease in the bioavailable vitamin B1 in the subjects' diet. The content of 
vitamins B2 and B6 in blood plasma and urine changed slightly throughout the study, namely, 
most of these values decreased, but did not go beyond the normal ranges. According to the authors' 
conclusion, the bacterial flora of the studied yogurt did not affect the content of vitamins B1, B2 
and B6 in the human body. No adverse effects were reported. 
Schultz et al. (2003) conducted a study of the immunomodulatory effects of LGG. Ten healthy 
adults (6 men and 4 women) aged 21 to 43 (average age 29.9) took a single dose of lyophilized 
LGG strain 2 × 109 CFU in capsules daily for 35 days. Stool samples were collected 3 weeks 
before the start of the study, the day before the first dose, and the day after the last dose. Blood 
samples were also collected during the last two designated periods. As part of this study, the 
reaction of peripheral blood cells to "own" and "allogenic" fecal samples was evaluated, the 
content of microorganisms of the Bacteroides fragilis, Escherichia coli group, pro- and anti-
inflammatory cytokines (IL-10, IL-4, IL-6, IFN-γ, TNF-α) in the culture's supravascular fluid was 
measured, as well as the activation of CD4 T-lymphocytes. 


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Lactobacilli not distinguishable from LGG were isolated from the feces of all subjects at the end 
of the administration period. Three subjects had mild bloating, but no other adverse effects. There 
was a slight modulation of the cellular immune response, which was manifested mainly by an 
increase in CD4 T-lymphocyte activity and a decrease in the secretion of cytokines such as TNF-
α and IL-6. 
Di Caro et al. (2005) studied the effects of the L.rhamnosus GG (LGG) strain on the gene 
expression profile on the small intestine mucosa. Six men (average age is 38) with endoscopically 
confirmed esophagitis received esomeprazole with placebo or LGG at a dose of 1.2 × 1010 
CFU/day in the form of lyophilized powder in sachets twice a day for 1 month. During endoscopic 
procedures, biopsies of the distal duodenal mucosa were taken before and after the treatment. The 
extraction of all DNA and RNA was performed and the expression of more than 22,000 genes was 
studied. In the LGG strain group, but not in the placebo group, there was an upregulation of 
316 genes and a downregulation of 78 genes. Genes that mediate the immune response and 
inflammation (for example, TGF-b, members of the TNF family, cytokines, nitric oxide synthase), 
apoptosis, cell growth and differentiation (for example, cyclins and caspases, oncogenes), 
intercellular signaling, cell adhesion, signal transcription and transduction were most affected. The 
authors did not report any adverse effects associated with taking LGG. 
To study the effects of three probiotics on immune response indicators, Kekkonen et al. (2008) 
conducted a prospective double-blind randomized placebo-controlled intervention study in parallel 
groups involving 62 healthy adults (17 men and 45 women aged 23-58; average age was 44 ). 
After a three-week introduction period, subjects were randomly assigned to 1 of 4 groups for the 
indicated intervention (in the form of a fruit milk drink) for 3 weeks: placebo (n = 16), LGG at a 
dose of 1.6 × 1010 CFU/day (n = 13), Bifidobacterium animalis ssp. lactis Bb12 at a dose of 3.5 × 
1010 CFU/day (n = 16) or Propionibacterium freudenreichii ssp. shermanii JS at a dose of 3.3 × 
1010 CFU/day (n = 17). Initially, on days 1, 7, and 21, as well as after a 3-week washout period, 
venous blood samples were taken for analysis for leukocytes, monocytes, neutrophils, basophils, 
eosinophils, lymphocytes, IgA, IgG, IgM, C-reactive protein, and cytokines (TNF - α, IL-6, IFN-γ, 
and IL-10).  At each designated evaluation period, an unstimulated saliva sample was collected 
for analysis for secretory IgA. Initially and on day 21, the fecal samples were collected to identify 
and count probiotic strains. Participants kept a diary in which they recorded symptoms from the 
respiratory system, gastrointestinal tract, other symptoms, and medication. The content of 
probiotic strains studied in feces significantly increased relative to the initial values in all groups 
of probiotic therapy. The use of the LGG strain, but not other probiotic strains, resulted in a 
significant decrease in the level of C-reactive protein. The content of white blood cells, 


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immunoglobulins, and cytokines did not differ significantly between the groups. No adverse 
effects were reported. 
3.3.2.4 General conclusions on clinical pharmacology 
The results of clinical and pharmacological studies support preclinical observations. Thus, the 
Lactobacillus GG strain was shown to survive in the human gastrointestinal tract and temporarily 
colonize it, as well as affect the metabolic activity of resident microflora. This strain was detected 
in the feces of volunteers after three days of administration and did not affect the total number of 
lactobacilli in the feces. Various studies have demonstrated high survival and, which is more 
important, maintenance of metabolic activity. There was no long-term colonization of any of the 
studied bacterial strains.  
Increasingly, the results obtained also confirmed that the bacteria of the strain L.rhamnosus GG 
are capable of adhesion to the colon mucosa in vivo, where they remain for a long period of time 
after stopping taking the GG strain bacteria. The results of pharmacodynamic studies in healthy 
subjects showed that the L.rhamnosus GG strain is able to regulate the host's immune response 
through a variety of microorganisms, which confirms preclinical observations. Through this 
immunomodulatory effect, probiotics can influence the course of various diseases, which was 
further demonstrated in clinical studies of efficacy and safety (see section 3.3). No adverse effects 
were observed in any of the presented studies. Thus, the ability of the L.rhamnosus strain to survive 
in the gastrointestinal tract and to adhere to the intestinal mucosa has been demonstrated, which is 
one of the main aspects of the pharmacokinetics of probiotic strains. It has also been shown that 
the pharmacodynamic properties of probiotics identified in in vitro and in vivo studies can be 
reflected in favorable clinical effects, especially in gastrointestinal and immune diseases.  
3.3.3. Review of efficiency data in children and adults 
3.3.3.1 Treatment of acute diarrhea in adults 
Allen et al. (2010) conducted a systematic review of clinical trials to study the effects of probiotic 
strains in confirmed or suspected acute infectious diarrhea. The review included 63 studies 
conducted from 1961 to 2010, involving a total of 8,014 participants. 56 studies of these were 
conducted with infants and younger children. The selected studies differed in the definition of 
acute diarrhoea used and the completion of diarrhoeal disorder, as well as the risk of systematic 
error. These studies were conducted under different conditions and varied significantly as to the 
microorganisms studied, the doses used, and the characteristics of the participants. 


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No adverse events of probiotic therapy were registered. Probiotics reduced the duration of diarrhea, 
although the magnitude of this effect varied significantly between studies. Significant average 
effects were determined for the average duration of diarrhea (average difference of 24.76 h; 95% 
confidence interval from 15.9 to 33.6 h; n = 4555, 35 studies), diarrhoeal episodes lasting more 
than 4 days (risk ratio of 0.41; CI: 0.32 to 0.53; n = 2853; 29 studies), and stool frequency on day 
2 (average difference of 0.80; CI: 0.45 to 1.44; n = 2751; 20 studies). The difference in the effects 
size between studies was not related to the quality of studies, the probiotic strains studied, the 
number of different strains, microbial vitality, microbial doses, the causes of diarrhea, the severity 
of diarrhea or the country of study (developed or developing country). According to the authors' 
conclusion, probiotics used on the background of rehydration therapy are safe and have clear 
beneficial effects, which is manifested in the reduction of diarrhea duration and stool frequency in 
case of acute infectious diarrhea. 
Sazawal et. al. (2006) analyzed available data from medical publications and concluded that this 
data was sufficient to confirm the role of probiotics in the prevention of acute diarrhea. Positive 
effects of probiotics have also been observed in adults, however to a lesser extent than in children. 
The most pronounced effect was observed for antibiotic-associated diarrhea, but also for diarrhea 
not associated with antibiotics and travel.  
Gross et. al. (2010) conducted an open randomized controlled trial in parallel groups involving 
174 patients with acute diarrhea who were treated in primary health care facilities. The two groups 
studied initially had homogeneous distribution of prognostic variables. The average duration of 
diarrhea since the start of treatment was 4.24 days (CO 2.73) in the Flortec drug group (L. 
paracasei B-21060) and 5.09 days (CO 3.72) in the FlorVis drug group (L. rhamnosus GG) 
(P = 0.09). Clinical efficacy rates expressed by absence of abdominal pain and diarrhea (less than 
two defecations by watery or loose stool), which were recorded at different times, were statistically 
significantly higher in the Flortec group (P = 0.05 for Kaplan-Meier assessment for both 
symptoms). According to the medical report, the overall effectiveness was high or very high in 
91.8% of Flortec patients. In FlorVis group, the corresponding figure was 83.7% (P = 0.003). In 
the two groups studied, a very good tolerance profile was demonstrated, based on a low and similar 
frequency of adverse events and a similar frequency of consumption of concomitant drugs.  
Bennet et. al. (1996) evaluated the effectiveness of the L. rhamnosus GG strain in treating C. 
difficile-induced acute diarrhoea in adults. Thirty-two patients with recurrent C. difficile-induced 
diarrhea received the Lactobacillus GG bacteria in the form of lyophilized powder; of these, 23 
were outpatients from Boston, Massachusetts, and 9 were residents of a nursing home in Baltimore, 
Maryland state. All subjects who took the Lactobacillus GG strain had a symptomatic 


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improvement after administration. Twenty-seven (84%) patients have registered a recovery after 
one course of therapy according to the data of the observation period of at least 2 months. Five 
patients had a relapse within 10 days of the first course of Lactobacillus GG therapy; of these, 
three were re-treated and cured and two were dropped out of observation and placed in the group 
of ineffective therapy. The authors conclude that the use of probiotic strain Lactobacillus GG is a 
safe and sufficiently effective alternative to antibiotic therapy for recurrent diarrhea caused by C. 
difficile. 
3.3.3.2  Antibiotic-associated diarrhea: data on prevention and treatment in adults and 
children 
Doses of Lactobacillus rhamnosus GG used in therapy of antibiotic-associated diarrhea 
During the study of the efficacy and safety of Lactobacillus rhamnosus GG in the treatment of 
antibiotic-associated diarrhea, several meta-analyses were carried out, all of which indicated a 
significant effect in the use of Lactobacillus rhamnosus drugs. Children and infants were more 
likely to have significant effects, but positive effects were also observed in adults. Information on 
the doses of Lactobacillus rhamnosus GG used in clinical trials in patients with antibiotic-
associated diarrhea is given in Table 4 below. 
Table 4. Information on the doses of Lactobacillus rhamnosus GG used in clinical trials in patients 
with antibiotic-associated diarrhea 
Reference 
Study Population 
Duration of study 
Applied dose 
Szajewska, 
2015 
Adults and children, 
meta-analysis of 12 
randomized controlled 
trials (RCTs) 
From 
10 days 
to 
3- months 
Doses in the range from 4 x 108 to 
12 x 1010 CFU 
Hempel, 
2012 
Adults (including the 
elderly people) and 
children, meta-analysis 
82 RCTs 
Different 
Different doses. 
Dose data used in the studies are 
not included in the meta-analysis. 
McFarland, 
2006 
Adults and children, 
meta-analysis of 25 
RCTs 
Different 
Different doses range from 1 × 107 
to 1 × 1011 CFU, with the mean 
value of 3 × 109 CFU. The use of 
high-dose probiotic (≥1010/day) has 
been associated with significant 


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Reference 
Study Population 
Duration of study 
Applied dose 
efficacy in curing of antibiotics-
induced diarrhea. 
Vanderhoof, 
1999 
Children aged from 6 
months to 10 years 
receiving antibiotics 
Equivalent duration of 
antibiotic therapy 
LGG 1 x 1010 - 2 x 1010 CFU per 
day 
Arvola, 1999 Children aged from 
2- weeks to 12.8 years 
receiving antibiotics 
Equivalent duration of 
antibiotic therapy 
LGG 2 x 1010 CFU 
Johnston, 
2006 
Children aged from 
2- weeks to 15 years, 
meta-analysis 
of 
6 clinical trials 
7-14 days 
Johnston et. al. analyzed the 
subgroups based on the applied 
dose of probiotic. Primary results 
were compared for daily doses of 5 
× 109 CFU and higher with results 
for lower doses. In 4- studies in 
which children received 5.5-40 × 
109 bacteria or yeast cells per day, 
evidence of the prophylactic effects 
of probiotics (RR = 0.36, 95% CI: 
0.25-0.53) was obtained, while in 
one study in which significantly 
lower daily dose of probiotic 
bacteria (2 × 109) is used, the effect 
was negligible. 
Goldenberg, 
2015 
Children, 
systematic 
review of 23 studies 
Different 
Goldenberg 
et. 
al 
in 
their 
systematic 
review 
analyzed 
subgroups based on the applied 
dose of probiotic. It is reported that 
when administered in doses greater 
than 5 x 109 CFU RR (random 
effects model) is 0.37 (95% CI): 
0.27-0.51), while at lower doses 
(less than 5 x 109 CFU) RR is 0.62 
(95% CI: 0.41-0.92). In both cases 
the level of statistical significance 
was achieved, but the probiotic had 


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Reference 
Study Population 
Duration of study 
Applied dose 
a significantly better effect when 
used in higher doses. 
A large number of studies have been conducted on the role of probiotics in the prevention and 
treatment of antibiotic-associated diarrhoea. Due to the large volume of publications, this section 
presents basic meta-analyses, systematic reviews and guidelines.  
Szajewska and Kolodziej (2015) conducted a meta-analysis of 12 RCTs to assess the impact of the 
L. rhamnosus GG strain on antibiotic-associated diarrhea performed between 1998 and 2008. 
According to the results of the review, treatment with LGG strain reduced the risk of AAD in 
patients treated with antibiotics from 22.4% to 12.3% compared to placebo or no additional therapy 
(11 RCTs, n = 1308, relative risk (RR) 0.49, 95% confidence interval (CI) 0.29-0.83, low number 
of sick days). However, when children and adults were evaluated separately, the difference was 
significant only in children (5 RCTs; n = 445; RR: 0.48; 95% CI: 0.26-0.89, moderate number of 
sick days). In adults the difference was insignificant (6 RCTs; n = 863; OR: 0.48; 95% CI: 0.20-
1.15; low CHD), except for a subgroup of patients receiving antibiotics as part of the Helicobacter 
pylori eradication therapy (4 RCTs; n = 280; RR: 0.26; 95% CI: 0.11-0.59; low number of sick 
days). 
Hempel et. al. (2012) performed a meta-analysis of 82 RCTs. Most of these studies used only 
lactobacillus or lactobacterial interventions in combination with bacteria from other genera; the 
strains studied were not documented in detail. The value of the combined relative risk in the meta-
analysis of random effects by the DerSimonian and Laird model for 63 RCTs, including 11,811 
participants, indicated a statistically significant connection between taking probiotic and reducing 
the severity of AAD (relative risk 0.58; 95% of MDIs): 0.50-0.68; P = 0.001; I2, 54% [risk 
difference -0.07; 95% CI: -0.10 to -0.05] [number of patients requiring treatment - 13; 95% CI: 
10.3-19.1]) in studies that recorded the number of patients with AAD.  
The main observation from this review is that the use of probiotics as an adjunctive therapy reduces 
the risk of AAD (RR: 0,58). This result was comparable for several subgroups and sensitivity 
analyses. The therapeutic effect corresponds to the value of NNT = 13. The main limitations of 
the result obtained include unexplained residual heterogeneity, inadequate documentation of 
probiotic strains and failure to assess probiotic specific adverse events. 
McFarland (2006) compared the efficacy of probiotics in the prevention of antibiotic-associated 
diarrhoea (AAD) and the treatment of diarrhea induced by Clostridium difficile (CSD), according 
to published randomized controlled clinical trials by meta-analysis. In 25 randomized controlled 


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trials (RCTs) against the background of taking probiotics a significant decrease in relative risk of 
AAD was determined (RR = 0.43; 95% CI: 0.31-0.58; p < 0.001). In 6 randomized studies, the 
significant efficacy of probiotics for CsD was found (RR = 0.59; 95% CI: 0.41-0.85; p = 0.005). 
It has been observed that three types of probiotics (Saccharomyces boulardii, Lactobacillus 
rhamnosus GG and probiotic mixtures) significantly reduced the risk of antibiotic-associated 
diarrhea. Based on stratified data for L. rhamnosus GG strain, the value of the combined RR = 0.31 
(p = 0.006) for 6 RCTs was determined. Only the S. boulardii strain was effective in CsD. 
Vanderhoof et. al. (1999) studied the effectiveness of Lactobacillus rhamnosus (Lactobacillus GG; 
LGGG) strain in reducing the incidence of antibiotic-associated diarrhea when used in 
combination with oral antibiotics in children with acute infectious diseases. The study enrolled 
202 children aged 6 months to 10 years, of whom 188 completed all phases of the protocol. In a 
double blind randomized trial, children receiving oral antibacterial therapy in outpatient settings 
were injected with LGG at a dose of 1 × 1010 to 2 × 1010 colony-forming units per day or a 
comparable placebo. Principal caregivers were asked questions every three days about the 
frequency of gastrointestinal symptoms, mainly the frequency and consistency of stool, during a 
telephone conversation with researchers who did not have access to patient data. Diarrhoea, which 
was defined as loose stool 2 or more times per day, was maintained in 25 placebo group subjects 
and only 7 subjects in the LGG group. Compared to the placebo group, the Lactobacillus GG 
bacteria as a whole reliably reduced the stool frequency and improved its consistency against the 
background of antibacterial therapy on day 10.  
Arvola et. al. (1999) studied the role of the L. rhamnosus GG strain in preventing diarrhea in 
children who were prescribed antibiotics for acute respiratory infections. Patients were randomly 
identified as groups of placebo or Lactobacillus GG in a dose of 2 × 1010 CFU in capsules 2 
times/day during antibiotic treatment. Diarrhoea was established when there was a watery or loose 
stool with a frequency of at least three times a day for at least two consecutive days. In case of 
diarrhea, feces were tested for viral (adenovirus, rotavirus, calcivirus and astrovirus) and bacterial 
(Salmonella, Shigella, Yersinia, Campylobacter, Clostridium difficile, Staphylococcus aureus and 
yeast) etiology. Metabolic activity of intestinal microflora by analyzing faecal urease, β-
glucosidase and β-glucuronidase was studied. The main indicator of outcome was diarrhea in the 
first 2 weeks after the beginning of antibiotic therapy, as this period is most likely to characterize 
the effects of antibiotics. The activity of faecal urease, β-glucosidase and β-glucuronidase were 
considered as secondary endpoints of the study. 
Within the observation period 80% of all gastrointestinal symptoms were observed in the first 
2 weeks after the start of antibiotic therapy. The incidence of diarrhea during the two-week period 


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of antibiotic therapy was 5% in the Lactobacillus GG strain group and 16% (x2 5 3.82).  The 
authors have concluded that Lactobacillus GG strain is effective in preventing diarrhea in children 
receiving antibacterial therapy for respiratory infections. 
Szajevska et. al. (2016) published clinical guidelines developed by the European Society for 
Pediatric Gastroenterology, Hepatology and Nutrition's (EU) Working Group (WG) on Probiotics 
concerning the use of probiotics to prevent antibiotic-associated diarrhoea (AAD) in children, 
based on a systematic review of previously performed systematic reviews and randomised 
controlled trials published after these reviews. The following recommendations are given for the 
L. rhamnosus GG strain: If the use of probiotics to prevent AAD in children is considered, the 
working group recommends the use of L. rhamnosus GG. This recommendation has an average 
quality of evidence, although the credibility of the recommendation is considered to be high. 
Johnston et al. (2006) carried out a review to assess the effectiveness of probiotics (any identified 
strain or dose) in preventing antibiotic-associated diarrhoea in children and adverse events 
associated with the use of probiotics against the background of antibiotic therapy in children. Six 
studies were included in this review (total n = 707 patients). The summary results, analyzed in the 
population of patients who fulfilled the requirements of the protocol with the registration of the 
incidence of diarrhea during antibiotic therapy, indicated a significant benefit of using probiotics 
in comparison with placebo (relative risk [RR] = 0.43, 95% confidence interval [CI] 0.25-0.75, I2 
= 70.1%). In contrast, the results of the analysis in the population according to the prescribed 
treatment were generally insignificant (RR: 1.01; 95% CI: 0.64-1.61). In subgroup analysis for 
4 studies in which probiotic doses of at least 5 billion single-stage colony-forming units (CFU) 
were applied daily (range 5.5-40 × 109 Lactobacillus GG, L. or Saccharomyces boulardii), 
convincing evidence with narrow CI for the preventive effects of probiotics on antibiotic-
associated diarrhea has been obtained (RR: 0.36; 95% CI: 0.25-0.53; I2 = 3.5%). There were no 
serious adverse events reported. According to the authors' conclusion, regardless of the 
unsuccessful analysis in the ITT population, promising results have been obtained for 
Lactobacillus GG, L. sporogenes and S. boulardii strains, which should be further studied.  
Doron et al. (2008) conducted five meta-analyses of studies on the role of probiotics in AAD 
prevention. The results indicated an overall reduction in the risk of AAD when administered 
simultaneously with antibiotics. Moreover, McFarland (2006) performed the largest meta-analysis 
to date on 25 randomized controlled trials of the role of probiotics in AAD prevention, involving 
2,810 participants. The effectiveness of the probiotic strain under study has been demonstrated in 
more than half of the studies. In particular, the efficiency of Lactobacillus GG, Saccharomyces 
boulardii strains and probiotic mixtures was determined.  


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Goldenberger et al. (2015) published a systematic review and meta-analysis of RCTs to assess the 
use of probiotics to prevent antibiotic-associated diarrhoea in children. 23 studies 
(3938 participants) met the inclusion criteria. In these studies the use of Bacillus spp., 
Bifidobacterium spp., Clostridium butyricum, Lactobacillus spp., Lactococcus spp., Leuconostoc 
cremoris, Saccharomyces spp. or Streptococcus spp. has been investigated individually or in 
combination. In eleven studies used a single strain probiotic has been used, in four studies a 
combination of two probiotic strains has been used, in three studies a combination of three 
probiotic strains has been used, in one study a combination of four probiotic strains has been used, 
in two studies a combination of seven probiotic strains has been used, in one study a combination 
of ten probiotic strains has been used, and the last study included two groups of probiotic therapy 
based on three and two strains respectively. The risk of systematic error was high or uncertain in 
13 studies and low in 10 studies. Available case data (patients who did not complete their studies 
were not included in the analysis) for 22 of the 23 studies that recorded the incidence of diarrhea 
indicates a clear benefit of probiotics versus active control, placebo and untreated control. AAD 
occurrence rate was 8% in the group of probiotic therapy (163 from 1992) and 19% (364 from 
1906) in the control group (RR: 0,46; 95% CI: 0,35-0,61; I2 55%; 3898 participants). The GRADE 
analysis indicated an average level of overall quality of evidence for this outcome. The revealed 
benefit remained statistically significant in the sensitivity analysis of extreme plausible variants 
(diarrhea in 60% and 20% of children who dropped out of observation in the probiotic therapy 
group and the control group, respectively), namely, the frequency of AAD was 14% in the 
probiotic therapy group (330 out of 2294) and 19% in the control group (426 out of 2235) (RR): 
0.69; 95% CI: 0.54-0.89; I2 63%; 4529 participants). None of the 16 studies that registered adverse 
events (n = 2455) reported the development of serious adverse events in the background of taking 
probiotics. All differences in adverse events between active treatment and control groups were 
included in the meta-analysis, except for extremely small differences (RR 0.00; 95% CI: -0.01-
0.01). Most of the undesired effects have been observed in placebo, standard therapy or non-
therapy groups. Adverse events in these studies included rash, nausea, flatus, meteorism, 
tympanites, abdominal pain, vomiting, increased mucus secretion, chest pain, constipation, 
distortion of the sense of taste and decreased appetite. 


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Based on the evidence of medium quality, it was suggested that probiotics were effective in AAD 
preventing. The summary data indicate an exact probiotic effect (RR: 0.46; 95% CI: 0.35-0.61) 
corresponding to the value of NNT = 10. Among the various probiotics studied, the most 
appropriate is the strain Lactobacillus rhamnosus or Saccharomyces boulardii at a dose of 5 to 40 
billion colony-forming units per day due to the modest size of the NNT and very low probable 
frequency of undesirable events. 
Hojsak (2017) summarized the available data on probiotic use for clearly defined clinical 
indications of importance in paediatrics. Individual probiotic strains (Lactobacillus rhamnosus GG 
and Saccharomyces boulardii) are reported to have proven efficacy in treating acute gastroenteritis 
and preventing antibiotic-associated diarrhea. Moreover, the effectiveness of the LGG strain in 
preventing nosocomial diarrhea and respiratory tract infections in nursing homes has been 
confirmed. The author has concluded that probiotic strains have different efficacy depending on 
the clinical indication and therefore recommends the use of strains with proven efficacy and safety. 
Thomas et al. (2001) studied the effectiveness of the LGG strain in preventing antibiotic-associated 
diarrhea in adults. In a prospective, double-blind, randomized, placebo-controlled trial, 
302 hospitalized patients (143 males and 159 females, average age 55.8 years, range 18-90 years) 
undergoing intravenous or oral antibiotic therapy were randomized to placebo groups in a daily 
dose of 2 × 109 CFU 2 times/day in capsule form or strain LGG for 14 days. The main outcome 
was the proportion of patients who had diarrhea within 21 days of recruitment, defined as the 
presence of watery or loose stool for two consecutive days or at three times the usual frequency 
for a particular patient. Patients were also asked to record unwanted effects such as nausea, 
abdominal cramping, flatus or tympanites. 
Against the background of the LGG strain, the incidence of diarrhea did not change; diarrhea 
occurred in 29-30% of patients in the trial and control groups. The study group and placebo group 
did not differ in the number, type and severity of reported undesirable effects. 
Ruszczynski et al. (2008) studied the safety, tolerability and efficacy of a combination of 3 strains 
of L. rhamnosus in the prevention of antibiotic-associated diarrhea in children in a prospective, 
double-blind, randomized, placebo-controlled study. A total of 240 children, 130 boys and 
110 girls, aged 3 months to 14 years, who received standard antibiotic treatment for common 
infectious diseases also received a combination of L. rhamnosus E/N, Oxy and Pen' strains in a 
dose of 2 × 1010 CFU 2 times/day (n = 120) or placebo, sucrose in skimmed milk (n = 120), during 
antibiotic treatment. Children or their parents recorded the frequency of the stool per day as well 
as any symptoms they considered to be important. The frequency and consistency of the stool was 


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recorded daily. All samples of loose stool were analyzed for viral pathogens. Children received 
antibiotic therapy (and L. rhamnosus in the test group) for 3 to 30 days, an average of 8 days. The 
addition of L. rhamnosus to antibiotic therapy has resulted in a significant reduction in the 
incidence of diarrhea. Two children in the control group and one child in the probiotic group 
required intravenous rehydration. No adverse or undesirable effects were observed. The authors 
noted high tolerability of Lactobacillus rhamnosus and absence of undesirable phenomena 
associated with antibiotic therapy (or placebo). 
3.3.3.3  Coadjuvant therapy for the eradication of Helicobacter pylori in adults 
Cremonini et al. (2002) studied the effect of probiotics on the side effects of eradication therapy 
with Helicobacter pylori, namely the probiotic strains LGG, Saccharomyces boulardii and the 
combination of Lactobacillus spp. and bifidobacteria. A total of 97 H. pylori-infected patients with 
no clinical manifestations (43 men and 54 women aged from 18 to 61 years) were randomized to 
one of the probiotic therapy groups or placebo for 2 weeks. The trial period was preceded by a 
three-week induction period during which 12 individuals were excluded from the trial due to 
symptoms or medications related to gastrointestinal side effects. All patients received eradication 
therapy based on rabeprazole, clarithromycin and tinidazole for 7 days and probiotic or placebo 
2 times/day for the same 7 days and the following week. The daily dose of the LGG strain was 1.2 
× 1010 CFU. Patients filled out side effects assessment questionnaires at the end of the week of 
antibiotic treatment and weekly for the next three weeks. 
No side effects requiring early exclusion from the study were observed. All three probiotic 
treatment options resulted in a reduction in observed side effects compared to placebo group; the 
intergroup difference was significant only in the first week and gradually decreased until week 4. 
The most noticeable effect was a significant reduction in diarrhea. 
Tong et al. (2007) performed a meta-analysis of 14 RCTs and compared different outcomes, such 
as the frequency of eradication and the frequency of side effects. According to the obtained results, 
the frequency of eradication was slightly higher during probiotic therapy against the background 
of standard triple eradicative therapy in the analysis samples assuming that all patients received 
the prescribed intervention (83.6 vs. 74.8%; OR 1.84; CI: 1.34-2.54) and that all patients met the 
protocol requirements (85.4 vs. 77.6%; OR 1.82; 95% CI: 1.30-2.56). The meta-analysis also 
demonstrated the potential effectiveness of probiotics in treating patients with unsuccessful 
eradication therapy. When estimating the eradication frequency against the background of L. 
rhamnosus GG strain reception, the value of OR 2.09 was determined in favor of probiotic (χ2 = 
4.01, d.f.). = 3 (P = 0.26) and I2 = 25.1%). 


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Also in meta-analysis the effect of probiotic therapy on antibiotic-associated side effects of the 
gastrointestinal tract on the background of therapy aimed at eradication of H. pylori was studied. 
The results showed a positive effect on the overall frequency of side effects associated with 
eradication therapy, especially diarrhea and taste disturbances. Subanalysis demonstrated that the 
frequency of H. pylori eradication did not depend on age, but was higher in patients with clinical 
manifestations.  
Dang et al. (2014) conducted a similar meta-analysis of the RCTs that took place between 2000 
and 2013. Analysis by subgroups was performed to compare different probiotic strains and 
antibiotic treatment schemes of different efficacy in control subjects. This analysis evaluated the 
systematic error of publication using funnel charts and the Harbor criterion. The quality of research 
was assessed using the Cochrane Collaboration tool to assess the risk of systematic error. 33 RCTs 
with 4459 patients met the inclusion criteria based on the eradication frequency, including 
20 studies evaluating the total frequency of side effects. The total frequency of eradication was 
generally significantly higher in probiotic therapy groups than in control groups (analysis in ITT 
sample: RR: 1,122; 95% CI: 1,086-1,159; analysis in PP- sample: 1,114; 95% CI: 1,070-1,159). 
However, subgroup analysis confirmed this observation for only four strains (Lactobacillus 
acidophilus, Lactobacillus casei DN-114001, Lactobacillus gasseri, and Bifidobacterium infantis 
2036) and for relatively ineffective antibiotic treatment regimens. The total frequency of side 
effects differed significantly between the groups (RR: 0.735; 95% of CI: 0.598-0.902). However, 
this result was only confirmed for studies without masking. The combined data indicate that the 
use of additives of individual probiotic strains, in comparison with traditional regimens of 
eradication therapy, can be considered an option to increase the frequency of eradication, 
especially when antibiotic therapy regimens are relatively ineffective. The impact on side effects 
remains unclear.  
Armuzzi et al. (2001) conducted a prospective, double-blind, randomized, placebo-controlled 
study to evaluate the possibility of using the LGG strain in the eradication therapy of Helicobacter 
pylori. Sixty healthy non-clinical patients (25 men and 35 women, average age 40 years) with 
positive screening results on H. pylori received rabeprazole, clarithromycin and tinidazole for 7 
days in combination with placebo or LGG in a dose of 1.2 × 1010 CFU/day in the form of 
lyophilized powder in sachets. Patients continued to take LGG or an appropriate placebo for 7 days 
after completion of eradication therapy. During the first week of therapy and the following three 
weeks, patients filled out acceptability and side effects assessment questionnaires. Patients in the 
LGG group reported significantly lower rates of nausea and diarrhea than placebo patients and 
gave significantly higher scores on therapy tolerance. The LGG strain and placebo did not differ 


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in the influence on the success of H. pylori eradication, and no side effects were observed against 
the background of LGG intake. 
3.3.3.4 Treatment of acute gastroenteritis in children  
Kaila et. al. (1992) studied the role of the LGG strain in the recovery of children with acute 
rotavirus diarrhea in a prospective double-blind randomized placebo-controlled study. After 
rehydration, 39 children aged from 7 to 37 months (average age 16 months) with satisfactory 
nutritional status who had diarrhea for less than 7 days, were given 125 g of pasteurized usual 
yogurt (n = 17) or fermented dairy product with LGG supplement (n = 22) 2 times/day (1010-1011 
CFU/day), for 5 days. Children were weighed daily, their parents filled out stool quality 
questionnaires during the study and observation period, and on days 1 and 21 blood samples were 
taken to assess their immune status. 
The duration of diarrhea was significantly lower in the study group than in the control group, and 
there was no disease recurrence in the three-week follow-up period. According to the number of 
IgG-, IgA- and IgM-secreting cells, patients who received the LGG strain had a statistically 
significantly higher nonspecific humoral response during the acute phase of infection; at the end 
of the observation period, a response from cells secreting specific IgA antibodies to the rotavirus 
was observed in a significantly higher number of patients in the test group than in the control group 
(90% vs. 46%). The authors have not reported any undesirable phenomena.  
As part of a prospective double blind randomized placebo-controlled study (Isolauri et al. 1994) 
42 children aged from 5 to 28 months (average age 14 months) with satisfactory nutritional status 
who had severe diarrhea were given the LGG strain in a dose of 1010 CFU in the form of 
lyophilized powder or placebo 2 times/day, for 5 days. The Lactobacillus GG strain was isolated 
from feces of 83% of patients in the test group. In this group, a reduction in the phase of diarrhea 
was noted. Administration of lactobacillus supplement had a significant effect on the enzymatic 
profile of bacteria: in the control group, urease activity increased temporarily against the 
background of diarrhea, but it did not change in the test group (F = 8.6, P = 0.01). There were no 
intergroup differences in the activity of beta-glucuronidase, beta-glucosidase and glycocholic acid 
hydrolase. According to our assumption, rotavirus infection is accompanied by two-phase 
diarrhea: in the first phase, osmotic diarrhea is developing, while in the second phase an excess 
growth of specific urease-producing bacteria is observed. Oral bacteriotherapy is a promising 
method for impaired microflora balance restoration. 


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Kaila et. al. (1995) conducted a double blind randomized study to assess the effect of a viable or 
heat-inactivated LGG strain on the immune response to rotavirus acute diarrhea in children. Forty-
one children aged from 1 to 38 months (average age 13 months) with satisfactory nutritional status, 
who had acute gastroenteritis for less than 7 days, were given a viable (n = 20) or heat-inactivated 
strain of LGG (n = 21) in a dose of 1010-1011 CFU with water 2 times/day, for 5 days. The patients 
were weighed daily, stool quality was recorded throughout the study and during the follow-up 
period, and blood samples were collected on days 1 and 30 after recruitment, and tested for 
immune status parameters. The groups studied did not significantly differ in terms of recovery 
from diarrhea. However, a viable LGG strain stimulated a significantly higher response from the 
IgA antibodies to the rotavirus than the heat-activated strain. No security indicators have been 
reported by the authors. 
Majamaa et. al. (1995) compared different strains of lactobacteria in terms of their effect on the 
immune response to rotavirus in children with acute rotavirus gastroenteritis. After initial oral 
rehydration, 49 children aged from 6 to 35 months, with rotavirus gastroenteritis were randomly 
distributed to obtain Lactobacillus casei subsp., a strain of casei GG (LGG), L. casei subsp. 
rhamnosus (Lactophilus) or a combination of Streptococcus thermophilus and L. delbrückii subsp. 
bulgaricus (Yalacta) twice a day, for 5 days. At the acute stage of the disease and at the stage of 
recovery serum antibodies to rotavirus were determined, the total number of cells secreting 
immunoglobulin (CSI) and cells secreting specific antibodies to rotavirus (CSSA). The average 
duration of diarrhea (AD) was 1.8 (0.8) days in children in the LGG group, 2.8 (1.2) days in 
children in the Lactophilus group and 2.6 (1.4) days in children in the Yalacta group (F = 3.3, 
p = 0.04). The response from the ISC was comparable in the three study groups, but the rotavirus-
specific immune response varied. LGG intake was accompanied by an increase of the level of IgA 
to the rotavirus secreted by the CSSA and the level of serum IgA antibodies in the recovery phase. 
The authors concluded that certain strains of lactobacteria, especially LGG, stimulate serum and 
intestinal immune response to rotavirus and, as a result, play an important role in developing 
immunity to repeated rotavirus infections. 
Raza et al. (1995) conducted a prospective triple blind placebo-controlled clinical study in Pakistan 
to determine the effect of the Lactobacillus GG strain on progression of acute diarrhea in 
hospitalized children. Forty children (average age 13 months) were enrolled in the study and were 
given Lactobacillus GG (n = 21) or placebo (n = 19) 2 times/day after rehydration therapy for 
2 days in addition to the usual diet. The clinical course of diarrhea was followed-up during 
treatment. Patients had similar characteristics in the distribution of treatment groups that included 
severe diarrhea, nutritional deficiencies and inappropriate treatment before admission. The 


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response to the treatment was detected on the 2nd day, when a lower incidence of vomiting and 
diarrhea was determined in the lactobacillus group. Among children hospitalized with acute, 
bloodless diarrhea (n = 32), the percentage of children with persistent watery diarrhea 48 hours 
later was significantly lower in the lactobacillus group: 31 vs. 75% (P < 0.01). Among children 
with diarrhea with an admixture of blood, this figure was not significantly different after 48 hours.  
Guarino et al. (1997) conducted a prospective randomized controlled study to assess the effect of 
the LGG strain on the duration of diarrhea in hospitalized children aged from 3 to 36 months 
(average age 19 months). 
100 children (51 boys and 49 girls) were enrolled in the study and randomized into the study group 
(n = 52) and the control group (n = 48). After primary oral rehydration, children were injected with 
an additional solution 
separately or in combination with LGG additives in a dose of 3 × 109 CFU, in 200 ml of milk or 
mixture of 2 times/day, for up to 5 days. After primary rehydration children were provided an age-
appropriate complete diet as soon as possible. At the time of enrollment and 6 days after the onset 
of diarrhea, fecal samples were taken for rotavirus analysis by ELISA. At the time of enrollment, 
a narrow majority of children (61%) had positivity for rotavirus. Diarrhea was determined as 
frequency of watery stool three or more times a day. 
Recovery from diarrhea was determined as the period of time from the last thin or loose stool. The 
outcome of diarrhea was assessed by the mothers of the enrolled children, who received 
instructions and were interviewed daily. 
The duration of diarrhea was significantly reduced (by 50%) in all children, regardless of the 
rotavirus test results, who received the LGG strain compared to the control group. Among children 
with initially positive rotavirus test results, the number of children who excreted rotavirus at the 
end of the treatment period was significantly lower in the LGG intake group than in the control 
group (4 children from the active treatment group and 26 children from the control group). No 
adverse effects were reported. 
In a controlled study conducted by Shornikova et al. (1997) in Petrozavodsk (Karelia), the effects 
of oral rehydration and the introduction of Lactobacillus GG (LGG) strain on recovery from acute 
diarrhea were studied in 123 children aged 1 to 36 months (27% cases of rotavirus, 21% cases of 
bacterial etiology). On admission to hospital, children were first randomized to the group of 
isotonic oral rehydration solution  (ORS) with osmolarity of 311 mOsmol/l and sodium content of 
90 mmol/l (WHO-ORS) or the group of hypotonic ORS with osmolarity of 224 mOsmol/l and 


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sodium content of 60 mmol/l (Light-ORS), then they were assigned either to a LGG strain (in a 
dose of 5 × 109 CFU) administration group or a corresponding placebo group. The two ORS 
studied had similar efficacy in emergency rehydration, in addition, oral rehydration by either ORS 
resulted in a shorter duration of diarrhea than in case of intravenous rehydration (p = 0.036). 
Patients who received the LGG strain had significantly shorter duration of watery diarrhea 
(2.7 [2.2] days on average) than patients from placebo group (3.7 [2.8] days, p = 0.03). The 
introduction of LGG significantly reduced the duration of rotavirus diarrhea, but not diarrhea with 
confirmed bacterial etiology. 
Within the scope of a multicentre prospective double blind randomized placebo-controlled study, 
Guandalini et al. (2000) studied the effect of the LGG strain introduced into oral rehydration 
solution on the course of acute diarrhea in children aged from 1 to 36 months (average age 
12.3 months). A total of 287 children hospitalized with acute diarrhea of any etiology received an 
oral rehydration solution in the first 4-6 hours containing the strain LGG in a dose of 1010 CFU 
per 250 ml (n = 147), or placebo (n = 140). 
At the time of admission, anthropometric measures, including weight, were measured and feces 
were sampled; additional feces were sampled 48 hours later and, if possible, 7 and 30 days later. 
During the observation period liquid intake, frequency and characteristics of the stool and the 
frequency of vomiting were monitored. The incidence of diarrhea over 7 days long was 
significantly lower in the test group than in the control group (2.7 vs. 10.7%), as was the average 
hospitalization term. 
The weight gain in the first 24 h of rehydration therapy did not differ between the groups. 
Despite the fact that adverse reactions were not discussed separately, the authors conclude that the 
use of oral rehydration solution with Lactobacillus GG supplement in children with acute diarrhea 
is safe and results in shorter duration of diarrhea, lower probability of protracted diarrhea and 
reduction of hospital discharge term. 
Szajevska et. al. (2013) published a meta-analysis on the efficacy of LGG strain in the treatment 
of acute gastroenteritis (AGЕ) in children. Fifteen RCTs (2963 participants) met the criteria for 
inclusion in this updated meta-analysis. Combined data from 11 RCTs (n = 2444) showed that 
taking the LGG strain significantly reduced the duration of diarrhea compared to placebo or non-
treatment (mean difference [MD] -1.05 days, 95% of CI: -1.7 to -0.4). The use of LGG was more 
effective with a daily dose of ≥ 1010 CFU (eight RCTs, n = 1488, MD - 1.11 days, 95% CI: -1.91 
to -0.31) than with a dose of < 1010 CFU (three RCTs, n = 956, MD - 0.9 days, 95% CI: -2.5 to 
0.69). LGG use was effective in children treated in Europe (five RCTs, n = 744, SR -1.27 days, 


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95% CI: 2.04 to -0.49); in non-European studies, the difference between the LGG group and the 
control group was of borderline statistical significance (six RCTs, n = 1700, MD -0.87, 95% CI: 
from -1.81 to 0.08). The authors concluded that taking Lactobacillus GG strain reduces the 
duration of diarrhea. The number of patients who are more likely to benefit from such treatment 
includes patients with a high daily dose of LGG (≥ 1010 CFU/day) undergoing inpatient or 
outpatient treatment in Europe. 
The ESPGHAN position statement contains data from Szajevska et al. (2014) on the effectiveness 
of probiotics in treating acute gastroenteritis in children. The following recommendation has been 
published for the L. rhamnosus GG strain: "The use of Lactobacillus GG strain is possible in the 
treatment of children with AGE as an adjunct to rehydration therapy"; this is a recommendation 
of "high" strength despite the poor quality of the evidence. The quality of the evidence base for 
this recommendation has been lowered due to methodological limitations in many of the studies 
included. 
Szajevska et al. (2001) studied the effectiveness of the LGG strain in preventing nosocomial 
diarrhea in younger children admitted to children's hospitals. 81 children aged from 1 to 36 months 
who were hospitalized for reasons other than diarrhea were enrolled in the double-blind study. At 
the time of admission, children were randomly assigned to LGG injection groups (n = 45) at a dose 
of 6 × 109 CFU or a corresponding placebo (n = 36) 2 times/day ingestion during the entire period 
of hospitalization. Taking the LGG strain reduced the risk of nosocomial diarrhea (≥ 3 loose or 
watery stools/24 h) compared to placebo (6.7 and 33.3%; relative risk: 0.2; [95% CI: 0.06-0.6]; 
number of patients requiring treatment: 4 [95% CI: 2-10]). The prevalence rate of rotavirus 
infection was similar in the LGG and placebo injection groups (20 vs. 27.8% respectively; relative 
risk 0.72; 95% CI 0.33-1.56). However, the use of LGG in comparison with placebo has 
significantly reduced the risk of rotavirus gastroenteritis (1/45 [2.2%] and 6/36 [16.7%] 
respectively; relative risk: 0.13; 95% CI: 0.02-0.79; number of patients requiring treatment: 7; 
95% CI: 3-40). 
According to the authors' conclusion, prophylactic administration of LGG strain significantly 
reduced the risk of nosocomial diarrhea in infants, especially nosocomial rotavirus gastroenteritis. 
Salazar-Lindo et al. (2004) studied the effect of the introduction of the LGG strain suspended in 
the milk formula on the duration and severity of non-rotavirus acute diarrhea in Peruvian boys. A 
total of 179 boys aged from 3 to 36 months received oral rehydration therapy with an oral 
rehydration solution and were randomly assigned to milk formula feeding groups with LGG 
supplement in the dose of 109 CFU/ml (n = 90) or without LGG supplement (n = 89). The first 


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portion of the mixture was given immediately after rehydration therapy, and subsequent portions 
were given every four hours until the diarrhea ceased, but not longer than for five days. Each child 
was given a mixture of 150 to 1000 ml per body weight per day. In this study, LGG administration 
was studied at a dose of 6-8 × 1011 CFU/day. Before treatment, clinical analysis was collected, 
physical examination was performed and blood samples were taken, and additional blood samples 
were taken 24 hours after the start of treatment. The feces volume was measured periodically, and 
the duration of diarrhea was calculated based on the physical characteristics of the feces. Eight 
boys from the LGG administration group and 11 boys from the control group were prematurely 
excluded from the study for various reasons not related to treatment (blood admixtures in the feces 
in the first 24 hours after admission, failure to comply with the scheme of treatment by parents, 
etc.). The volume of feces was significantly higher in the LGG injection group than in the control 
group, although there was no significant difference in the duration of diarrhea. Approximately 
12% of patients did not have diarrhea resolved and a further 20% were found to have had 
unsuccessful treatment, mainly due to high severity of diarrhea. The percentage did not differ 
between the two groups. The authors concluded that this study did not find a beneficial effect of 
the LGG strain on the clinical course of acute watery diarrhea, but there were no adverse effects 
associated with the intake of the test milk formula in both groups during the study. 
Canani et. al. (2007) conducted a major (571 participants) simple blind clinical study to evaluate 
the use of probiotics in the management of acute diarrhea in children  
from 3 to 36 months old. Five options for probiotic drugs were studied: 1) LGG; 2) Saccharomyces 
boulardii; 3) Bacillus clausii; 4) a mixture of L. delbrueckii ssp. bulgaricus, Streptococcus 
thermophilus, L. acidophilus, Bifidobacterium bifidum; 5) the strain Enterococcus faecium SF68. 
Oral rehydration solution was administered for 3–6 hours in children (282 boys and 289 girls; aged 
from 8 to 28 months; average age 17.5 months) with acute diarrhea having developed less than 
48 hours before, and then lactose- or cow's milk (depending on age)-based formula was 
administered. The enrolled children were randomly assigned to groups of oral rehydration (n = 92), 
LGG administration at a dose of 6 × 109 CFU/day (n = 100) or one of four probiotic therapy options 
(n = 91, 100, 97 and 91, respectively). At the time of enrollment, the duration and severity of 
diarrhea and associated clinical characteristics were assessed for each child, and parents received 
a special form for daily recording of the frequency and consistency of the stool, the presence of 
vomiting and fever, as well as adverse events. The parents purchased probiotics at a pharmacy; 
family doctors were responsible for prescribing treatment, providing written instructions to the 
parents and monitoring compliance; researchers who collected reports did not have information 
about the treatment prescribed. 


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Two studied options for probiotic therapy, namely LGG and a mixture of L. delbrueckii and other 
bacteria, significantly reduced the duration and severity of diarrhea, while the other three options 
did not have significant effects. The parents of the children who received experimental probiotic 
therapy settings did not report any adverse effects. 
Basu et al. (2007) conducted a randomized controlled study to assess the role of Lactobacillus 
rhamnosus GG (LGG) as a probiotic in resistant diarrhea (RD) in children in West Bengal, India. 
The study included all RD patients hospitalized within a two-year period, based on predetermined 
inclusion criteria. In this double-blind controlled study, patients were randomized into oral 
rehydration solution (ORS) or powder-supplemented ORS (60 million cells), twice a day, for at 
least 7 days or until diarrhea ceases with rehydration using ORS and/or intravenous solutions in 
accordance with the WHO protocol, and antibiotic therapy in patients with positive culture results. 
The study included 235 patients randomized into 2 groups: active treatment group (117 people) 
and control group (118). Both groups were comparable as to the age, the number of breastfed 
children, dehydration rate on admission to hospital, degree of protein-energy deficiency and 
distribution of infections by etiology. Stool seeding was positive in 90 (38.3%) patients, with 
Escherichia coli and, more rarely, Shigella spp. and Clostridium difficile. The average duration of 
diarrhea was significantly lower in the active treatment group than in the control group (5.3 versus 
9.2 days). The average duration of hospitalization was also significantly lower in the active 
treatment group. No complications associated with the application of the LGG strain studied dose 
have been observed. The introduction of the LGG strain (at a dose of 120 million CFU) resulted 
in a decrease in the frequency and duration of diarrhea and vomiting, and the hospital stay 
reduction in patients with persistent diarrhea. 
Basu et al. (2009) conducted a randomized controlled study to evaluate the effective dose of the 
Lactobacillus rhamnosus GG (LGG) strain as a probiotic for acute watery diarrhea (AWD) in 
children from India. All hospitalized AWD patients, older than 1 year, were randomized into 
3 groups: oral rehydration solution (ORS) administration group without additives (group A / 
control, n = 185), ORS administration group with LGG powder supplement in a dose of 1010 CFU 
(CFU) (group B, n = 188) and ORS administration group with LGG powder supplement in a dose 
of 1012 CFU (group C, n = 186) twice a day for at least 7 days or until diarrhea ceases against the 
background of rehydration therapy. The duration and frequency of diarrhea and vomiting were 
assessed in the study. The frequency and duration of diarrhea, the need for intravenous therapy 
and the duration of hospitalization were significantly lower in both active therapy groups, 
compared with the control group. There was no significant difference between the two active 


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therapy groups. No complications associated with the application of the studied dose of LGG strain 
have been observed.  
Nixon et al. (2012) conducted a double blind randomized controlled study in children (aged from 
6 months to 6 years) who were admitted to the admission office of the children's hospital with a 
complaint of diarrhea. Patients were randomized into placebo or LGG, in powder form, groups, 
2 times/day for 5 days. After each dose was administered, the parents recorded the characteristics 
of the stool in their home diary and the secret researcher looked through the diaries daily. The 
study compared time to stool normalization and frequency of diarrheal stools between groups. The 
study was completed by 129 of 155 recruited patients: 63 patients in the LGG group and 
66 patients in the placebo group. No significant differences in median (midspread) time before 
stool normalization (60 h [37-111] in the LGG administration group and 74 h [43-120] in the 
placebo group; P = 0.37) and diarrheal stool frequency (5.0 [1-10] in the LGG administration 
group and 6.5 [2-14] in the placebo group; P = 0.19) were observed. Among children admitted 
after at least 2 days of diarrhea, the LGG administration group showed earlier normalization of 
stool (51 h [32-78] in the LGG administration group and 74 h [45-120] in the placebo group; 
P = 0.02), fewer episodes of diarrhea (3.5 [1.0-7.5] in the LGG administration group and 7 [3.0-
16.3] in the placebo group; P = 0.02) and 2.2 times higher probability of normalization of stool 
(95% confidence interval: 1,3-3,9; P = 0.01) in comparison with placebo group. According to the 
authors' conclusions, the introduction of Lactobacillus GG strain may reduce the duration of acute 
diarrheal disease in children with symptoms that last longer than 2 days. 
Pieścik‐Lech et al. (2013) published a review article on the case management in children with 
acute gastroenteritis. Attempts to improve the taste and/or efficacy of oral rehydration solution 
(ORS) are ongoing, and some interventions are promising. So far, the standard (more than 
24 hours) nasogastric rehydration has been applied, but new evidence of the rapid (more than 
4 hours) rehydration effectiveness has been obtained. As for intravenous rehydration, new data 
have been obtained concerning the comparison of fast or ultra-fast rehydration and rehydration of 
large and standard volumes. Due to the inconsistency of new observations, rehydration will 
continue at 20 ml/kg until new data are available. Strong evidence that ondansetron reduces the 
risk of vomiting has been obtained, but proof of the drug's safety in children is needed. New data 
have confirmed the fact that in Europe, where zinc deficiency is rare, zinc intake can help in 
diarrheal syndrome. Also new data, obtained mainly in non-European countries, confirmed the 
efficacy of smectite or racecadotril as a supplement to oral rehydration. The effectiveness of certain 
probiotics such as Lactobacillus GG or S. boulardii has been proven. 


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3.3.3.5 Functional disorders of the gastrointestinal tract associated with abdominal pain in 
children 
Apart from diarrhea, gastrointestinal disorders can manifest themselves in a variety of symptoms. 
Probiotics, in particular Lactobacillus rhamnosus GG, have been shown to relieve abdominal pain 
in children, regardless of diagnosis. Abdominal discomfort may be associated with inflammation, 
and the strain Lactobacillus rhamnosus GG reduces the inflammatory response. 
Francavilla et al. (2010) conducted a randomized controlled study of Lactobacillus GG in children 
with functional abdominal pain. The study involved 141 children with irritable bowel syndrome 
or functional pain. Children received LGG (in a dose of 6 × 109 CFU/day) or placebo for 8 weeks 
after a 4-week induction period, after which they were followed-up for another 8 weeks. The LGG 
strain administration caused the significant decrease in occurrence (P < 0.01) and severity 
(P < 0.01) of abdominal pain from baseline. During the follow-up period the difference found was 
still significant (P < 0.02 and P < 0.001 respectively). By the 12th week, improvement was 
observed in 48 children in the LGG treatment group, compared with 37 children from the placebo 
group (P < 0.03). The difference remained also significant until the end of the follow-up period 
(the 16th week, P < 0.03). In the LGG treatment group, the results of the intestinal permeability 
assessment, mainly in children with IBS, improved significantly (P < 0.03). The administration of 
the LGG strain resulted in significant decrease in the abdominal pain occurrence and severity in 
children with IBS; this effect maintained and could be related to the improvement of intestinal 
barrier. 
Gawronska et. al. (2007) performed the double-blind randomized placebo-controlled study of the 
role of the Lactobacillus GG strain in abdominal pain-associated diseases in children. A total of 
104 children were enrolled to this double-blind randomized placebo-controlled study, they met the 
Roman II criteria for functional dyspepsia (FD), irritated bowel syndrome (IBS) or functional 
abdominal pain (FAP) wherein they received LGG (n = 52) or placebo (n = 52) for 4 weeks. 
In the general study group, the probability of successful treatment (pain disappearance) was higher 
in patients from the LGG treatment group than in patients from the placebo group (25 vs 9.6 %, 
relative benefit (RB) 2.6, 95 % confidence interval (CI): 1.05–6.6, the number of patients needed 
to treat  (NNT) 7, 95 % CI: 4–123). In the group of children with IBS (n = 37) the probability of 
successful treatment in the LGG treatment group was higher than in the placebo group (33 vs 5 %, 
RB 6.3, 95 % CI: 1.2–38, NNT 4, 95 % CI: 2–36); furthermore, the LGG treatment resulted in the 
abdominal pain occurrence (P = 0.02) but not severity (P = 0.10). No difference between patient 
groups with FD (n = 20) and FAP (n = 47) was found. 


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As a part of the double-blind randomized placebo-controlled study, Bausserman и Michail (2005) 
investigated the administration of LGG strain at a dosage of 2 × 1010 CFU/day or placebo (inulin) 
during 6 weeks in 50 children with irritated bowel syndrome (IBS). 64 children (12 boys and 52 
girls, the average age was 12 years old, the age range was 6–20 years old) diagnosed with IBS 
were enrolled in the study. Patients were clinically examined at enrollment and at the end of the 
study. Six participants (4 in the LGG treatment group, 2 in the control group) were withdrawn 
before the study start, 3 patients from each group were lost from the follow-up, and 2 patients in 
the placebo group did not comply with the treatment regimen, so the analysis included 50 patients 
(25 in each group). The group of analysis included patients aged between 6 and 17 years old (the 
average age is 12 years old), 10 boys and 40 girls. 
No significant difference in the rate of abdominal pain decrease between the LGG and placebo 
groups was observed, but it has been established that the use of the LGG supplement allows to 
reduce such symptoms as abdominal distension. Authors pointed out the absence of the 
Lactobacillus GG strain treatment-associated adverse events. 
Horvath et al. (2011) performed the meta-analysis aimed at systematic evaluation of the 
Lactobacillus rhamnosus GG (LGG) strain role in the treatment of functional gastrointestinal 
disorders associated with abdominal pain in children. In the LGG intake the higher treatment 
response rate (absence of pain or decrease of its intensity) compared with placebo intake was 
observed in the total population of patients with functional gastrointestinal disorders associated 
with abdominal pain (three RCT n = 290; risk ratio [RR]: 1.31; 95 % CI: 1.08–1.59; number of 
patients in need of treatment [NNT]: 7; 95 % CI: 4–22) and irritated bowel syndrome (IBS) (three 
RCT; n = 167; RR: 1.70; 95 % CI: 1.27–2.27; NNT: 4; 95 % CI: 3–8). But there was no difference 
in treatment respondents among those children who had functional abdominal pain or functional 
dyspepsia and received placebo or LGG. In the general study group and in the IBS patients 
subgroup the pain intensity decreased significantly. Only in the IBS patients subgroup, the pain 
occurrence decreased significantly. The use of the Lactobacillus rhamnosus GG strain results in a 
moderate increase in treatment success in children with functional gastrointestinal disorders 
associated with abdominal pain, particularly in children with IBS. 
3.3.3.6  Traveler's diarrhea 
Oksanen et al. (1990) investigated the efficacy of the Lactobacillus GG strain in the prophylaxis 
of traveler's diarrhea. They performed the double-blind randomized placebo-controlled study with 
820 participants (aged between 10 and 80 years old), who traveled in two directions in South 
Turkey. The participants were randomized into two groups: receiving the Lactobacillus GG 


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treatment (at a dose of 2 × 109 CFU/day) or placebo in identical sachets. During the overflight 
home each participant completed the questionnaire, where the diarrhea and associated symptoms 
occurrence during the travel was stated. In the first group 756 (92 %) participants completed the 
study properly. The total occurrence of diarrhea was 43.8 % (331 event). In the placebo group, the 
total occurrence of diarrhea was 46.5 %, and in the treatment group with the Lactobacillus GG 
strain — 41.0 %, which indicates the mean protective effect value of 11.8 %. Protective effect 
values varied between two target places, and the maximum value was 39.5 %. There were fewer 
diarrhea events in older participants compared with younger ones. The treatment with the 
Lactobacillus GG strain appears to be efficient for the decrease of diarrhea occurrence in travelers 
in one of two target points, and is not associated with any adverse events. 
Riddle et al. (2017) published the guidance for the prophylaxis and treatment of traveler’s diarrhea. 
According to the authors’ conclusion, the use of prebiotics and probiotics designed for the 
prophylaxis and treatment of acute infectious diarrhea is an attractive strategy for its simplicity 
and safety. The concept of host organism resistance to intestinal infections, commonly referred as 
colonization resistance as well, describes the capability of microflora for prophylaxis and 
limitation of pathogens’ colonization and growth. In recent decades our understanding of different 
colonization resistance mechanisms has extended to elucidation of main direct and indirect 
mechanisms. In spite of the studies on the efficacy of prebiotics and probiotics in the prophylaxis 
of acute diarrhea infections in traveling adults having been performed, they vary in test conditions, 
reasons of the acute diarrhea development, probiotic strains used, have a short follow-up period 
and don’t include any analysis of person-days. These studies also have great differences of 
dosages, administration frequency and probiotic forms. Times and routes of administration of these 
preparations relative to various factors, including traveler’s groups and target places, as well as 
concomitant antibiotics use are also different. In spite of the establishment of the probiotics margin 
effect for the DT prophylaxis in two meta-analyses, the data collected in both studies were 
insufficient to extrapolate them to International recommendations.  
Vae (2018) published the meta-analysis of RCT to evaluate the role of probiotics in the prophylaxis 
of travel’s diarrhea. Eleven papers were selected for this meta-analysis. The standardized relative 
risk value (SRR) was 0.85 (95 % CI 0.79–0.91), indicating the statistical significance of the results. 
No heterogeneity of results (I2 = 28.4 %) or systematic error due to the publication of results were 
noted. The authors observed the statistically significant efficacy of probiotics in the DT 
prophylaxis based on which the guidance for the prophylaxis of traveler’s diarrhea should be 
updated (International Society of Travel Medicine, 2017).  


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3.3.3.7  Study of occurrence and severity of respiratory and gastrointestinal infections in 
children 
Hatakka et al. (2001) studied the effect of the LGG prolonged use with cow milk occurrence and 
severity of gastrointestinal and respiratory infections in children at day-care services. As a part of 
the multicentre, prospective, double-blind, randomized, placebo-controlled study 571 children, 
aged between 1 and 6, received milk supplemented with LGG (n = 282) or without LGG (n = 289). 
Supplemented milk contained 5–10 × 105 CFU of LGG/ml, and the mean daily milk exposure 
(5 days a week) for the active treatment group and the control group was 260 mL (1.3–2.6 × 
107 CFU). During the study, children’s parents kept daily records of respiratory symptoms (fever, 
rhinorrhea, sore throat, cough, wheezing, ear pain) and gastrointestinal symptoms (diarrhea, 
vomiting, abdominal pain) as well as absence from school due to the disease. Stool samples were 
taken at the start, in the middle and at the end of the study for measuring of the LGG recovery and 
assessment of compliance with the therapy. The study included the 8-month follow-up period, 
though 58 children did not complete this phase of the study. 
At the end of the study period the LGG strain was recovered from the stool of 97 % patients 
receiving the therapy (versus 9 % of patients in the control group). In children from the group of 
the LGG treatment, the statistically significant lower number of absence from day-care facilities 
was established (in average 4.9 days vs 5.8 days in the control group). In the active therapy group, 
the statistically significant decrease in the complication-associated respiratory infections and lower 
respiratory tract infections as well as the significant relative decrease of the antibiotic use for 
respiratory infections was established as well. There was no difference observed between the group 
of the LGG strain treatment and the control group, including stool frequency and consistence, 
abdominal pain, allergic symptoms or adverse effects. 
Hojsak et al. (2010a) performed the double-blind, randomized, placebo-controlled study with 
participation of 281 children attending day-care facilities. The children were randomly distributed 
into the LGG treatment group at a dose of 109 CFU per 100 mL of the fermented milk product 
(LGG treatment group, n = 139) or the placebo group, wherein the same pasteurized fermented 
milk product without the LGG strain supplement (placebo group, n = 142) for 3-month 
interventional period. The children from the LGG treatment group had significantly lower risk of 
the upper respiratory tract infections occurrence compared to the children in the placebo group 
(RR: 0.66; 95 % CI: 0.52–0.82; NNT: 5; 95 % CI: 4–10), lowered risk of respiratory tract 
infections with more than 3-day duration (RR: 0.57; 95 % CI: 0.41–0.78; NNT: 5; 95 % CI: 4–11) 
and the significantly lower number of days with respiratory symptoms (p < 0.001). No lower risk 


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for the lower respiratory tract infections occurrence was established (RR: 0.82; 95 % CI: 0.24–
2.76). When compared with the placebo group, the children from the group of LGG treatment had 
significantly lower risk of gastrointestinal infections (RR: 0.63; 95 % CI: 0.38–1.06), vomiting 
episodes (RR: 0.60; 95 % CI: 0.29–1.24) and diarrhea episodes (RR: 0.63; 95 % CI: 0.35–1.11) as 
well as fewer days of gastrointestinal symptoms (p = 0.063). According to the authors’ conclusion, 
the LGG administration may be recommended as an efficient action to lower the risk of upper 
respiratory tract infections in children attending kindergartens. 
Hojsak et al. (2010b) performed the double-blind, randomized, placebo-controlled study with 
participation of 742 hospitalized children. For the in-patient period, the children were randomly 
distributed into the LGG treatment group at a dose of 109 CFU per 100 mL of the fermented milk 
product (LGG treatment group, n = 376) or the placebo group, wherein the same pasteurized 
fermented milk product was used without the LGG strain supplement (placebo group, n = 366). 
When compared with the placebo group we found the significant decrease of the risk of 
gastrointestinal infections (relative risk [RR]: 0.40; [95 % confidence interval (CI): 0.25–0.70]; 
NNT: 15; [95 % CI: 9–34]), respiratory infections (RR: 0.38; [95 % CI: 0.18–0.85]; NNT: 30 
[95 % CI: 16–159]), vomiting episodes (RR: 0.5; [95 % CI: 0,3–0,9]), diarrhea episodes (RR: 0,24; 
[95 % CI: 0.10–0.50]), gastrointestinal infection episodes of the duration of more than two days 
(RR: 0,40; [95 % CI: 0.25–0.70]) and respiratory infection episodes of the duration of more than 
three days (RR: 0,4; [95 % CI: 0.32–0.9]). Groups did not differ by the in-patient period (P = 0.1). 
According to the authors’ conclusion, the LGG administration may be recommended as an 
efficient action to lower the risk of nosocomial gastrointestinal and respiratory infections in 
children at day-care facilities. 
Liu et al. (2013) performed the systematic review on efficacy of the Lactobacillus rhamnosus GG 
(LGG) strain in the prophylaxis of respiratory infections in children. Four RCT with 1805 study 
subjects met the inclusion criteria. When compared with placebo, the LGG strain administration 
was associated with the decrease in the occurrence of acute otitis medium (four RCT; n = 1805; 
RR: 0.76; 95 % CI: 0.64–0.91; the constant-effect model; NNT: 17; 95 % CI: 11–46), the risk of 
upper respiratory tract infections (one RCT; n = 281; RR: 0.62; 95 % CI: 0.50–0.78; NNT: 4; 95 % 
CI: 3–8) and the frequency of antibiotic use (four RCT; n = 1805; RR: 0,80; 95 % CI: 0.71–0.91; 
the constant-effect model). The LGG group and the control group did not significantly differ in 
the risk of respiratory infections in total and the occurrence of lower respiratory tract infections. 
But the subgroup analysis of the two studies with participation of children of more than 1 year old 
showed the major risk lowering of total respiratory infections (two RCT; n = 794; RR: 0.73; 95 % 
CI: 0.57–0.92; the random-effect model; NNT: 8; 95 % CI: 5–14). Adverse events were similar in 


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both groups. There were no serious adverse events reported. According to the authors’ conclusion, 
the administration of the Lactobacillus rhamnosus GG strain allows to lower the occurrence of 
acute otitis medium, upper respiratory tract infections and antibiotic use in children, when 
compared with placebo. 
3.3.4 Other effects studied in human 
3.3.4.1  Immunological effects 
According to assessments, more than two-thirds of all lymphocytes of the organism are located in 
epithelial and sub-epithelial layers of the intestine wall. The immune system of the mucous 
membrane is the first-line defense and decreases the requirement of the systemic immunity 
involvement in the host organism maintenance. The immune system of the mucous membrane 
carries out a complicated task of balance maintenance between the mediation of various protective 
immune responses to infectious agents and the limitation of antigenic load present in the intestinal 
lumen. The Lactobacillus rhamnosus GG strain was shown to support innate and acquired 
immunity reaction by providing the integrity of the intestinal epithelial barrier and mediating the 
cellular immune response (Bäckhed et al. 2005; Gogineni et al. 2013). 
Hatakka et al. (2003) performed the pilot double-blind, randomized, placebo-controlled study to 
evaluate the efficacy of the LGG strain in mild rheumatoid arthritis. Totally 21 patients aged from 
18 to 64 years old were randomly distributed into the LGG treatment group or the placebo group, 
2 capsules BID for 12 months; the daily dose of LGG was 1010 CFU. Feces samples were 
examined to confirm the compliance with the treatment. The arthritis activity was assessed based 
on the results of clinical examination and laboratory investigations. The treatment had no effect 
on any arthritis characteristics, but in the LGG group the patients’ significantly improved general 
well-being was observed. There was no reports of any cases of the treatment discontinuation 
because of adverse events. 
Szachta et al. (2010) performed the simple blind, randomized, placebo-controlled study to evaluate 
the efficacy of the Lactobacillus rhamnosus GG (LGG) strain in elimination of vancomycin-
resistant enterococci (VRE) from the gastrointestinal tract of the children with confirmed 
colonization, as well to evaluate the effect of the probiotic strain on the colony count of 
Lactobacillus spp. in the gastrointestinal tract. Children (aged between 0 and 18) who were 
hospitalized to the children’s hospital, and carried VRE in their gastrointestinal tract, were 
randomized into the group of LGG treatment at a dose of 3 bln. CFU daily or placebo for 
21 consecutive days. In total 61 children completed the study (32 in the active treatment group 
and 29 in the control group). Samples by means of rectal tampons for the VRE and Lactobacillus 


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spp. analyses were taken at the baseline, once a week during the supplement administration and 
one month after the supplement administration completed. The antibiotic control was performed 
during the whole period of analysis. After 3 weeks, the significant intergroup difference in the 
numbers of children with gastrointestinal colonization by VRE was found (P = 0.002). The VRE 
carrier status was lost in 20 of 32 study subjects in the active treatment group and in 7 of 29 study 
subjects in the control group. The increase of Lactobacillus spp. colony count in the 
gastrointestinal tract of the children receiving LGG. Starting from the first week, the statistically 
significant difference in the frequency of the detection of bacteria was found, while their growth 
intensity began to differ starting from the 2nd week. When compared with placebo, LGG 
temporarily eliminates VRE carrying and increases the count of the Lactobacillus spp. strain in 
the children’s gastrointestinal tract. 
Bruzzese et al. (2007) performed the prospective, randomized, placebo-controlled cross-over study 
aimed to examine effects of the Lactobacillus GG (LGG) strain on pulmonary exacerbations in 
cystic fibrosis (CF). Nineteen children received LGG for 6 months, after which they were switched 
to the oral rehydration solution (ORS) for 6 months. In parallel, nineteen children initially received 
ORS, and then were switched to LGG. The main studied outcomes included the following: the 
occurrence of pulmonary exacerbations and hospitalizations, forced expiratory volume (FEV1) 
and body weight changes. In children receiving the LGG supplement the lower number of 
pulmonary exacerbations (median 1 vs 2; range 4 vs 4; median difference 1; 95 % CI: 0.5–1.5; 
p = 0.0035) and hospitalizations (median 0 vs 1; range 3 vs 2; median difference 1; 95 % CI: 1.0–
1.5; p = 0.001) compared with the children from the ORS group. During the LGG administration 
the higher extent of FEV1 (3.6 ± 5.2 % vs 0.9 ± 5 %; p = 0.02) and body weight increase (1.5 ± 
1.8 kg vs 0.7 ± 1.8 kg; p = 0.02) were noted. The LGG administration resulted in decrease of 
occurrences of pulmonary exacerbations and hospitalizations in patients with CF. Based on that, 
the delay of pulmonary function disturbances during the probiotic intake and the association 
between inflammatory processes in the intestine and lungs were proposed. 
Kekkonen et al. (2008) performed double-blind, randomized, placebo-controlled interventional 
study for evaluation of effects of three potentially anti-inflammatory bacteria of three genera on 
immune function parameters in healthy adults in clinical practice settings. In this double-blind, 
randomized, placebo-controlled interventional study, the total of 62 volunteers participated. Study 
subjects were randomized into the groups using a diary beverage with the supplement of 
Lactobacillus rhamnosus GG (LGG), Bifidobacterium animalis ssp. lactis Bb12 (Bb12) or 
Propionibacterium freudenreichii ssp. shermanii JS (PJS) strains, or the placebo beverage for 
3 weeks. Samples of venous blood and saliva were taken initially and on Days 1, 7 and 21. Stool 


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samples were taken initially and at the end of the intervention period. The serum hs-CRP level 
expressed as the median AUC0–21 (relative to the baseline), was 0.018 mg/L in the placebo group, 
-0.240 mg/L — in the LGG group, 0.090 mg/L — in the Bb12 and -0.085 mg/L — in the PJS 
group (P = 0.014). In vitro synthesis of TNF-α in peripheral blood mononuclear cells (PBMC) 
cultured in vitro was significantly lower than in study subjects from the LGG group compared with 
the placebo group. Synthesis of IL-2 by PBMC in the Bb12 group. Thus, probiotic bacterial strains 
demonstrate strain-specific anti-inflammatory effects in healthy adults. 
3.3.4.2 Efficacy in inflammatory intestine diseases 
As a part of the prospective, double-blind, randomized, placebo-controlled study Prantera et al. 
(2002) studied the efficacy of the LGG strain in the prophylaxis of symptom recurrence after the 
radical intestine resection for Crown disease. Forty-five patients with Crown disease who 
underwent the total resection of all affected parts of the intestine within previous 10 days (29 men 
and 16 women aged from 22 to 71, average age 37 years old) were randomized into groups 
receiving the LGG strain at a dose 1,2 × 1010 CFU or placebo in two sachets per day for 1 year. 
After 13, 26, 39 and 52 weeks of the treatment start control visits were performed; for the purpose 
of control, urine and blood samples were collected and analyzed for blood cell number, serum 
levels of iron and ferritin, creatinine, alanine aminotransferase, aspartate aminotransferase and 
alkaline phosphatase. Ileocolonoscopy was performed at the end of the study. As it was observed, 
the LGG strain intake for 1 year had no effect on the Crown disease recurrence rate or the severity 
of intestine affection in recurrences. In total thirteen patients did not complete the study until the 
end; nine discontinued patients were withdrawn due to adverse events. The reasons for 
discontinuation did not differ between the active treatment group and the control group. The 
treatment groups did not differ in such symptoms as diarrhea, abdominal distension and flatulence. 
No effects on liver enzyme activities were noted. Adverse events occurred in 2 patients from the 
LGG and 6 patients in the placebo group; none of them was considered as study-associated and 
did not result in discontinuation. 
The study for evaluation of the efficacy of the combination of 4 probiotic strains, L. rhamnosus 
GG, L. rhamnosus LC-705, Propionibacterium freudenreichii ssp. shermanii JS and 
Bifidobacterium breve Bb99 for the decrease of irritated bowel syndrome (IBS) was performed 
(Kajander and Korpela (2006)). As a part of the double-blind, randomized, placebo-controlled 
study 103 patients with RCT were randomized into the placebo group or the group receiving the 
probiotic combination in one capsule (containing 8–9 × 109 CFU of each strain) QD for 6 months. 
Patients kept a diary of abdominal symptoms and stool characteristics. The study was completed 
by 86 patients. According to observations, the probiotic intake significantly decreased IBS 


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symptoms: by 42 % in the probiotic therapy group and by 6 % in the placebo group. No changes 
in stool characteristics or quality of life were observed. The reasons for discontinuation were not 
reported, as well as the data on distribution of withdrawn patients by groups were absent. Detected 
undesirable effects of the probiotic therapy were not discussed. 
Baroja et. al. (2007) performed the open-label study (with the control group) in which 20 adults 
with clinically manifested inflammatory bowel disease (IBD) (15 patients with Crown disease and 
5 patients with ulcerous colitis) and 20 healthy control persons consumed the yogurt supplemented 
with 2 × 107 CFU/mL of L. rhamnosus GR-1 and 103 CFU/mL of L. reuteri RC-14 corresponding 
to the daily dose of L. rhamnosus and L. reuteri 2.5 × 109 CFU and 1.25 × 105 CFU, respectively. 
The intake of probiotic yogurt was associated with beneficial anti-inflammatory effects in patients 
with IBD in combination with an extending pool of regulatory Т-cells in peripheral blood. In other 
eight patients with IBD, who consumed yogurt without supplements, no anti-inflammatory effects 
were observed. According to the authors’ conclusion, “the short-time consumption of yogurt 
supplemented with Lactobacillus GR-1 and RC-14 strains induced the formation of beneficial anti-
inflammatory environment in peripheral blood of IBD patients and was not associated with any 
adverse effects”. It’s particularly noticeable, that in this study there were no detected effects which 
could indicate the penetration of affected gastrointestinal barrier in patients with IBD, supporting 
the previous evidence for the infectivity absence in these strains. 
3.3.5 Overview of safety data 
In studies performed in different groups (adults, children) reviewed above, most authors did not 
observe and report any adverse reactions to the LGG administration even in such high dose as 
1012 CFU/day. There are anecdotal reports of mild gastrointestinal symptoms such as nausea, 
abdominal cramping, flatulence or abdominal distension, but no cases of discontinuation due to 
adverse events were reported in any of the studies. Even in these cases the occurrence of AE was 
comparable with that in the control group. No serious adverse reactions were encountered in any 
of clinical studies.  
In total these observations indicate the safety of the LGG supplement used at recommended doses. 
However due to the fact that there are live bacteria, the probability for the development of adverse 
effects, associated with their pharmacokinetic properties, remains. As stated above, the bacteria of 
the LGG strain are metabolically active and are able to regulate the immune response in the host 
organism. This capability is commonly characterized as positive, but in some cases it is the reason 
of adverse effects. In this section we’ll discuss relevant cases and perform the overview of adverse 
reactions reported.  


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According to the report of 2002, collectively published by the World Health Organization (WHO) 
and Food and Agricultural Organization  (FAO) which are structural divisions of the United 
Nations Organization, probiotics can theoretically induce the following four types of side effects: 
1. Systemic infections 
2. Adverse metabolic activity 
3. Immune hyperstimulation in sensitive persons 
4. Gene transfer 
Slight gastrointestinal symptoms were reported as well. The Working group of WHO/FAO 
recommends to perform the safety assessment of novel probiotic strains based on antibiotic 
resistance, toxin production and hemolytic potential, metabolic activity, including the synthesis of 
D-lactate and deconjugation of bile salts; to perform studies in human for adverse effects 
evaluation and post-marketing observation of commercial users; and, ideally, to assess their use in 
immunocompromized animals in order to determine the probiotic organism’s infectivity in the 
particular host (Doron et al. 2015). 
Hibberd et al. (2014) published the data from the safety study of a drug containing Lactobacillus 
rhamnosus GG in elderly healthy volunteers. The main goal of this open-label clinical study was 
to evaluate the safety and tolerability of 1 × 1010 CFU of Lactobacillus rhamnosus GG taken orally 
twice a day in elderly volunteers for 28 days. 
Fifteen elderly volunteers aged 66-80 received Lactobacillus rhamnosus GG capsules containing 
1 × 1010 CFU twice a day for 28 days, and were monitored for 56 days. 
No serious adverse events were reported in healthy volunteers during the study. A total of 
47 adverse events were reported in 15 volunteers (1 to 7 per volunteer), 39 (83%) of which were 
assessed as mild, and 40% were assessed as possibly related to the use of Lactobacillus 
rhamnosus GG. The most common adverse events were recorded from the gastrointestinal tract 
(bloating, gas, and nausea), 27 of which were assessed as mild adverse events, and 3 as 
moderate. The study showed that Lactobacillus rhamnosus GG is safe and well tolerated by 
healthy adult volunteers aged 65 and older. In the first week of taking LGG, mild and passing 
gastrointestinal symptoms were recorded, which did not affect the daily activity of the volunteers. 
After the first week, most of the gastrointestinal symptoms appeared periodically during treatment 
and during the follow-up period with no identified Association with LGG. 
In studies with healthy participants, the AE occurrence in the use of Lactobacillus rhamnosus GG 
at doses 3.6 × 1011 CFU are usually not reported. Only in the study by Schultz et al. (2004) in 3 
study subjects, abdominal distension was registered; there were no reports about other AE in this 


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study. Summarized information on AE occurrence during the Lactobacillus rhamnosus GG intake 
by healthy subjects is represented in the Table 5. 
Table 5. Summarized safety data of Lactobacillus rhamnosus GG in healthy subjects  
Author  
Study Population 
(N) 
Study goal 
Duration 
Strain/Dose 
AE 
Goldin 
1992 
Healthy 
volunteers (N=76) 
Survival in GIT 
7, 28 and 
35 days 
LGG 4 x 1010, 
1.6 x 1011, and 
3.6 x 1011 CFU 
No reports 
Saxelin 
1995 
Healthy 
volunteers (N=20) 
Survival in GIT 
7 days 
LGG 1.6 x 108 
CFU and 1.2 x 
1010 CFU 
No reports 
Jacobsen 
1999 
Healthy 
volunteers (N=12) 
Survival in GIT 
18 days 
LGG 
1010 
CFU/day 
No reports 
Saxelin 
1993 
Healthy 
volunteers (N=44) 
Determination 
of 
LGG 
concentration in 
feces  
7 days 
1 x 109 CFU, 4 x 
109 and 8 x 109 
in tablets/ 
2 x 109 CFU and 
1,2 x 1010 CFU 
with fermented 
milk 
No reports 
Alander 
1999 
Healthy 
volunteers (N=24) 
GIT 
colonization 
12 days 
LGG 6 x 1010 
CFU 
No reports 
Saxelin 
1999 
Healthy 
volunteers (N=40) 
GIT 
colonization 
7 days 
LGG 1.5 x 106, 
1.5 x 107, 1.5 x 
108, 1.5 x 109, 
1.5 x 1010, and 
1.1 
x 
1011 
CFU/day 
No reports 
Millar 
1993 
Prematurely-born 
children (N=20) 
GIT 
colonization 
14 days 
LGG 2 x 108 
CFU 
No reports 
Schultz 
2004 
Pregnant women 
(N=6)  
LGG 
colonization in 
children through 
the intake by 
pregnant women  
6 weeks 
LGG 2 x 109 
CFU/day 
Mild abdominal distension 
in 3 study subjects 
Elmadfa 
2001 
Healthy 
volunteers (N=12) 
Vitamin Serum 
Levels 
4 weeks 
LGG 2.5 x 1010 
CFU/day 
No reports 
Hatakka 
2001 
Children 
at 
kindergartens (1-6 
years, N=571) 
Prevention 
of 
infections 
30 weeks 
1.3-2.6 x 107 
CFU  
No differences in AE, 
including stool rate and 
consistency, 
abdominal 


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Author  
Study Population 
(N) 
Study goal 
Duration 
Strain/Dose 
AE 
pain, 
allergy 
symptoms 
between 
groups 
were 
observed. 
Hojsak 
2010a 
Children 
at 
kindergartens (1-6 
years, N=281) 
Prevention 
of 
infections 
3 months 
LGG 
109 
CFU/day 
No reports 
Oksanen 
1990 
Adults 
and 
children 
(10-80 
years old, N=820) 
Prophylaxis 
of 
traveler’s 
diarrhea 
During the 
travel 
LGG 
2x109 
CFU/day 
No reports 
Kalliomä
ki 2003 
Children aged 4 
years (N=107) 
Prophylaxis 
of 
atopic dermatitis 
4 weeks 
LGG 2 x 1010 
CFU  
No reports 
Galpin 
2005 
Children aged 36-
60 
months 
(N=164) 
Effect of LGG 
on 
intestinal 
wall integrity 
30 days 
1011 CFU/day 
No reports 
Pelucchi 
2012 
Pregnant women 
in 
the 
3rd 
trimester, children 
aged less than 2 
years (NA) 
Prophylaxis 
of 
atopic dermatitis 
varied 
LGG 2 x 1010 
CFU/day 
No reports 
Panduru 
2015 
Pregnant women 
in the 1st and 3rd 
trimester, children 
aged less than 9 
years (NA)  
Prophylaxis 
of 
atopic dermatitis 
varied 
LGG 1-2 x 1010 
CFU/day 
No reports 
3.3.5.1  Systemic infections 
In a number of reports on adverse reactions, episodes of infections caused by microorganisms 
similar to probiotic strains, were described in patients who used probiotics before the occurrence 
of symptoms. However, most of those cases can be explained by characteristics of the host 
organism, namely by the immunodeficiency or the immunity weakening due to serious underlying 
diseases. DeGroote et al. (2005) described a bacteriemia case, caused by L. rhamnosus GG, in use 
of this probiotic in a child with “short gut” syndrome. Barton et al. (2001) reported three cases in 
infants with gastrointestinal congenital abnormalities requiring a surgical correction, who 
developed sepsis, caused by Pediococcus sp.; the pathogenesis of these infections could be 
associated with probiotic strains. Tommasi et al. (2008) described a bacteriemia case, caused by 
Lactobacillus casei, in 66 years old, non-immunocompromized man with the history of unclear 
genesis fever. The blood culture showed bacteriemia caused by leuconostoc, however the 


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subsequent analysis by means of polymerase chain reaction with 16S RNA sequencing the 
Lactobacillus casei was identified, and the successful antibiotic therapy was performed. According 
to the authors’ conclusion, bacteriemia, caused by probiotic strains, is rarely-occurring, however 
it is commonly underestimated because of being related to contaminating species and being not 
considered to be the main causative agent. Vahabnezhad et al. (2013) described a bacteriemia case, 
caused by Lactobacillus, in 17 years old boy with ulcerous colitis, being treated with systemic 
corticosteroids and infliximab. The patient was admitted with complaints for body temperature 
rise to 38.9 °С, flushing and shivers after 1 week after starting with the Lactobacillus rhamnosus 
GG probiotic. The results of the first blood culture on the 2nd- day of the temperature rise 
Lactobacillus had been identified, however the subsequent blood cultures on 3rd and 5th days were 
negative. The patient was administered with the empiric antibiotic therapy for 5 days, wherein the 
body temperature normalized up to the 8th day of the disease. This report indicates a potential risk 
of the bacteriemia development caused by Lactobacillus bacteria, in immunocompromised patients 
with underlying highly severe ulcerous colitis. 
Kunz et al. (2004) published two cases of bacteriemia, caused by Lactobacillus bacteria, with the 
background probiotic therapy associated with the “short gut” syndrome. This publication was 
commented by Young and Vanderhoof (2004), who had demonstrated in several studies, that the 
L. rhamnosus probiotic strain strengthens intercellular contacts of the mucous membrane and 
subsequently decreases the intestinal penetrance, which may be the main factor responsible for the 
efficacy of this strain in the prophylaxis of food allergy in infants. In view of above mentioned 
observations bacterial translocation is less likely factor in the development of sepsis. It appears to 
be possible that one of etiological factors is the contamination of the central catheter, especially in 
hospitalized patients characterized by a high incidence of nosocomial infections in principle, since 
opening capsules is necessary to administer the preparation to infants. Caregivers must take special 
precautions changing diapers for an infant with the installed central catheter; obligatory measures 
include the thorough handwashing to prevent any bacterial dissemination. These precautions are 
usually ignored in opening of capsules containing powder and its preparing for administration, 
nevertheless this powder contains live bacteria in much higher concentration than feces do. 
Authors did not indicate by what means blood samples had been drawn for culturing (from the 
central catheter or peripheral vein), while it could help to establish the source of the bacterial 
invasion. This publication underlines the importance of the observation obtained, namely that all 
probiotics are necessary to be used with caution in patients with weak health, which especially 
relates to patients with the central catheter.  


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Land et. al. (2005) described two patients receiving Lactobacillus probiotic strains, who had 
subsequently developed bacteriemia and sepsis due to Lactobacillus bacteria. The molecular 
analysis by the DNA fingerprinting method had shown that the Lactobacillus strain isolated from 
blood samples was undistinguishable from one consumed by patients. This report for the first time 
demonstrated, that invasive disease may be caused by Lactobacillus. Authors highlighted that this 
report is not a base to refuse from the proper use of Lactobacillus or other probiotic strains, rather 
it should serve as a reminder that in selected populations these medications may cause invasive 
disease. Mackay et al. (1999) published a case of 67-year-old man with the diagnosis of mild mitral 
valve regurgitation due to the mitral valve prolapse, who developed bacterial endocarditis, caused 
by L. rhamnosus on the blood culture data. The complete recovery was the result of intravenous 
administration of beta-lactams. Furthermore, Presterl et al. (2001) published the report on bacterial 
endocarditis and septic arthritis in man who consumed a large amount of probiotic yogurt.  
In 2018,  Naqvi et al. published the report on fatal endocarditis, caused by Lactobacillus, in a 
young patient with complicated cirrhosis and past colitis, caused by Clostridium difficile. In the 
same publication the literature review is provided. There were entering reports on the development 
of invasive infections, such as meningitis, endometritis, peritonitis, pneumonia, bacteriemia and 
endocarditis. Lactobacillus are the causative factor in 0.05–0.4 % of all endocarditis cases. As the 
tendency for the development of said infections in immunocompromised patients was noted, the 
related mortality varies from 23 to 29 %.  
Griffiths et al. (1992) reviewed 2 Lactobacillus-induced endocarditis cases and 39 cases from 
literature, and according to the results the lower (39 %) response rate to isolated drug therapy and 
mortality in the studied cohort on the level of 27 % had been established. As possible reasons low-
quality studies of antibiotic sensitivity and the absence of standardized therapy were proposed, 
including the use of semi-optimal antibiotics inactive for Lactobacillus (Griffiths et al. 1992; Husni 
et al. 1997). Similarly, Cannon et al. (2005) reviewed 241 cases of clinical Lactobacillus-induced 
infections. 73 patients in this sample had endocarditis. Most of these patients initially had the 
structural cardiac abnormalities (63 %), dental problems or underwent a dental procedure recently 
(47 %). The development of clinical infections was also related to invasive interventions, such as 
endoscopy and colonoscopy. Lactobacillus have a capability for collagen and fibrinogen binding, 
platelet aggregation and glucosidase and protease enzymes production which may facilitate 
colonization of the vascular endothelium (Harty et al. 1994; Oakey et al. 1995). In indicated cases 
the most commonly identified species were L. casei and, more rarely, L. rhamnosus and L. 
plantarum. There are only 11 reports in literature of the development of endocarditis, caused by L. 


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rhamnosus, in adults, two of them were associated with the probiotic use (Mackay 1990, Presterl 
et al. 2001).  
As several cases of the development of Lactobacillus-induced bacteriemia are known in patients 
with the central catheter in intense therapy settings, experts recommend to maintain the thorough 
hand hygiene during manipulations with the central catheter after manipulations with probiotic 
medications.  
Furthermore, Forestier et al. (2008) performed the pilot prospective, double blind, randomized, 
placebo-controlled study in patients of the resuscitation and intensive care unit (ICU). Starting 
from the 3rd day after the admission to ICU and until the discharge patients received Lactobacillus 
casei rhamnosus 35 at a dose of 109 CFU BID; the number of treatment days is not provided. 
Totally 208 patients were involved in the study (146 men and 62 women, average age was 
58.4 years old): 102 in the probiotic therapy group and 106 in the placebo group. The goal of this 
study was to determine the potential of probiotic therapy to decrease the occurrence of respiratory 
infections, caused by Pseudomonas aeruginosa. The most patients had undergone a surgery or had 
an injury or respiratory disorders. During the probiotic therapy the significant decrease in the 
occurrence of infections caused by P. aeruginosa was noted, and the time to the development of 
infections, whereas no effect on the occurrence of infections caused by other microorganisms was 
determined. No cases of sepsis caused by Lactobacillus, were observed. In spite of the fact that in 
the study the measurement of the occurrence of L. rhamnosus-induced bacteriemia was not 
contemplated, it was shown that the probiotic use is safe and may provide the protective effect on 
pseudomonas infections. However, the study group was relatively small, and the study was 
performed on the base of the single center. 
Strong evidence for the safety of the L. rhamnosus GG (LGG) strain (one of the most popular 
probiotic strains in Finland) was obtained in the Finnish review indicating the absence of increase 
in Lactobacillus-induced bacteriemia cases over ten years from 1990 to 2000, in spite of increasing 
popularity of this probiotic (Salminen et al. 2002). Lactobacillus were identified as causative 
factors in 0.02 % of all positive blood cultures. There were no time variations of said occurrence 
parameter over the considered ten years. Eleven of 89 strains isolated from blood were similar to 
the probiotic LGG strain according to the results of pulse-field gel electrophoresis (Salminen et al. 
2004), however within the subsequent study the difference between LGG-like isolates from the 
blood culture and the probiotic LGG strain based on phenotypical characteristics was established 
(Ouwehand et al. 2004) according to the results of studies demonstrating pathogenicity, including 
adhesion parameters in vitro and induction of respiratory burst. 


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There are known studies of the safe probiotic use in recipients of solid organ grafts and other 
immunocompromised patients, wherein no systemic infections were reported (Rayes et al. 2002; 
Rayes et al. 2005; Doron et al. 2015).  
Anukam et al. (2008) studied the efficacy of probiotics in 24 adult women (between 18 and 
44 years old) with HIV infection / AIDS with clinical manifestations of moderate diarrhea, CD4-
cell count more than 200, receiving no antiretroviral medications or dietary supplements. Patients 
consumed 100 mL of yogurt with or without supplements daily for 15 days. The hematologic 
profile, CD4-cell count and quality of life were evaluated on the baseline and after 15 and 30 days 
of the probiotic yogurt consumption. No significant differences in hematologic parameters before 
and after the probiotic yogurt consumption were noticed in either of groups. In the probiotic yogurt 
group, the mean WBC quantity was measured as 5.8 ± 0.76 × 109/L, 6.0 ± 1/02 × 109/L and 5.4 ± 
0.14 × 109 L on the baseline, after 15 and 30 days, respectively. However, the mean CD4-cell 
count remained unchanged or increased to 15th and 30th day in 11 of 12 probiotic-consuming 
patients compared with 3 of 12 patients in the control group. Diarrhea, flatulence and nausea 
resolved in 12 of 12 patients from the probiotic yogurt group within 2 days compared with 2 of 
12 patients from the conventional yogurt group after 15 days. In this study the beneficial effect of 
probiotic yogurt on the quality of life in patients with HIV infection / AIDS was demonstrated, 
and a little benefit of simple fermented products in the AIDS treatment was established.  
Within the prospective, double-blind, randomized, placebo-controlled study of the effect of the 
LGG on the intestine wall integrity the evaluation of clinically healthy children from Malavi with 
the increased risk of enteropathy was performed (Galpin et al. 2005). Tropic enteropathy is a 
condition of asymptomatic atrophy of intestinal villi, being common in developing countries. 
164 children were enrolled in the study, 161 of them completed it. Enrollment criteria included the 
age between 36 and 60 months; the average age of children (76 boys and 88 girls) was 46.4 months 
at the entrance. At the time of enrollment, children were clinically examined, and their parents 
completed the questionnaire on demographic data and sanitary conditions. Children were given 
2 capsules of the LGG strain each at a dose of 5 × 1010 CFU daily (daily dose = 1011 CFU) or 
placebo for 30 days. Children were examined twice a week during the entire study period. 
The main outcome of the study was the absorption parameters for mannitol, lactulose and sucrose 
according to urinalysis results. As observed, the administration of the LGG strain had no effects 
on mannitol, lactulose and sucrose absorption. 
Caregivers did not report any vomiting development or other undesirable effects during the study. 
There were no differences in growth parameters or the occurrence of fever, cough and diarrhea. 


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Honeycutt et al. (2007) undertook the prospective, double-blind, randomized, placebo-controlled 
study in the pediatric resuscitation and intensive care unit for 16 in-patient beds to in order to 
evaluate the LGG strain potential for the decrease in the occurrence of nosocomial infections. 
During the period from April 2004 to December 2004 61 children were enrolled in the study. The 
everyday screening of all newly admitted patients was performed. Patients were withdrawn from 
the study if the following criteria were met: confirmed or suspected intestine perforation, 
confirmed or suspected mechanical intestinal obstruction, absolute neutrophils count < 0.5 × 
109 cells/L, intolerance of required enteral nutrition volume on the attending physician’s opinion, 
use of the probiotic medication in any day of the week before the enrollment in the study, 
participation in another clinical study, absence of parents or their consent. Patients were 
randomized into the groups of Lactobacillus rhamnosus GG strain treatment (Culturelle, ConAgra 
Foods, Omaha, Nebraska) or placebo (inulin) one capsule daily, until the discharge from the 
hospital. 61 patients were randomized: 31 into the active treatment group and 30 into the placebo 
group. In the control group, four infectious diseases were registered in three patients. In the active 
treatment group 11 infectious diseases were registered in six patients. The relative risk of infection 
development in the active treatment group was 1.94 (confidence interval [CI]: 0.53–7.04; 
p = 0.31). The mean number of infectious diseases was 1.83 and 1.33 in the active treatment group 
and in the control group respectively (difference = 0.5; p = 0.52). There were no adverse events in 
the study group. But due to recent safety concerns for the L. rhamnosus GG strain use and the 
absence of benefits according to the interim analysis data, the study was discontinued on the 
decision of Investigators. 
Salminen et al. (2004) published the review article on the clinical relevance of Lactobacillus-
induced bacteriemia with a special attention for the L. rhamnosus GG strain. Authors performed 
the review of 89 cases of L. rhamnosus-induced bacteriemia in order to evaluate risk factors and 
outcomes. In 53 % of cases the analysis of causative species was performed. In 11 cases the 
isolated species from the isolate was identical to the species being used in the probiotic 
composition. Most patients in all groups had underlying diseases with inevitable or soon lethal 
outcome (Class 3 or 4 on McCabe criteria). These are 91 % of patients from the LGG group. 
Predisposing factors for bacteriemia development included immunosupression, previous 
prolonged hospitalization and underwent surgery. No significant difference in said predisposing 
factors and clinical characteristics between patients with bacteriemia caused by different 
Lactobacillus species except the higher level of С-reactive protein in patients with L. rhamnosus-
induced bacteriemia, was determined. The mortality rate was 26 and 48 % after 1 month and 1 year 
respectively. The contribution of other concomitant bacteria to the results obtained could be 


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completely excluded, because in 39 % of cases bacteriemia had the polymicrobial etiology, but 
respective cases were not associated with higher mortality rate. Within the study period serious 
septicemic complications were detected in several cases only.  
3.3.5.2  Unfavorable metabolic effects 
In the double-blind, randomized, placebo-controlled study (Besselink et al. 2008) the evaluation 
of the multistrain probiotic efficacy in the prophylaxis of infection complications in 296 patients 
with severe pancreatitis was performed. In the probiotic therapy group the higher mortality rate 
associated with intestine ischemia was registered. As a proposed reason of intestine ischemia in 
critically ill patients receiving the contemplated combination of 6 probiotics, authors stated a 
possible growth in oxygen requirement of the intestine mucous under the conditions of already 
reduced blood supply. It’s also possible that probiotics trigger an inflammatory reaction in small 
intestine which results in the decrease of capillary blood flow. 
The results of this study caused serious concerns and stimulated the detailed study of this issue by 
health authorities of Netherlands. According to the results of evaluation it was established that the 
represented study had a number of significant drawbacks in the design, approval and performance, 
so these results should be interpreted with caution (the comment by Lancet editors; 2010). 
In two previously performed less-scaled studies (Olah et al. 2002; Olah et al. 2007) the decrease 
in septic complications occurrence, surgical interventions and infected necrosis was observed in 
patients with pancreatitis receiving the symbiotic medication, containing lactic acid bacteria and 
cellulose. Intestine ischemia was not mentioned by authors.  
At the same time, in two other studies in critically ill adults (Jain et al. 2004) and children 
(Honeycutt et al. 2007) the insignificant but potential increase in the occurrence of infectious 
complications was stated during the probiotic therapy.  
Other metabolic risks include effects of D-lactate, being synthetized by probiotic strains, and bile 
acid deconjugation. There are five reports in literature on acidosis induced by D-lactate (Kee et al. 
2006; Munakata et al. 2010; Oh et al. 1979), one of which had been reported for the patient with 
the “short gut” syndrome. 
In 2017, Vitetta et al. published the review article related to D-lactate-acidosis and strain 
specificity. Authors criticize the discipline-specific approach to the safety of probiotic medications 
and unwillingness to consider scientifically justified evidence. However, there is an experience of 
the satisfactory use of the probiotic L. rhamnosus strain in studies, and authors are aware of its 
efficacy and safety.  


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3.3.5.3 Immune hyperstimulation 
Because of probiotics’ influence on congenital and acquired immunity reactions, including effects 
on cytokine secretion and dendrite cell function (Vaarala et al. 2003; Veckman et al. 2004; Braat 
et. 2004; Drakes et al. 2004), the concerns about the risk of immune response hyperstimulation in 
some persons possibly leading to autoimmune or inflammatory reactions arises. Theoretical 
concerns are not supported by any clinical cases. 
3.3.5.4 Gene transfer 
Lactic acid bacteria carry plasmids with genes, conferring the resistance to tetracyclines, 
erythromycin, chloramphenicol or lincosamide, macrolids, streptomycin and streptogramin (Lin 
et al. 1996; Gevers et al. 2003). The capability for conjugation transfer of genes from enterococci 
to Lactobacillus and Lactococci in animal intestine and in vitro was observed; but the gene transfer 
to Lactobacillus is observed rather rarely (Morelli et al. 1988). The attempts were made for 
molecular identification of genes for vancomycin resistance in the Lactobacillus genome. Related 
genes were not found. 
Based on the results of hybridization analysis or polymerase chain reaction no genes Van A, B, H, 
X, Z, Y or S were identified (Klein et al. 2000; Tynkkynen et al. 1998). Despite the theoretical 
possibility of lateral gene transfer between probiotic bacteria and other bacteria living in or outside 
the intestine, there is no clinical evidence of the possibility of antimicrobial resistance transfer. 
This observation is especially important in view of the widespread use of probiotics 
simultaneously with antibiotics. 
3.3.5.5  Gastrointestinal adverse effects 
In studies, minor symptoms of the gastrointestinal tract, such as abdominal cramps, nausea, soft 
stools, flatulence and distortion of taste sensations, were recorded against the background of 
probiotic therapy. Nevertheless, according to a meta-analysis and a systematic review of the use 
of probiotics aimed at prevention of diarrhea caused by Clostridium difficile, the probability of 
developing these adverse effects is 18–20% lower in patients receiving probiotics than in control 
individuals (Johnston et al. 2012; Goldenberg et al. 2013) 
3.4 
A brief description of the known and potential risks and benefits to research subjects, 
if there are any 
Preclinical and clinical studies of the components of the products planned for use in this study 
indicate a good safety profile and good tolerability of LRG-002, capsules. A list of known adverse 
effects of these products is presented in section 3.2.  


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During the study, venous blood is supposed to be taken for analysis - about 12 ml (about 
1 tablespoon) on day 1, day 7 ± 2 and day 15 ± 2, i.e. the total volume of blood that will be taken 
for the study shall not exceed 36 ml for the entire period of the study. This is a clinically 
insignificant amount and rate of blood loss for an adult without severe concomitant diseases. 
Potentially, a bruise or hematoma is possible due to venipuncture, as well as the development of 
phlebitis or thrombophlebitis at the injection site. 
The research center staff will make every possible effort to minimize the risks for patients 
associated with the research procedures and treatment within the study. In the case of adverse 
events or other health problems, the patient will be provided with the necessary medical care. 
The benefits of participating in the study are related to the possibility of conducting a series of 
laboratory and instrumental examinations, treatment under the supervision of highly qualified 
doctors, and treatment with the investigational drugs free of charge for the study participant. 
3.5 
Description and justification of the method of administration, dosage, dosing regimen 
and course of treatment 
3.5.1 Description and justification of the method of administration, dosage, dosage regimen 
and course of treatment with the investigational drug 
To achieve a positive effect, probiotics should be taken in sufficiently high doses. The proposed 
dose of Lactobacillus rhamnosus GG is within the range of doses that have proven effective in 
well-planned and conducted randomized controlled trials described in the metanalysis Szajewska, 
2015, Hempel, 2012, McFarland, 2006, as well as in the studies, carried out by Vanderhoof, 1999, 
Arvola, 1999, Johnston, 2006, Goldenberg, 2015. Besides, a dose of Lactobacillus rhamnosus GG 
in LRG-002 product corresponds to the doses recommended in the published guidelines of the 
World Gastroenterological Organization (WGO, 2017) and the European Society of Pediatric 
Gastroenterologists, Hepatologists and Nutritionists (ESPGHAN, 2016).  
According to the recommendations of the World Gastroenterological Organization, given in the 
international guidelines on probiotics and prebiotics (WGO, 2017) considering dosage in the case 
of antibiotic-induced diarrhea, the recommended dose of Lactobacillus rhamnosus GG for children 
is 1–2 × 1010 CFU, and for adults −1010 CFU twice daily.  
The developed product contains at least 1010 CFU of Lactobacillus rhamnosus GG per capsule.  
The investigational medicinal product and placebo in the frameworks of this study in accordance 
with the draft instructions for medical use of LRG-002 medicinal product will be prescribed 
according to the following scheme:  


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Single dose - 1 capsule; the investigational medicinal product/placebo will be taken orally 2 times 
a day (morning and evening) for 14 days. The tested product / placebo capsule is swallowed with 
some water. In case Visit 1 took place in the afternoon, only one capsule is allowed on the first 
day. 
The medicinal product is recommended to be taken with meals, as this ensures its maximum 
efficacy, not less than 3 hours after taking antibiotics. 
It must not be taken concomitantly with alcohol, fruit juices or hot beverages. 
3.5.2 Justification of placebo use 
Due to the need for blinding of this study, a placebo will be used in the form of capsules for oral 
administration.  The use of placebo is necessary for formation of objective conclusions about the 
efficacy and safety of the investigational medicinal product and is a standard practice. Efficacy of 
probiotic strains in comparison with placebo is shown in a number of clinical studies. 
In this study, patients will not be exposed to the excess risk associated with placebo, as they will 
receive antibacterial therapy of the underlying disease. 
Thus, the use of placebo in the study does not threaten the safety of patients and is fully consistent 
with international practice in clinical trials. 
3.5.3 Regulatory frameworks 
This document is a clinical trial protocol, which is planned in accordance with the principles of 
the World Medical Association Declaration of Helsinki (Adopted by the 18th World Medical 
Assembly in Helsinki in June 1964, the latest revision was approved at the 64th Assembly in 
Fortaleza in October 2013), the Tripartite Guideline for Good Clinical Practice (GCP, ICH E6 
(R2) dated 11/09/2016) and is regulated by the current legislation of the Eurasian Economic Union 
(EAEU) and the Russian Federation (RF): 
• The rules of marketing authorization and assessment of medicinal products for medical use 
(approved by Decision No.78 of the Council of the Eurasian Economic Commission dated 
November 3, 2016); 
• The rules of Good clinical practice of the Eurasian Economic Union (approved by Decision of 
the Council of the Eurasian Economic Commission dated November 3, 2016 No. 79); 
• Federal law No. 61-FZ dated 12.04.2010 “On circulation of medicines” (in the current edition); 
• Federal law No. 152-FZ dated 27.07.2006 "On personal data” (in the current edition); 


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• Order of the Ministry of Health of the Russian Federation dated April 1, 2016,  N 200n “On 
Good Clinical Practice Approval”; 
• Russian Federation national standard GOST R 52379-2005 "Good clinical practice”; 
• Resolution of the government of the Russian Federation No.714 dated 13.09.2010 (as amended 
and supplemented) "On approval of standard rules of compulsory life and health insurance of a 
patient participating in clinical trials of a medicinal product”; 
• The order of the Ministry of health of the Russian Federation No. 986n dated November 29, 
2012 “Approval of the Regulations of the Board of Ethics” (in the current edition). 
• The order of the Federal Service for Surveillance in the Health Care Sector (“Roszdravnadzor”) 
of the Russian Federation No. 1071 dated February 15, 2017, “On approval of the 
pharmacovigilance procedure” 
3.6 
Description of study population 
Men and women aged 18 to 65 years old with acute respiratory disease who signed an informed 
consent to participate in the study, meeting the inclusion criteria (see section 6.1.) and not having 
the criteria for non-inclusion (see section 6.2.) 
4 
Study aims and objectives  
4.1 Study goal 
The goal of this study is to investigate the efficacy and safety of LRG-002 investigational 
medicinal product, capsules (Lek d.d., Slovenia) in comparison with placebo, as an adjunct 
treatment for prophylaxis of antibiotic-associated diarrhea (AAD) in patients with acute 
respiratory diseases (ARDs) receiving a standard antimicrobial therapy. 
4.2 
Study objectives 
Main objective: 
To evaluate the incidence of AAD while taking LRG-002, hard capsules (Lek d.d., Slovenia), as 
compared to placebo in antibiotic-treated patients with ARDs, receiving standard antimicrobial 
therapy; 
Secondary objective: 
To evaluate the safety of LRG-002 therapy, hard capsules (Lek d.d, Slovenia), as compared with 
placebo in antibiotic-treated patients with ARDs, receiving standard antimicrobial therapy. 


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5. 
Study Design  
5.1 Main and additional studied parameters 
5.1.1 Efficacy parameters 
5.1.1.1 Primary efficacy parameter 
An assessment of frequency of occurrence of AAD from 1 to the last day of LRG-002 
administration compared with placebo in antibiotic-treated patients with ARDs, receiving standard 
antimicrobial therapy is selected as the primary efficacy endpoint. The primary efficacy criterion 
will be considered achieved if the odds ratio for the AAD incidence between two groups is 
significantly higher than 1 (i.e. AAD incidence in the LRG-002 group is lower than in placebo 
group). 
AAD is defined as diarrhea associated with the AB use caused by C. difficile or of otherwise not 
identified etiology, upon analysis of stool samples and differential diagnostics according to 
investigator's judgment.  
Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale) three 
times a day (frequent bowel movements with formed stool is not considered as diarrhea) in 
accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the 
investigator. 
5.1.1.2 Secondary efficacy parameters 
The following criteria were selected as secondary efficacy criteria of the therapy in all study groups 
for a comparative assessment of the therapeutic effect: 
• The occurrence of bowel movements per day (according to the diary data) in the treatment group 
compared with the placebo group;  
• The incidence of any diarrhea in the treatment group compared with the placebo group;  
• The incidence of C. difficile-associated AAD in the treatment group compared with the placebo 
group;  
• The incidence of AAD not associated with C.  difficile in the treatment group compared with the 
placebo group;  
• The duration of AAD (the time from the onset of AAD to the normalization of stool form 
according to BSFS (types 1, 2, 3 and 4) and the presence of normal stool within 48 hours)) in the 
treatment group as compared to the placebo group;  


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• Duration of any diarrhea (the period from the diarrhea onset to the normalization of stool form 
according to BSFS (types 1, 2, 3 and 4) and the presence of normal stool within 48 hours)) in the 
treatment group vs the placebo group;  
• The changes in stool consistency (according to Bristol Stool Form Scale) (according to the diary 
data) in the treatment group as compared to the placebo group;  
• The changes and severity of gastrointestinal symptoms, including nausea, vomiting, flatulence, 
abdominal pain and decreased appetite (according to the diary data) in the treatment group as 
compared to the placebo group;  
• Change in body weight at Visit 3 compared with Visit 1 in the placebo group as compared to the 
treatment group;  
• Hospitalization rate in the treatment group compared with the placebo group;  
• The number of days of using standard symptomatic therapy (as “rescue medication”) to relieve 
symptoms of acute diarrhea in the treatment group as compared to the placebo group; 
• The number of patients using standard symptomatic therapy (as “rescue medication”) to relieve 
symptoms of acute diarrhea in the treatment group as compared to the placebo group. 
5.1.2 Safety parameters 
Safety evaluation will be based on the following parameters (between Visits 1 and 3), compared 
between the investigational medicinal product and placebo: 
Frequency of adverse events (AEs) and/or serious adverse events (SAEs) in the treatment groups, 
including:  
• Overall AE rate as compared to placebo; 
• Frequency of AEs according to the results of physical examinations during each visit compared 
with placebo; 
• AE incidence according to the results of the vital signs assessment (HR, BP, BT, RR) at each 
visit compared with placebo; 
• AE incidence according to the ECG results on Day 15 (± 2) compared with placebo; 
• AEs incidence according to the results of laboratory examinations on Days 7(± 2) and 15(± 2) 
compared with placebo; 
• Frequency of AEs according to the everyday patients’ records of well-being self-evaluation in 
the diary. 
Diary records will be reviewed by the Investigator. In case the researcher considers that the records 
in the diary meet criteria of AE, the patient will be questioned about this event, and all information 
(including an evaluation of causality) will be documented. 


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Adverse event will be described according to the following scheme: 
• Description of adverse event; 
• Seriousness of adverse event (compliance with seriousness criteria); 
• severity; 
• duration; 
• causal relationship with the investigational product; 
• actions taken in relation to the study drug; 
• actions taken in relation to the patient; 
• outcome. 
Adverse events will be coded according to MedDRA terms. 
5.2 Description of study design 
5.2.1 Study type 
A multi-center, double-blind, randomized, placebo-controlled, parallel-group clinical study in two 
parallel groups. 
5.2.2 Flowchart of study design 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 7 ± 2 
Screening  
Antibacterial therapy +  
LRG-002 n=260 
Randomization n=520 
Day 1 
Visit 1 
Antibacterial therapy +  
Placebo n=260 
Visit 2 
LRG-002 n=260 
Placebo 
n=260 
Visit 3 
Day 15 ± 2 


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5.2.3 Study procedures 
5.2.3.1 Schedule of research procedures in tabular form 
Table 6. Visit schedule 
Study period 
Screening/ 
randomization/ 
start of 
treatment 
Treatment 
Unscheduled 
visits 
Visits 
Visit 1 
Visit 2 
Visit 3 
 
Day after starting therapy 
Day 1 
Day 7 ± 2 
Day 15 ± 2 
 
Study procedures 
 
 
 
 
Signing 
the 
Informed 
Consent Form 
● 
 
 
 
Demographic data (date 
of birth, sex, age) 
● 
 
 
 
Body 
weight 
measurements  
● 
● 
● 
 
Height measurement 
● 
 
 
 
Medical history 
● 
 
 
 
Complaints 
collection, 
medical history update 
● 
● 
● 
● 
Reporting 
concomitant 
treatment 
● 
● 
● 
● 
Physical examination 
● 
● 
● 
● 
Vital signs assessment1 
● 
● 
● 
● 
Complete blood count2 
● 
● 
● 
 
Blood chemistry profile3 
● 
● 
● 
 
Urine pregnancy test4 
● 
 
 
 
Rapid 
test 
for 
the 
qualitative detection of 
immunoglobulin G (IgG) 
● 
 
 
 
 
1 SAD (mmHg), DAD (mmHg), respiratory rate (per minute), heart rate (beats per minute), axillary body temperature (°С) 
2 hemoglobin content, red blood cells, white blood cells, leukogram, ESR) will be carried out in the laboratory of the study site 
3 total protein, ALT, AST, total bilirubin 
4 only for women with preserved reproductive potential 
 


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Study period 
Screening/ 
randomization/ 
start of 
treatment 
Treatment 
Unscheduled 
visits 
Visits 
Visit 1 
Visit 2 
Visit 3 
 
Day after starting therapy 
Day 1 
Day 7 ± 2 
Day 15 ± 2 
 
Study procedures 
 
 
 
 
and immunoglobulin M 
(IgM) 
antibodies 
to 
COVID-19 
A 
12-lead 
electrocardiogram 
● 
 
● 
● 
Evaluation 
of 
the 
inclusion/non-inclusion 
criteria 
● 
 
 
 
Randomization 
● 
 
 
 
Dispensing 
of 
the 
investigational medicinal 
product 
● 
 
 
 
Dispensing 
of 
patient 
diary and thermometer 
● 
 
 
 
Dispensing a laboratory 
stool collection kit 
● 
● 
 
 
Collection 
of 
unused 
medication  
 
 
● 
 
Collection of patient diary 
 
 
● 
 
Collection of unused lab 
kits 
 
 
● 
 
Assessment of adverse 
events  
● 
● 
● 
● 
Evaluation of exclusion 
criteria 
 
● 
● 
● 
Assessment 
of 
the 
adherence 
to 
study 
 
● 
● 
● 


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Study period 
Screening/ 
randomization/ 
start of 
treatment 
Treatment 
Unscheduled 
visits 
Visits 
Visit 1 
Visit 2 
Visit 3 
 
Day after starting therapy 
Day 1 
Day 7 ± 2 
Day 15 ± 2 
 
Study procedures 
 
 
 
 
procedures (compliance 
with diary completion and 
study treatment) 
Assessment of diarrhea, if 
documented in the diary 
and 
face-to-face 
interview regarding its 
classification as AAD 
(according 
to 
investigator’s judgment) 
 
● 
● 
● 
5.2.3.2 Description of study procedures 
5.2.3.2.1. Collection of medical history, demographic data, anthropometry 
When compiling medical history, it is necessary to pay attention to past diseases, concomitant 
chronic diseases, hereditary background, habitual intoxications (smoking status, alcohol 
consumption, drug addiction), allergic history, previous operations and injuries, occupational 
history, and constant or periodic medicinal therapy. In relation to this disease: the date and time of 
the onset of the first symptoms, the diagnostic and therapeutic measures carried out at the time of 
the examination, their effectiveness. The data about contraception method used by the male/female 
patient should be clarified; upon signing the informed consent, the male/female patient agrees to 
use one of the methods of contraception recommended in accordance with the study protocol 
throughout the study and a month after the completion of the study. 
The primary documentation indicates gender, age of the patient, race and ethnicity of the patient. 
Patient's height is measured in centimeters using a height meter, and body weight in kilograms – 
using balance. 
Height measurement should be performed for all patients (the reasons that make it impossible to 
measure height include hairstyle features (e.g., mohawk), the patient’s refusal to take off his 


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headdress for various reasons, - for example, a turban, the patient’s inability to stand, and 
exceedence of height meter scale). Height is determined with the help of a height meter - a 
vertically placed board with divisions by centimeters and a horizontal ruler sliding on it. Scale 
error according to the standard should not exceed two millimeters. The patient is asked to remove 
shoes, heavy clothes, hairpins, and hair ornaments. The patient should touch the vertical board 
with the back of the head, back, buttocks, calves and heels; feet together. The upper border of the 
external auditory meatus should be on the same horizontal level with the lower border of the orbit 
(zygomatic bone). The patient is asked to look straight ahead. If the height of patient above the 
one of the researchers, the latter stands on the platform.  The ruler of height meter must touch the 
head, then the divisions are counted. Reading of height meter should be taken while the patient is 
still under the ruler. The error should not exceed half a centimeter. 
Patients should be weighed in the morning on an empty stomach, after urination and stool, in 
underwear (followed by a subtraction of the average clothes weight from a readout). The balance 
must stand on a rigid base, horizontally. The measurement error according to standards should not 
exceed 0.5 kg. Patient stands strictly in the center of balance with both foots. It is not allowed to 
record the body weight based on patient’s words even in cases where weight measurement is not 
possible. 
5.2.3.2.2. Physical examination and vital signs assessment 
Physical examination will be carried out according to the general rules of propaedeutics of internal 
diseases in the following sequence: general examination, examination of mucous membranes, 
including pharyngoscopy, palpation of the lymph nodes, assessment of the musculoskeletal 
system; palpation, percussion and auscultation of the main organ systems (cardiovascular, 
respiratory, digestive, urinary systems). 
Determination of the vital signs (measuring HR, RR, BP, body temperature) should be performed 
before a physical examination at rest (after 15 minutes of rest, not earlier than an hour after 
smoking cigarettes and 2 hours after eating). The pulse rate should be determined on the radial 
artery (or on the carotid artery if pulsation on the radial artery is weak) for a minute in a sitting 
position. The respiratory rate (RR) should be measured for a minute at rest in a sitting position, 
noting the respiratory movements of the chest or abdominal wall without attracting the attention 
of the patient. 
Blood pressure should be measured on the brachial artery in the patient’s sitting position according 
to the Korotkoff's method using a certified sphygmomanometer or tonometer and cuff with length 
and width to fit the length and circumference of the patient’s shoulder. 


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Body thermometry should be measured using the same type of thermometer (mercury-filled or 
electronic one) and the method (axillary temperature), which will be constant throughout the study. 
5.2.3.2.3. Laboratory Tests 
Blood sampling for analysis will be performed not earlier than 4 hours after the last meal from the 
cubital vein with a disposable sterile syringe subject to aseptic/antiseptic conditions. A sampling 
of approximately 12 ml of blood (1 tablespoon) on visits 1, 2 and 3 is necessary for analysis.  
Complete blood count (hemoglobin content, red blood cells, white blood cells, differential, ESR) 
and blood biochemistry profile (includes the following parameters: total protein, ALT, AST, total 
bilirubin) will be carried out in the laboratory of the study site. 
Urine pregnancy test using a test strip (immunochromatographic determination of beta-chorionic 
gonadotropin in the urine) is performed in all women with preserved reproductive potential at the 
screening visit. 
5.2.3.2.4. Electrocardiography 
Electrocardiography (ECG) will be performed at visit 1 and at visit 3. The ECG includes the 
registration of an electrocardiogram in 12 leads (in 3 standard and 3 augmented limb leads, as well 
as, in 6 precordial leads) at rest in the supine position. ECG interpretation will be performed by a 
cardiologist, therapist or functional diagnostics practitioner. 
5.2.3.2.5. Collection of stool samples 
Stool samples are collected in case of diarrhea by patients of both groups. Samples will be collected 
in containers dispensed in advance with the appropriate labeling: 
• 1 container - a stool sample for presence of common diarrheal pathogens - Rotavirus, 
Adenovirus, Norovirus, Campylobacter spp, Salmonella spp, Shigella spp.; 
• 1 container – stool sample for presence of C. difficile toxins  А and В; 
• 1 container - collection of stool samples for the culture of opportunistic flora: Klebsiella 
pneumoniae, Staphylococcus aureus, Proteus mirabilis, Candida spp, E. Coli, and culture of 
Yersinia spp. (special container). A detailed description of the procedure of stool sample 
collection and instructions for the patients are provided in Appendix 2. 
The drugs for the treatment of acute diarrhea can be used only in case of acute diarrhea, namely: 
the presence of liquid, watery stools (Type 6, 7 on the Bristol scale) with a frequency of 3 or more 
times within 24 hours). 
Patients will be instructed that in the case of acute diarrhea (the presence of liquid, watery stools 
(Type 6, 7 on the Bristol scale) with a frequency of 3 or more times within 24 hours), the physician 


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investigator will prescribe an oral rehydration therapy to the patient, as well as give diet 
recommendations. 
After the third stool of type 6 and/or 7, the patient should consult the physician investigator and 
get medical advice before using any remedy for acute diarrhea. 
If the patient has stools of type 6 and/or 7 according to the Bristol scale at least three times a day, 
the physician investigator will prescribe an oral rehydration therapy to the patient, give 
recommendations on the diet and can instruct the patient about the possibility of using additional 
drugs to relieve symptoms of acute diarrhea. 
5.2.3.2.6. Evaluation of patient diary 
Evaluation of patient diary is done by investigator. The assessed parameters include: 
 Dosing regimen of investigational medicinal products;  
 Dosing regimen of concomitant treatment; 
 Occurrence of bowel movements a day; 
 Stool consistency; 
 Occurrence of gastrointestinal symptoms; 
 Body temperature. 
At each visit, diarrhea is assessed and classified as AAD or non-AAD by the investigator (in the 
absence of fecal analysis results at the time of the visit, the assessment is carried out after the 
investigator receives the results from the laboratory). 
5.2.4 Study Periods 
It is allowed to conduct visits in the form of outpatient visit of a doctor and a nurse at the patient's 
home. 
5.2.4.1 Screening/randomization/treatment initiation (Visit 1) 
Visit 1 is carried out on Day 1. At this visit, the physician evaluates the patient's compliance with 
the criteria for participation in the study on the same day. If non-inclusion criteria are not 
identified, randomization is performed, the patient is given the investigational medicinal 
product/reference product, containers for collecting stool samples with the appropriate 
instructions, the patient’s diary, and training is carried out to fill out the patient’s diary (Appendix 
3). 
Procedures at Visit 1: 
Visit 1 (Day 1) 
• Collection of demographic data (year of birth, sex, age); 
• Body weight and height measurements; 


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• Medical history; 
• Reporting concomitant treatment (including medications, food supplements and medical 
devices); 
• Complaints reporting, medical history update; 
• Physical examination; 
• Measurement of vital signs (BP, HR, RR, BT); 
• Complete blood count; 
• Blood chemistry profile; 
• Rapid test for the qualitative detection of immunoglobulin G (IgG) and immunoglobulin M 
(IgM) antibodies to COVID-19; 
• Urine pregnancy test; 
• A 12-lead electrocardiogram; 
• The assessment of inclusion/non-selection criteria; 
• Randomization; 
• Dispensing of the investigational medicinal product (IMP)/placebo; 
• Dispensing of patient diary and relevant training; 
• Dispensing of a laboratory kit with the necessary consumables for collecting stool samples; 
• Adverse event assessment. 
5.2.4.2 Intermediate Follow-up Visit 
Visit 2 (Day 7 ± 2) 
Procedures at Visit 2 in each study group: 
• Complaints reporting, medical history update; 
• Reporting concomitant medications; 
• Body weight measurements; 
• Physical examination; 
• Vital signs assessment; 
• Complete blood count; 
• Blood chemistry profile; 
• Adverse event recording; 
• Evaluation of exclusion criteria; 
• Dispensing of a laboratory kit with the necessary consumables for collecting stool samples (if 
necessary); 
• Assessment of the adherence to study procedures (compliance with diary completion and study 
treatment); 


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• Diarrhea assessment based on patient diary entries and face-to-face interviews in relation to the 
use of antibiotics (AAD or non-AAD) as assessed by the investigator (in the absence of results 
of stool analysis at the time of the visit, the assessment is carried out after the investigator 
receives the results from the laboratory). 
5.2.4.3 Treatment completion visit (Visit 3, Day 15 ± 2) 
Visit 3 is carried out in the morning on the day 15 ± 2, the patient must come to the study site on 
an empty stomach, bring a completed diary and an unused product. 
• Complaints reporting, medical history update; 
• Body weight measurements; 
• Reporting concomitant medications; 
• Physical examination; 
• Vital signs assessment; 
• Adverse event recording; 
• Evaluation of exclusion criteria; 
• Assessment of the adherence to study procedures (compliance with diary completion and study 
treatment); 
• Complete blood count; 
• Blood chemistry profile; 
• A 12-lead electrocardiogram; 
• Diarrhea assessment based on patient diary entries and face-to-face interviews for classification 
as AAD as assessed by medical doctor (in the absence of results of stool analysis at the time of 
the visit, the assessment is carried out after the investigator receives the results from the 
laboratory); 
• Collection of unused medication; 
• Collection of unused containers for stool samples; 
• Collection of patient diary. 
5.2.4.4 Unscheduled Visits 
The unscheduled visits will be conducted when necessary, e.g., in case of the index disease 
deterioration, AEs development, or intolerability to therapy of LRG-002 medicinal product or 
placebo. 
Every unscheduled visit, irrespective of its cause, must include the procedures listed below with 
completion of the relevant eCRF pages (Unscheduled Visit): 


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• Physical examination; 
• Measurement of vital signs (BP, HR, RR, body temperature); 
• A 12-lead ECG; 
• AE assessment; 
• Evaluation of the concomitant treatment; 
• If indicated, any of the study procedures may be additionally performed upon the decision of 
the Principal Investigator. 
Taking into account frequency of visits, unscheduled visits may be conducted on the same days as 
the scheduled ones but at a different time (e.g., in case of worsening the patient may visit the trial 
site in the afternoon).  
Procedures for planned clinical study visits are the same in each treatment group during each study 
period.  
5.2.5 Early study termination 
Sponsor has the right to terminate the trial, and Investigator has the right to stop enrolling patients 
at any time. In case of early discontinuation of the site/study, all completed and unused CRFs 
(including unused pages of partially filled CRFs) and other documentation (excluding the 
documentation that should be kept on site) must be returned to the Sponsor. Materials of study 
may be destroyed by the permission of the Sponsor only. 
5.3 Handling of investigational medicinal products 
5.3.1 Supply of the medicinal products to the study site 
LRG-002 and placebo are provided to study sites by the Sponsor. The sponsor is responsible for 
the production, packaging, labeling and supply of medicinal products, determination of storage 
conditions and shelf life of the medicinal products. Primary and secondary packaging of the 
medicinal products will contain the labeling “For clinical trial use only”.  
At each study site, the investigator or authorized person will accept supplies of the investigational 
medicinal products. The drugs should be stored in a room with limited access, the temperature 
regime of which corresponds to the storage conditions of the medicinal products. Each supply of 
medicinal products to the study site will be confirmed by Delivery-Acceptance Act.  
Investigator is responsible for the proper storage of the medicinal product, its disposal to the study 
participants and accounting. In case of breach of the storage conditions of the medicinal product, 


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as well as if defects or damage to the investigational medicinal product or packaging are detected 
upon supply to the site, the investigator should immediately inform the study monitor. 
5.3.2 Quality complaints 
5.3.2.1 Terms and definitions 
Nonconformities of the studied medicinal product (investigational medicinal product and 
reference product) or medical device may include:  
1) Complaints related to the quality of the medicinal product or medical device, such as: 
• any deficiency of quality and (or) effectiveness, for example, a change in appearance, a change 
in the quantity, damaged tablets or capsules, the presence of foreign matter. 
• any defect of containers and outer packaging, for example, a surface damage, leakage of a 
container, a broken syringe or piston, lack of contents, malfunction of the device. 
• any defect of labeling, such as, a missing label or an unreadable label. 
• any falsification of a pharmaceutical product or medical device, such as suspicion on drug 
mixing, opening-up of packages or counterfeiting. 
2) Deviations associated with the transportation of the product, such as a damaged transport 
package and/or damaged secondary packaging after receipt of the goods, missing quantity of 
pharmaceutical product in transport package, improper transportation conditions. 
5.3.2.2 Terms and definitions 
If any of the nonconformities listed above are identified or information on these nonconformities 
is received, a filled-up Non-conformity Report must be sent to the Sponsor (Study Manager or 
Clinical Study Manager) within 24 hours. Simultaneously On-site Monitor or Clinical Research 
Associate (CRA) of corresponding study should be informed of nonconformities. If possible, a 
photograph of the damaged material should be attached to the report. Damaged material should be 
saved and stored in accordance with the storage conditions indicated on the label and/or returned 
to the sponsor upon sponsor's request. 
5.3.3 Dispensing and collection of medical products 
The investigational medical products are intended only for patients participating in this study and 
should be used in accordance with the protocol. 
The study drugs will be dispensed to patients at the first visit in an amount sufficient for the entire 
course of therapy in the study. Patients will be asked to bring with them all used and unused drug 
packages to the study site at each visit. 


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5.3.4 Product Accountability 
The investigator or authorized person must keep records of medicinal products at the site during 
the study, by filling out special accounting forms for the medicinal products provided by the 
Sponsor. The aspects of account of the study products will be regularly checked by the monitor. 
The investigator or any authorized person should calculate the number of packages of the used and 
unused product returned by patient and write down these data in the accounting forms for the 
medicinal products and in CRFs. Besides, the number of days of skipping the administration of 
the investigational medicinal products, changes in their dosage (if there are any, according to 
patient's diary) should be recorded in CRFs. 
5.3.5 Collection and destruction of the medicinal products 
After completion of the study or in case of premature termination of the site participation in the 
study, all unused investigational medicinal products and packaging of the used medicinal products 
shall be returned to the Sponsor. The sponsor is responsible for the destruction of the study 
medicinal product. After the packages of the used and unused medicinal products are counted and 
the labels on the packages are checked, the monitor arranges the dispatch of the medicinal products 
to the Sponsor for subsequent destruction. 
5.4 Measures aimed at minimizing/eliminating subjectivity 
5.4.1 Randomization 
The study will be double-blinded, randomized. 
Patients will be included by applying stratified randomization in two strata:  
• age <50 years 
• age ≥ 50 years 
Each treatment group will be balanced at a ratio of 1: 1 within each stratum. 
Stratified randomization is a two-stage procedure in which patients who enter a clinical trial are 
first grouped into strata. Within each stratum, patients are then assigned to a treatment according 
to separate randomization schedules. Randomization module of EDC system assigns patient 
unique randomization code based on group of treatment and stratum. Randomization schedules 
will be hidden from medical personnel and all other persons involved in the study (monitors, data 
management, biometry, sponsor etc.), except the specialists responsible for labeling of the 
investigational medicinal products, and the emergency unblinding. 


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5.4.2 Blinding methods 
Within the framework of this study, neither investigators nor patients should be aware whether the 
investigational medicinal product or placebo is used in a patient.  
Investigator will receive LRG-002 product/placebo for dispensing to the patient in identical 
packaging, which will differ by individual numbers. The lot of the medicinal product is individual 
for the patient and includes the medicinal product for the entire blinded period of treatment of the 
patient.  
When the patient is included in the study (randomization), Investigator receives from the Sponsor 
the patient identification number and the corresponding lot number of the medicinal product that 
the patient will take. In case of using an electronic randomization system, all the necessary 
numbers will be automatically generated after data entry by Investigator. The investigator records 
the numbers obtained in the primary documentation and eCRF.  
The sets with the medicinal product in the required quantity will be formed for patients of each 
group. 
The set provides additional packs in case of damage or loss of the medicinal product/placebo. 
5.5 Dosage regimen of the study medicinal products 
Investigational medicinal product LRG-002 is used according to the following dosage regimen: 
a single dose is 1 capsule for oral administration during meals with a small amount of water; the 
medicinal product will be taken orally 2 times a day for 14 days.  
Placebo is used according to the following dosage regimen: a single dose is 1 capsule for oral 
administration during meals with a small amount of water; the medicinal product will be taken 
orally 2 times a day for 14 days.  
If treatment order is received in the afternoon, the protocol allows only one capsule to be taken on 
the first day. The interval between taking the oral antibiotic and investigational medicinal product 
should be at least 3 hours in both groups. 


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Dosing regimen of investigational medicinal products: 
Day 
No. 
Date 
Dosage frequency of LRG-002 
product or placebo 
Intake of antibiotic 
1 
__/__/_____ 
1 or 2 
Yes  
2 
__/__/_____ 
2 
Yes 
3 
__/__/_____ 
2 
Yes 
4 
__/__/_____ 
2 
Yes 
5 
__/__/_____ 
2 
Yes 
6 
__/__/_____ 
2 
Yes 
7 
__/__/_____ 
2 
Yes 
8 
__/__/_____ 
2 
No  
9 
__/__/_____ 
2 
No 
10 
__/__/_____ 
2 
No 
11 
__/__/_____ 
2 
No 
12 
__/__/_____ 
2 
No 
13 
__/__/_____ 
2 
No 
14 
__/__/_____ 
2 
No 
 
 
5.6 Dosage form, packaging and labeling of investigational medicinal products 
5.6.1 Dosage form 
Investigational medicinal product: LRG-002, capsules 
Reference product: Placebo, capsules. 


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5.6.2 Packaging 
Investigational medicinal product: The product will be packaged in blisters 
Reference products: The product will be packaged in blisters 
5.6.3 Labeling of investigational medicinal product 
The study is double blinded. The research cite will be supplied with blinded packages of study 
drugs.  
Each package will contain information about the name, composition, expiration date and 
manufacturer of the medicinal product, the inscription "for clinical trials only", the clinical trial 
protocol number, the name and contact information of the trial sponsor. 
5.7 Duration of patient participation in the study 
Duration of study will be for patients not more than 17 days: 
Screening/randomisation/study treatment initiation– Day 1. 
Intermediate Follow-up Visit – Day 7 ± 2. 
Study Termination Visit - Day 15 ± 2 
The overall enrollment period is at least 8 months. 
5.8 Rules for stopping the parts of clinical study and/or the clinical study in general 
The study can be stopped for the following reasons: 
 At the initiative of Sponsor:  
a. obtaining new toxicological or pharmacological data, or data about SAE, which require to 
reconsider the earlier assessment of the benefit/risk of participation in the study; 
b. the frequency of AEs and/or their severity do not allow to continue the study; 
c. other reasons, including administrative ones. 
 At the initiative of Investigator: the frequency of AEs and/or their severity unacceptably 
increases the risk of the participation of patients in the study. 
 By decision of regulatory authorities. 
If the study is prematurely stopped, the sponsor is obliged to notify the staff of the study sites and 
regulatory authorities, indicating the reason for the premature termination of the study. 
5.9 Accounting procedures of the investigational medicinal products 
The study sites will receive the number of the study medicinal products (the investigational 
medicinal products, the reference product), sufficient for the study, taking into account the planned 
number of patients. 


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The responsible employee of the study site maintains the drug accounting journal, where deliveries 
of the medicinal products to the site, dispensing of the medicinal products to the study participants, 
and the collection of unused medicinal products are recorded. Storage conditions are also noted. 
The study medicinal products can only be used for the purposes of this clinical study. 
Specialists of the Sponsor or regulatory authorities during the monitoring/audit of the study site 
can check the drug accounting journal, as well as the availability of the medicinal products. The 
medicinal products should be stored in compliance with the storage conditions in the room, access 
to which is available only to the specialists of the study site responsible for dispensing the 
medicinal product. 
5.10  Storage of randomized codes and procedure for their disclosure 
The table containing the therapy randomization codes will be maintained by the CRO (Data 
Management Department) and by the provider providing the eCRF platform. Access to the 
randomization table will be restricted to authorized persons.  
In the course of the study, it may be necessary to unblind the therapy group to which the patient 
belongs, for the safety of the patient's life and health (for example, when serious adverse events 
are identified). The subject will be unblinded directly in the eCRF system by authorized users who 
have been assigned an access level for unblinding subjects. The treatment group unblinding right 
will be given to: 
• 
CRO Data Management Manager; 
• 
Designated Research Center Team member. 
In case of urgent need for a patient to be unblinded by the research center, but in the absence of 
technical feasibility to implement this process, the researchers will be provided with an emergency 
support phone number, full name and contact details of the CRO Data Management Manager.  
5.11  List of data recorded in Individual Case Record Form (without prior written or 
electronic recording) and considered as primary data 
All study data will be entered in the primary documentation, then in the eCRF. 
6. 
Patient inclusion and exclusion 
6.1 Inclusion criteria 
1. Voluntarily signed Informed Consent Form for participation in this clinical study; 
2. Male and female subjects, aged 18 to 65 years inclusive; 


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3. Antibacterial treatment for active ARDs started/to be started on the first day of the study 
(7-day course of oral beta-lactam antibiotic) (see  Background antibacterial therapy). Only 
one AB should be used per subject, in an outpatient setting. Diagnostic procedures of acute 
respiratory infections and the prescription of antibiotic therapy should be completed before 
signing of the Informed Consent Form; 
4. Female patients are eligible for inclusion in the study if they: 
• 
Unable to become pregnant (i.e. postmenopausal women or those after surgical 
sterilization). Surgically sterile women are defined as patients with documented 
hysterectomy, and/or bilateral oophorectomy, and/or tubal ligation. Postmenopausal 
women are defined as women with amenorrhea for more than 1 year with the relevant 
clinical profile (e.g., age > 45 years, and absence of hormone replacement therapy). 
However, in controversial cases, it is recommended to confirm menopause by drawing 
a blood sample which would show an FSH level of >40 IU/mL and estradiol level of 
<40 pg/mL (<140 pmol/L). 
OR 
• 
Capable of childbirth, but with negative pregnancy test at the screening visit, and the 
patient agrees to continuously and properly use one of the following suitable methods 
of contraception (i.e., in accordance with the approved Package Insert for the medicinal 
product and physician instructions) during the participation period: 
a. Complete abstinence  
b. Oral contraceptives (combination drugs containing progestogen, or 
progestogen alone) 
c. Injectable progestogen 
d. Levonorgestrel implants 
e. Estrogen-containing vaginal ring 
f. Transdermal contraceptive patches 
g. Intrauterine device or intrauterine system 
h. A male partner has been sterilized (vasectomy with documented azoospermia) 
prior to inclusion of a woman, provided that he is the only partner of the female 
patient. The definition "documented" is related to the result of a subject's 
medical examination performed by Investigator/responsible person or subject's 
past medical history review for assessment of eligibility for enrollment, 
obtained during the interview with the subject or from his medical records.  
i. 
Double barrier method: a condom or an occlusive cap (diaphragm or 
cervical/vault caps) with a spermicide (foam/gel/film/cream/suppository).  


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5. Male participants are obliged to use appropriate contraception during the entire study 
period starting from signing of the Informed Consent Form and until the study end, and for 
30 days after study completion; 
6. The ability to understand the information about the clinical study, readiness to comply with 
the study protocol requirements, ability to take the investigational products and evaluate 
symptoms on his (or her) own using diary/questionnaires as per protocol; 
7. Ability to maintain the habitual lifestyle throughout the study, including diet. 
8. Willingness not to consume any products containing probiotics during participation in the 
clinical trial. 
9. Willingness not to take part in any other study during the present trial. 
6.2 Non-inclusion criteria 
Patients will not be eligible for study enrollment if they have one or more of the following criteria:  
1. Any treatment (including medications, medical devices and food supplements) that can 
influence the stool consistency, according to the Investigator's opinion should not be 
used within 14 days prior to Visit 1; 
2. Use of anti-rejection medication after stem cell or solid organ transplant;  
3. Use of glucocorticosteroids within the last 8 weeks prior to the study start; 
4. Use of proton pump inhibitors within 3 months prior to Visit 1; 
5. Chemotherapy or radiation; 
6. History of recurrent diarrhea; 
7. Patient has diarrhea or loose stool in the last 2 days prior to the study start; 
8. Patient has severe ARD expected to require an administration of additional antibiotics 
or antibiotics therapy for more than 7 days; 
9. Use of antimicrobials in the last 3 months prior to the study start; 
10. Use of yeast/probiotic/fermented products within the last 2 weeks prior to the first visit; 
11. Known allergy/sensitivity to the investigational medicinal product; 
12. Immunocompromised patients; 
13. Patients with digestive / absorption disorders of the gastrointestinal tract (for example, 
inflammatory bowel disease, celiac disease, pancreatitis, motility disorders, etc.) and / 
or patients who underwent surgery on the organs of the gastrointestinal tract (with the 
exception of appendectomy more than 3 months prior to Visit 1); 
14. Known irritable bowel syndrome; 
15. Known small intestinal bacterial overgrowth; 
16. Patients with pyrexia over 38°C; 


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17. Pregnant and/or breastfeeding women; 
18. Participation in other clinical trials of medicinal products or medical devices at the 
screening Visit or for 30 days before the screening Visit; 
19. Surgical intervention within 30 days before the screening visit or planned surgical 
treatment during the trial (before a follow-up visit is completed), including diagnostic 
procedures or inpatient stay; 
20. Known or suspected alcohol and/or drug addiction; 
21. A suspected low compliance or incapability of the patient to perform the procedures 
and comply with restrictions according to the trial protocol (e.g., due to mental 
disorders); 
22. Potential for translocation of probiotic across bowel wall (active bowel leak, acute 
abdomen, active intestinal disease including colitis, or significant bowel dysfunction; 
presence of neutropenia or anticipation of neutropenia after chemotherapy; radiation 
therapy); 
23. Any diseases of cardiovascular, renal, hepatic, gastrointestinal, endocrine and nervous 
systems, or other conditions/diseases which, in the Investigator's opinion, may render 
study participation unsafe for a patient or may affect a test result; 
24. A positive result of a rapid test for the detection of immunoglobulin M (IgM) antibodies 
to COVID-19. 
6.3 Exclusion Criteria  
6.3.1 Timing and terms of subject exclusion from the study 
Subjects can be excluded from the study of their own free will at any time without explanation, as 
well as by decision of the physician investigator or Sponsor, in cases where continued participation 
in the study poses a threat to the health and/or life of the patient. In addition, the patient will not 
be able to continue participating in the study for the following reasons: 
Subject participation will be stopped in case any of the following reasons occur: 
1. Disease progression (including pyrexia above 38°C for 3 days or longer); 
2. Positive results of culture or PCR for the dysentery group, typhoid fever group, 
pathogenic E. coli and other pathogenic groups (incl. Cl. dificille), the treatment of 
which requires the prescription of additional antibiotic therapy; 
3. Need to change tactics of antibacterial therapy (extension course of antibacterial therapy 
or change of antibiotic group); 


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4. The Ethics Committee, regulatory authorities, or Sponsor can terminate the clinical 
study or participation of the specific trial site in the study for any reason; 
5. The investigator decided that the patient must be withdrawn from the study for the own 
interests of the patient;  
6. Informed consent withdrawal (patient reluctance to continue to participate in the study); 
7. Individual intolerability of Investigational medicinal products according to 
Investigator’s judgment; 
8. Occurrence of clinically significant adverse event or serious adverse event in the patient; 
9. Patient's non-compliance; 
10. Error enrollment (e.g., the patient was included with violation of the inclusion/non-
inclusion criteria); 
11. The patient complies with the non-inclusion criteria during the study; 
12. The patient receives/requires an additional treatment which might influence the study 
results or patient's safety (see “Prohibited concomitant therapy” section); 
13. Other conditions or events which, in the Investigator's judgement, require the patient's 
exclusion from the study. 
6.3.1.1 Timing and volume of data collection for excluded subjects. 
If the subject is excluded from the study at his/her request, the investigator should try to find out 
the reason for the termination of the study. If the study is terminated due to the occurrence of 
AE/SAE, monitoring of the subject continues until AE/SAE resolution. In case of premature 
termination of the patient’s participation in the study, the patient is invited to the study site to carry 
out the procedures of premature study termination visit (carried out within the frameworks of 
unscheduled visit); if the patient refuses to visit the study site, the premature study termination 
visit is carried out by phone, while as much as possible the available information is recorded. 
6.3.2 Terms and conditions of stopping/termination by the subject of treatment with the 
medicinal product under study  
Patients stop taking the study medicinal products upon completion of their participation in the 
study in accordance with the protocol or upon their exclusion from the study. 
6.3.3 Replacing the discontinued patients 
Replacement of the patients who discontinued their study participation is not provided.  


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7. 
Information about the medicinal products used in the clinical study 
7.1 Investigational medicinal product and reference product 
Investigational medicinal product: LRG-002 
Manufacturer: Lek d.d., Verovskova 57, 1526 Ljubljana, Slovenia. 
Dosage form, dosage: capsules 
Description: Each capsule contains live lyophilized probiotic bacteria of Lactobacillus genus. 
Composition per 1 capsule: each capsule contains at least 1 х 1010 CFU of Lactobacillus 
rhamnosus GG as a lyophilizate.  
Excipients: sucrose, maltodextrin, silicon dioxide, magnesium stearate, sodium ascorbate 
Capsule shell: hydroxypropyl methylcellulose, titanium dioxide (E171), gellan gum, water. 
Reference product: Placebo 
Duration of treatment 
Patients will take the investigational medicinal products in all groups daily for 14 days. 
7.2 Compliance control 
Compliance will be controlled by review of patient's diary and counting the amount of the 
medicinal product remaining. 
7.3 Allowed concomitant treatments 
Oral beta-lactam antibiotic (eg, amoxicillin, amoxicillin + clavulanic acid, cefixime, etc.) (See 
Background antibacterial therapy) according to inclusion criterion 3, at the same dosage as at the 
study initiation. 
Continuation of the drug administration, started prior to the inclusion into the study for treatment 
of concomitant diseases and not covered by any exclusion criterion. Female participants taking 
oral contraceptives may continue to take them during the study. 
Standard symptomatic treatment agents used to treat acute respiratory infections (in case of 
medical need), including anilides, triazole derivatives, with the exception of drugs that can induce 
a laxative effect (for example, throat lozenges with sugar substitutes). 
Agents for relieving symptoms of acute diarrhea (in case of medical need), including electrolyte 
solutions, with the exception of sorbents.  


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Prescribing therapy for acute diarrhea and symptomatic therapy for ARDs is possible only by the 
decision of the Investigator. 
7.4 Prohibited concomitant therapy 
1. Systemic glucocorticosteroids within last 8 weeks prior to and during the study; 
2. Any antibacterial agents in the last 3 months prior to the study and during the study, excluding 
the antibacterials according to inclusion criterion 3 during the study; 
3. Use of any proton pump inhibitor within 3 months prior to the study; 
4. Use of other probiotics (bacteria or yeast, medications, food supplements, fermented products) 
and the product Broncho-munal® within 2 weeks prior to and during the study; 
5. Any therapy (including medications, medical devices and food supplements) that can 
influence the stool consistency must not be used, according to the Investigator's opinion, 
within 14 days prior to Visit 1 (excluding the drugs specified in items 3 and 4 of the “Allowed 
Concomitant Treatments”).  
The list of prohibited medicinal products is presented in Appendix 1 
8. 
Efficacy Evaluation 
8.1 List of efficacy parameters 
Primary efficacy criterion 
Evaluation of AAD incidence from the first to the last day of LRG-002 administration vs placebo 
in patients with ARDs, receiving standard antimicrobial therapy. The primary efficacy criterion 
will be considered achieved if the odds ratio for the AAD incidence between two groups is 
significantly higher than 1 (i.e. AAD incidence in the LRG-002 group is lower than in placebo 
group). 
AAD is defined as diarrhea associated with the AB use caused by C. difficile or of otherwise not 
identified etiology, upon analysis of stool samples and differential diagnostics according to 
investigator's judgment. 
Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale) three 
times a day (frequent bowel movements with formed stool is not considered as diarrhea) in 
accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the 
investigator. 
 
 


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Secondary efficacy criteria 
The following criteria were selected as secondary efficacy criteria of the therapy in all study groups 
for a comparative assessment of the therapeutic effect: 
• The occurrence of bowel movements per day (according to the diary data) in the treatment 
group compared with the placebo group;  
• The incidence of any diarrhea in the treatment group compared with the placebo group;  
• The incidence of C. difficile-associated AAD in the treatment group compared with the 
placebo group;  
• The incidence of AAD not associated with C.  difficile in the treatment group compared with 
the placebo group;  
• The duration of AAD (the time from the onset of AAD to the normalization of stool form 
according to BSFS (types 1, 2, 3 and 4) and the presence of normal stool within 48 hours)) 
in the treatment group as compared to the placebo group;  
• Duration of any diarrhea (the period from the diarrhea onset to the normalization of stool form 
according to BSFS (types 1, 2, 3 and 4) and the presence of normal stool within 48 hours)) 
in the treatment group vs the placebo group;  
• The changes in stool consistency (according to Bristol Stool Form Scale) (according to the 
diary data) in the treatment group as compared to the placebo group;  
• The changes and severity of gastrointestinal symptoms, including nausea, vomiting, 
flatulence, abdominal pain and decreased appetite (according to the diary data) in the 
treatment group as compared to the placebo group;  
• Change in body weight at Visit 3 compared with Visit 1 in the placebo group as compared to 
the treatment group;  
• Hospitalization rate in the treatment group compared with the placebo group;  
• The number of days of using standard symptomatic therapy (as “rescue medication”) to relieve 
symptoms of acute diarrhea in the treatment group as compared to the placebo group; 
• The number of patients using standard symptomatic therapy (as “rescue medication”) to 
relieve symptoms of acute diarrhea in the treatment group as compared to the placebo group.   
8.2 Methods and timing for evaluating, recording and analyzing efficacy parameters 
The efficacy of the investigational therapy is based on diary data, laboratory and clinical data.   
Primary efficacy endpoint – assessment of frequency of occurrence of AAD from 1 to the last 
day of LRG-002 administration compared with placebo in antibiotic-treated patients with ARDs, 
receiving standard antimicrobial therapy. The primary efficacy criterion will be considered 


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achieved if the odds ratio for the AAD incidence between two groups is significantly higher than 
1 (i.e. AAD incidence in the LRG-002 group is lower than in placebo group). 
AAD is defined as diarrhea associated with the AB use caused by C. difficile or of otherwise not 
identified etiology, upon analysis of stool samples and differential diagnostics according to 
investigator's judgment. 
Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale) three 
times a day (frequent bowel movements with formed stool is not considered as diarrhea) in 
accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the 
investigator. 
 
Secondary efficacy endpoints, assessed based on the data of patient’s diary include: 
• The occurrence of bowel movements per day (according to the diary data) in the treatment 
group compared with the placebo group;  
• The incidence of any diarrhea in the treatment group compared with the placebo group;  
• The duration of AAD (the time from the onset of AAD to the normalization of stool form 
according to BSFS (types 1, 2, 3 and 4) and the presence of normal stool within 48 hours)) in 
the treatment group as compared to the placebo group;  
• The changes in stool consistency (according to Bristol Stool Form Scale) (according to the diary 
data) in the treatment group as compared to the placebo group; 
• The occurrence and severity of gastrointestinal symptoms, including nausea, vomiting, 
flatulence, abdominal pain and decreased appetite (according to the diary data) in the treatment 
group as compared to the placebo group;  
• Duration of any diarrhea (the period from the diarrhea onset to the normalization of stool form 
according to BSFS (types 1, 2, 3 and 4) and the presence of normal stool within 48 hours)) in 
the treatment group vs the placebo group;   
 
Secondary efficacy endpoints, assessed based on the data of stool analysis include: 
• • The incidence of C.  difficile-associated AAD in the treatment group compared with the 
placebo group;  
• • The incidence of AAD not associated with C.  difficile in the treatment group compared with 
the placebo group; 
Secondary efficacy endpoints, assessed based on the clinical data include: 


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• Change in body weight at Visit 3 compared with Visit 1 in the placebo group as compared to 
the treatment group;  
• Hospitalization rate in the treatment group compared with the placebo group; 
• The number of days of using standard symptomatic therapy (as “rescue medication”) to relieve 
symptoms of acute diarrhea in the treatment group as compared to the placebo group; 
• The number of patients using standard symptomatic therapy (as “rescue medication”) to relieve 
symptoms of acute diarrhea in the treatment group as compared to the placebo group.  
9. 
Safety Evaluation 
9.1 List of safety parameters 
Safety evaluation will be based on the following parameters (between Visits 1 and 3), compared 
between the investigational medicinal product and placebo: 
Frequency of adverse events (AEs) and/or serious adverse events (SAEs) in the treatment groups, 
including:  
• Overall AE rate as compared to placebo; 
• Frequency of AEs according to the results of physical examinations during each visit compared 
with placebo; 
• AE incidence according to the results of the vital signs assessment (HR, BP, BT, RR) at each 
visit compared with placebo; 
• AE incidence according to the ECG results on Day 15 (± 2) compared with placebo; 
• AEs incidence according to the results of laboratory examinations on Days 7(± 2) and 15(± 2) 
compared with placebo; 
• Frequency of AEs according to the everyday patients’ records of well-being self-evaluation in 
the diary. 
9.2 Methods and timing for evaluating, recording and analyzing safety parameters 
Safety parameters are evaluated at each visit planned in this study, as well as at unscheduled visits. 
Safety evaluation will be based on the following parameters (between Visits 1 and 3), compared 
between the investigational medicinal product and placebo: 
Frequency of adverse events (AEs) and/or serious adverse events (SAEs) in the treatment groups, 
including:  
• Overall AE rate as compared to placebo; 
• Frequency of AEs according to the results of physical examinations during each visit compared 


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with placebo; 
• AE incidence according to the results of the vital signs assessment (HR, BP, BT, RR) at each 
visit compared with placebo; 
• AE incidence according to the ECG results on Day 15 (± 2) compared with placebo; 
• AEs incidence according to the results of laboratory examinations on Days 7(± 2) and 15(± 2) 
compared with placebo; 
• Frequency of AEs according to the everyday patients’ records of well-being self-evaluation in 
the diary. 
Diary records will be reviewed by the Investigator. In case the researcher considers that the records 
in the diary meet criteria of AE, the patient will be questioned about this event, and all information 
(including an evaluation of causality) will be documented. 
Adverse event will be described according to the following scheme: 
• Description of adverse event; 
• Seriousness of adverse event (compliance with seriousness criteria); 
• severity; 
• duration; 
• causal relationship with the investigational product; 
• actions taken in relation to the study drug; 
• actions taken in relation to the patient; 
• outcome. 
9.3 Requirements for reports, procedures on recording and reporting of adverse events 
and intercurrent diseases 
9.3.1 Terminology of adverse events and serious adverse events 
Adverse event (AE) — any medically unfavorable event identified in a patient or subject in a 
clinical trial after the use of medicinal product, which may not have a causal relationship with its 
use. 
Thus, an adverse event (AE) may be any adverse and undesirable clinical sign (including 
laboratory deviation from the norm), symptom or disease, the time of occurrence of which does 
not exclude a causal relationship with the use of the drug, regardless of the presence or absence of 
such a relationship. 
Serious adverse event (SAE) — any adverse medical event that regardless of the dose of the 
medicinal product: 


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• causes fatal outcome; 
• is life threatening; 
• requires hospitalization or its extension; 
• results in persistent or significant disability/incapacity; 
• is a congenital anomaly or malformation; 
• is clinically relevant: the decision about whether the express reporting is appropriate in other 
situations (e.g., in cases of medically important events that do not pose an immediate threat to 
the patient's life, do not result in death or hospitalization, but put the patient at risk or require 
intervention to prevent one of the above outcomes given in the definition) is made on the basis 
of a medical and scientific assessment. Such cases should also be considered as serious adverse 
events. 
These characteristics / consequences must be considered at the time of event occurrence. For 
example, the concept of life-threatening AE refers to a medical event in which a subject is at risk 
of death at the time of the AE development; it does not refer to a medical event that could 
hypothetically cause death in case of a higher severity condition. 
(Serious) adverse reaction ((S)AR) — any (S)AE for which there is a reasonable probability of 
a causal relationship with the use of the medicinal product in the opinion of the Investigator or 
Sponsor (see paragraph 8.8.3 below). 
(Serious) unexpected adverse reaction — a (serious) adverse reaction whose nature or severity 
is inconsistent with Reference Safety Information (e.g., Summary of Product Characteristics 
(SmPC), Pharmacopoeial Product Monograph, Investigator’s Brochure). The term "severity" in 
this context describes the intensity of a particular adverse event. It is necessary to distinguish it 
from the term "seriousness". Reports that contain additional important information regarding the 
characteristics of the manifestation, increase in the incidence or severity of a known, documented 
serious adverse reaction should also be considered as reports of unexpected events. 
Information on commonly known adverse effects of the investigational medicinal product (IMP) 
can be found in the Reference Safety Information (e.g., in the SmPC, Product Monograph, 
Investigator’s Brochure). Otherwise, it shall be provided as a notification to the Investigator. This 
information will be included in the patient information and should be discussed with the patient. 
For more information, see the Brief Guideline for Completing the Report Form on the Serious 
Adverse Events. 


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9.3.2 Severity of adverse events 
The term "severity" in this context describes the intensity of a particular event. It is necessary to 
distinguish it from the term "seriousness". In the course of the study, the Investigator should 
identify any AEs manifested and assess their severity as follows: 
− Mild: 
commonly transient in nature AE, as a rule, not disrupting the usual 
daily activity. 
− Medium: 
accompanied by significant discomfort that disrupts normal daily 
activity. 
− Severe: 
interferes with normal daily activities. 
9.3.3 Causality to the investigational medicinal product: 
The Investigator should evaluate all AEs using all available data every time when new information 
is received. The term "IMP" includes the evaluated medicinal product and the reference medicinal 
product that patients received during any phase of the study. 
The Investigator should assess whether, in his expert opinion, the association of AE with the 
medical product is possible, based on the following considerations: 
Suspected: 
Temporality between the clinical event and the administration of 
the investigational medicinal product makes a causal 
relationship possible, whereas other medicinal products, 
therapeutic interventions or underlying disease do not provide a 
sufficient explanation for the observed event. 
Not suspected: 
Temporality between the clinical event and the administration of 
the investigational medicinal product makes a causal 
relationship unlikely, or other medicinal products, therapeutic 
interventions or underlying disease provide a sufficient 
explanation for the observed event. 
 


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Estimates of causal relationship are critically important and should be provided for each individual 
AE in relation to each IMP, non-investigational medicinal product (NIMP), or other concomitant 
medicinal product, if applicable. In the absence of causal relationship assessment, AEs will be 
considered by the Sponsor to be allegedly associated with the IMP. 
Investigators should report to the appropriate Country Organization Patient Safety Team about 
AEs suspected to be associated with NIMP or other concomitant medicinal products 
(manufactured by Sandoz or other companies), even if they are not serious (contact details are 
given in section 9.3.5 for contact details). 
9.3.4 Documentation of adverse events 
Any AEs (non-serious and serious) observed after the subject has given informed consent to 
participate in a particular study and prior to the subject's last visit in the course of the study should 
be documented on the AE page in the case report form (CRF). 
Information on AE should be collected by unobtrusive interviewing the subject on each visit during 
the study. AEs can also be identified if the subject reports them voluntarily during a visit, between 
visits, or during a physical examination, laboratory tests, or other examinations. An appropriate 
medical care should be provided in all AEs. The treatment may include one or more of the 
following: no action taken (i.e., follow-up only); dose adjustment / temporary discontinuation of 
IMP; complete discontinuation of IMP due to this AE; prescription of concomitant medicinal 
product; administration of non-drug therapy; hospitalization of the patient / extension of 
hospitalization. The treatment of AE shall be documented in CRF. Besides, actions taken with 
respect to IMP should be recorded and classified into one of the following categories: no change, 
discontinuation, dose reduction, dose increase, temporary discontinuation, unknown and not 
applicable. Concomitant medications, other treatment methods or changes in the IMP regimen 
should be clearly indicated and documented. 
Medical conditions / diseases that occurred prior to the IMP administration are considered as AE 
only in the case of exacerbation after inclusion of the patient in the study. Deviations of laboratory 
parameters and results of other studies from the norm are considered AE (only if they entail the 
development of clinical signs or symptoms), clinically significant or require treatment. 
After the detection of AE, the Investigator should continue the follow-up as indicated below. In 
all cases, AE outcomes should be documented and classified into one of the following categories: 
no resolution / unchanged, deterioration, recovery / resolution, improvement / in the process of 
recovery, recovery / resolution with consequences, fatal outcome or unknown. The AE assessment 
should be carried out at each scheduled visit (or more often, if necessary). The Investigator should 


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document in the CRF any changes in seriousness, severity, suspected association with IMP, AE 
related interventions, and outcome. 
Adverse events, observed in the period between giving the consent and the last visit 
The Investigator should continue to monitor all the AE that have developed after signing the 
informed consent to participate in a particular study and until the last visit of the subject, during 
which the assessment of the outcome will be documented in CRF. 
Serious adverse events not resolved at the moment of the last visit 
The Investigator should continue to monitor all SAEs not resolved during the last visit, up to the 
resolution or stabilization / recognition of permanent SAEs that were deemed to be associated with 
IMP (SAE), or up to 30 days after the last visit of the subject in respect of SAE not associated with 
IMP. The Investigator shall send the SAE follow-up reports to the recipients in accordance with 
section 9.3.5 "SAE Reporting" introduced below. 
Serious adverse events that have developed since the last visit 
SAEs recorded since the last visit should be reported to the Sponsor only if they are assessed by 
the Physician-Investigator as being related to the medicinal product. The Investigator should send 
SAE reports to recipients in accordance with section 9.3.5 "SAE Reporting" introduced below. 
9.3.5 SAE Reporting 
It is vitally important that the Investigator should immediately (i.e. not later than 24 hours 
after receiving the information) report any SAE or update previous SAE reports, even if the 
Investigator does not believe that the AE is related to the investigational medicinal product. 
The Investigator should send the SAE reports using the Serious Adverse Event Reporting Form 
(document of Novartis) as an initial or subsequent report by fax or e-mail to the relevant Country 
Organization Patient Safety Team, with a copy to the Executive Officer of the study (Sponsor / 
CRO) at the addresses shown in the table below. 
The Investigator should also send all updates / new information in the form of a new SAE report 
as subsequent data to the previously noted SAE. Subsequent data should describe whether the 
adverse event is resolved or still persists, if the diagnosis is known, if the treatment is provided 
(specify method of treatment), whether the subject continues to participate in the study or dropped 
out of it. 


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Recurring episodes, complications, or progression of the original SAE should be noted in the form 
of subsequent information to supplement the initial case description, regardless of when the AE 
occurred. 
Any new SAEs (which are considered to be completely independent of previously noted SAEs) 
should be reported in the form of a new and separate initial SAE report. 
The Investigator should answer any questions of the Country Organization Patient Safety Team, 
contract research organization (CRO), or Sponsor regarding the SAE report within 24 hours. 
For more information, see the Brief Guideline for Completing the Report Form on the SAE. 
The Investigator should store notifications about SAE report delivery to all recipients in the 
Investigator’s file. 
Addresses for the SAE reports 
 
 Novartis Pharma 
Name: 
 
Address: 72 Leningradsky prospect, bld.3, Moscow, Russia 125315 
Ph.: 
 
Mob.: 
 (24h.) 
Fax: 
 
E-mail: 
 
, Sandoz (Novartis division): 
Name: 
 
Address: 72 Leningradsky prospect, bld.3, Moscow, Russia 125315 
Tel: 
 
Fax: 
 
E-mail: 
 


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For further information contact the authorized persons: 
, ZAO Sandoz: 
Name:
 
Address: 72 Leningradsky prospect, bld.3, 
Moscow, Russia 125315 
Tel: 
 
Cell number: 
 
Fax: 
 
E-mail:  
 
 
Name: 
 
Address: 
 
 
Cell number: 
 
Fax: 
 
E-mail: 
 
 
If the SNR is not listed in the Reference Safety Information (e.g., in the SmPC, Investigator’s 
Brochure), the Sponsor may urgently request additional information from the Investigator to report 
to the Health Authorities. 
Sponsor may, if applicable, issue a notice to the Investigator and semi-annual tabular lists of 
suspected unexpected serious adverse reactions (SUSAR) to all Investigators participating in any 
clinical trial with the same IMP. 
According to the contract concerning the study conduction, Investigator or CRO is responsible for 
submission of this notification for Investigator and semi-annual lists, if applicable, to the local 
Institutional Review Board / Ethics Committee. CRO is responsible for submission of notification 
for Investigator and semi-annual lists to the National Ethics Committee, if applicable. 
Providing information to the Health Authorities  
The Sponsor submits information on all cases to be reported within the required period to all 
involved Health Authorities. 
9.3.6 Emergency SAE Unblinding  
The Investigator shall unblind information about the prescribed treatment (e.g., using an envelope 
for emergency situations, interactive voice response systems) for a specific case only in emergency 
situations and only if it is required for subsequent treatment of the subject 
9.3.7 Pregnancies 
The Investigator shall immediately (within 24 hours) inform the Country Organization Patient 
Safety Team of all pregnancies of the subjects during the study, with a copy to the Officer of the 


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study (Sponsor / CRO) as described in section 9.3.5. Cases of pregnancy are reported only from 
the moment of the first dose administration of IMP.  
The Investigator should immediately exclude the subject from the study and organize follow-up 
for each case of pregnancy, report its outcome, including spontaneous or voluntary termination of 
pregnancy, as well as provide detailed information about the birth, the presence of any 
malformations, congenital abnormalities and complications in mother and (or) newborn.  
Cases of pregnancy should be reported using the Report Form on the Use of the Medicinal Product 
During Pregnancy (Novartis document). Follow-up information during pregnancy should be 
reported using the same form. It should include an assessment of the association between any 
adverse pregnancy outcomes and IMP. Any SAE during pregnancy should be reported to the 
subject using the Report Form on the SAE, as described in Section 9.3.5. The Investigator should 
store the delivery notifications in the investigator’s file to all recipients of reports in the Report 
Form on the Drug Exposure During Pregnancy. For more information, see the  Brief Guideline for 
Completing the Report Form on the Drug Exposure During Pregnancy (Novartis document). 
9.3.8 Claims related to IMP / medical device 
In case of a claims regarding the quality of IMP / medical device, the Investigator shall inform the 
Sponsor within 24 hours of claim receipt in accordance with the instructions in Annex 5.3.2.  Any 
AEs related to quality claims shall be documented and reported by the Investigator additionally as 
described in sections 9.3.4 and 9.3.5. 
9.3.9 Special cases 
Special cases may be serious or not serious (see table below). They should be reported as AEs as 
specified in sections 9.3.4 and 9.3.5, even if no (other) AEs are associated with them. 
Special case 
The Investigator informs Country 
Organization Patient Safety Team 
in 24 hours 
Drug exposure during the breast-feeding period 
x 
Intentional overdose on the initiative of the patient 
(including suicide attempts, suicide attempt is always 
regarded as a serious event) 
Only if related to SAE 


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Special case 
The Investigator informs Country 
Organization Patient Safety Team 
in 24 hours 
Interaction with other medicinal products 
Only if related to SAE 
Syndrome/ discontinuation response 
Only if related to SAE 
Dependence on the medicinal product, misuse, abuse or 
drug addiction (always regarded as a serious event) 
x 
Suspected transmission of infectious agents (always 
regarded as a serious event) 
x 
Death (including without other AEs; always regarded as 
a serious event) 
x 
 
9.3.10 Reconciliation 
The coordination of information between the Sponsor's safety database and the CRO clinical 
database is carried out periodically / at the end of the study, as described in the coordination plan 
(by comparing the lists of the safety database with the data in the clinical database). 
Data managers will review the CRF/ clinical database for possible cases that have not been 
reported. For any case to be reported, the clinical database and the safety database must match 
exactly the following parameters: study number, research center number, participant / patient 
number, randomization number, investigational drug, severity, date of death (if applicable), and 
the existence of a causal relationship according to the investigator’s opinion. All other parameters 
should be consistent with the medical point of view and the most likely to fit each other. For any 
event to be reported and assessed as suspected to be treatment-related, or for other AE of particular 
interest (if applicable), more detailed coordination is required, including also dates of treatment, 
outcomes, history and concomitant therapy. 
9.3.11 Training of investigators 
By signing the study Protocol, the Principal Investigator confirms that he / she has passed the 
training provided by the CRO regarding the responsibilities of reporting of pregnancy and AE / 
SAE cases established by the Sponsor, as specified in the study Protocol. 


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10. Statistic  
10.1 Description of statistical methods to be used, including the timing of each planned 
interim analysis 
Statistical analysis will be carried out using specialized R Project software. 
All continuous (quantitative) indicators will be presented in the form of the following parameters 
of descriptive statistics: 
• Number of observations; 
• Arithmetic mean; 
• 95% confidence interval of the mean; 
• Standard deviation; 
• Median; 
• Interquartile range; 
• Minimal: 
• Maximum. 
All sequential, categorical and qualitative indicators will be presented in the form of the following 
parameters of descriptive statistics: 
• Absolute frequency (number of observations); 
• Relative frequency (%); 
• •95% CI for proportion. 
All performed types of statistical analysis will be identical with respect to the investigational 
medicinal product LRG-002 and in the placebo group. 
Concomitant diseases and AEs will be encoded using the MedDRA terms.  
This section briefly describes the planned analysis. A complete analysis will be described in terms 
of statistical analysis. 
 
10.1.1 Demographic and other source data (comparability of groups for analysis) 
All data obtained in groups prior to the administration of the investigational medicinal product or 
reference medicinal product (demographic data, laboratory data, instrumental and physical 
examination methods, vital signs, etc.) will be compared between groups in order to determine the 
comparability of groups for analysis. Fisher exact test χ2 (chi-square) will be used to compare 
qualitative data, and the Mann-Whitney-Wilcoxon test will be used for quantitative data. 


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If any of the source data reveals the incompatibility of the investigational groups (statistically 
significant differences in demographic and other source data between the groups), an additional 
analysis of the efficacy and safety parameters will be carried out together with the initial planned 
analysis using multivariate statistics (ANOVA, ANCOVA or logistic regression analysis 
depending on the type of the studied parameter) adjusted for the initial indicator(s), which vary 
between groups. 
10.1.2 Primary efficacy parameter analysis 
Primary efficacy endpoint: 
Evaluation of AAD incidence from the first to the last day of LRG-002 administration vs placebo 
in patients with ARDs, receiving standard antimicrobial therapy. The primary efficacy criterion 
will be considered achieved if the odds ratio for the AAD incidence between two groups is 
significantly higher than 1 (i.e. AAD incidence in the LRG-002 group is lower than in placebo 
group). 
AAD is defined as diarrhea associated with the AB use caused by C. difficile or of otherwise not 
identified etiology, upon analysis of stool samples and differential diagnostics according to 
investigator's judgment. 
Diarrhea is defined as loose or watery stool (Type 5-7 according to Bristol Stool Form Scale) three 
times a day (frequent bowel movements with formed stool is not considered as diarrhea) in 
accordance with WHO criteria; based on the diary data (BSFS) and confirmation of AAD by the 
investigator. 
Each patient will be assessed only once, even if more than one AAD episode occurs in one patient. 
The primary efficacy endpoint will be analyzed using a logistic regression model with fixed factors 
for the treatment group and age group. Treatment exposure will be displayed using the adjusted 
odds ratio and the corresponding bilateral 95% confidence interval. If necessary, an absolute risk 
difference will be presented with the bilateral 95% confidence interval and the amount needed for 
treatment. No central effects are expected in this study. Therefore, the center will not be added to 
the primary analysis model. However, the central effects will be studied in further sensitivity 
analysis and subgroups analysis. Additional sensitivity analyzes can be identified in terms of 
statistical analysis. 
The p value for testing the adjusted equality of the equivalence of the odds ratio to 1 will be 
compared with a significance level of 0.05. 


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10.1.3 Analysis of secondary efficacy parameters 
The entire secondary efficacy analysis will be considered investigational, so the multiplicity 
adjustment will not be conducted, and a formal capacity calculation will not be provided for the 
test results. 
• The occurrence of bowel movements per day (according to the diary data) in the treatment 
group compared with the placebo group;  
• The incidence of any diarrhea in the treatment group compared with the placebo group;  
• • The incidence of C.  difficile-associated AAD in the treatment group compared with the 
placebo group;  
• • The incidence of AAD not associated with C.  Difficile in the treatment group compared with 
the placebo group. 
Comparison of these parameters between the two groups will be performed using the chi-square 
test. 
• The duration of AAD (the time from the onset of AAD to the normalization of stool form 
according to BSFS (types 1, 2, 3 and 4) and the presence of normal stool within 48 hours)) in 
the treatment group as compared to the placebo group;  
• Duration of any diarrhea (the period from the diarrhea onset to the normalization of stool form 
according to BSFS (types 1, 2, 3 and 4) and the presence of normal stool within 48 hours)) in 
the treatment group vs the placebo group;  
• The changes in stool consistency (according to Bristol Stool Form Scale) (according to the diary 
data) in the treatment group vs the placebo group; for any individual changes in the stool 
consistency, it will be classified as improved / unchanged / worsened, and the difference 
between the groups will be analyzed using the chi-square test; 
• The incidence and severity of symptoms of the gastrointestinal tract, including nausea, 
vomiting, flatulence, abdominal pain and poor appetite (according to the diary) in the treatment 
group vs the placebo group; the incidence of symptoms will be compared using the chi-square 
test, and the comparison of severity by using the Mann-Whitney-Wilcoxon test; 
• Change in body weight at Visit 3 compared with Visit 1 in the placebo group as compared to 
the treatment group;  
• Hospitalization rate in the treatment group vs the placebo group; comparison between the two 
groups will be performed using the Fisher’s exact test or chi-square test depending on the 
number of expected observations per cell (<5 or ≥5); 


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• The number of days of using standard symptomatic therapy to relieve signs of acute diarrhea in 
the treatment group vs the placebo group; 
• The number of patients using standard symptomatic therapy to relieve signs of acute diarrhea 
in the treatment group vs the placebo group.  
 
10.1.4 Analysis of safety parameters 
Safety parameters should be evaluated at each visit planned in this study, as well as at unscheduled 
visits. 
Safety evaluation will be based on the following parameters (between Visits 1 and 3), compared 
between the investigational medicinal product and placebo: 
Frequency of adverse events (AEs) and/or serious adverse events (SAEs) in the treatment groups, 
including:  
 Determination of the overall incidence in:  
I. 
adverse events (AEs), regardless of their association to the treatment;   
II. 
AEs related or possibly related to the medicinal product administration;   
III. 
AEs requiring therapy discontinuation.   
AEs recording will be based on spontaneous report by the patient, as well as on the results of a 
patient survey by a physician. 
Adverse events will be encoded according to the last update of MedDRA terminology. They will 
be represented by a preferred term (PT) and a system organ class (SOC). 
 AEs incidence according to the results of the vital signs evaluation (HR, BP, BT, RR) at each 
visit vs placebo 
Changes in the main vital signs over time and the frequency of pathological abnormalities revealed 
during physical examination will be summarized in groups, and a comparison will be made 
between groups using appropriate tests for quantitative and qualitative data (see below). 
Quantitative data will be compared using the t-test or the Mann-Whitney test, depending on the 
normality of the distribution (which will be evaluated using the Shapiro-Wilk test). Qualitative 
data will be compared using the Fisher’s exact test or the chi-square test, depending on the number 
of prospective observations in one cell (<5 or ≥5).  
 AEs incidence according to the results of laboratory examinations on Days 7(± 2) and 15(± 2) 
and AEs incidence according to the ECG results 15(± 2) vs placebo; 


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Variations in the results of laboratory tests (carried out in the central laboratory) over time and the 
rate of pathological deviations from the norm of the study results (based on the central laboratory 
reference values), as well as the deviations rate of the ECG results at the Visit 3 will be summarized 
by groups, and comparison between groups shall be made using appropriate tests for quantitative 
and qualitative data (see paragraph 2).  
 AEs incidence according to the everyday patients’ diaries records of well-being self-
evaluation. 
Patient complaints based on the results of the daily records of well-being self-assessment in the 
diary will be summarized into groups, and comparison between groups shall be made using 
appropriate tests for quantitative and qualitative data. Gastrointestinal AEs (determined using 
standardized MedDRA requests for the corresponding symptoms), regarded by the Investigator as 
associated with the study therapy, will be analyzed separately. Descriptive statistics methods will 
be used for the results. Comparison of the incidence of new AEs in the study groups will be carried 
out using the Fisher’s exact test or the chi-square criterion, depending on the number of prospective 
observations in one cell (<5 or ≥5); the comparison of severity degree (and possible causal 
relationship between received medicinal product and AE) will be carried out using the Cochran – 
Armitage test for linear trends for ordered categorical data.  
 
10.2  Interim analysis 
Interim data analysis is not planned in this study 
10.3 Sample size calculation 
Sample size calculation is based on the following actions:  
 Efficacy of probiotics in prevention of acute diarrhea: a meta-analysis of masked, randomized, 
placebo-controlled trials. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, Black RE. 
Lancet Infect Dis. 2006 Jun; 6(6):374-82. Review. PMID:16728323. DOI:10.1016/S1473-
3099(06)70495-9 
 Chow S, Shao J, Wang H. Sample Size Calculations in Clinical Research. 2nd Ed. Chapman 
& Hall/CRC Biostatistics Series, 2008 
 McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea 
and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006 Apr;101(4):812-
22. 
 Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. 
Aliment Pharmacol Ther. 2012 Jun;35(12):1355-69. doi: 10.1111/j.1365-2036.2012.05104.x. 
Epub 2012 Apr 24. 


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 H. Szajewska, M. Kołodziej. Systematic review with meta-analysis: Lactobacillus rhamnosus 
GG in the prevention of antibiotic‐associated diarrhoea in children and adults. AP&T, Volume 
42, Issue 10, November 2015, Pages 1149-1157. 
Primary endpoint is the AAD incidence from 1 to the last day of LRG-002 administration vs 
placebo in ARD patients treated with standard antibiotic therapy. The primary efficacy criterion 
will be considered achieved if the odds ratio for the AAD incidence between two groups is 
significantly higher than 1 (i.e. AAD incidence in the LRG-002 group is lower than in placebo 
group). 
A test based on odd ratio was used for sample size calculation. 
The following data were obtained from Figure 2 in the meta-analysis [1] (only data on AAD were 
used): 
• Given only data for AAD studies in adults from the cited publication, the rate for the control 
group is 0.24, and for the treatment group - 0.14. 
• Given only data for LGG studies in adults and children, the rate for the control group is 0.26, 
and for the treatment group - 0.15. 
In meta-analysis [14], figures from Table 1 demonstrate a rate of 0.196 for the treatment group 
and 0.29 for the placebo group (only trials for adults with LGG were taken into consideration). 
In meta-analysis [15], figures from Table 2 demonstrate a rate of 0.188 for the treatment group 
and 0.269 for the placebo group (only trials for adults with LGG were taken into consideration). 
Consideration of AAD studies for LGG from the paper[16], concerning infections in adults 
(including H.pylori), resulted in 0.14 for the probiotic group and 0.22 for the control group. 
Combining all the strains, we obtained a rate of 0.26 for placebo and 0.15 for probiotic group. 
The following indicators were used for calculations: 
 Difference of AAD absolute risks in placebo and treatment groups is expected to be positive. 
 Incidence of AAD is assumed 0.26 for a placebo group and 0.15 for the treatment group. 
 Likelihood of type I errors: 0.05; 
 Power of the study is 80%, which corresponds to the type II error: 0.20 
 Statistical hypothesis is the evidence of superior efficacy: 
 
H0:OR=1  
H1 :OR≠1, 


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wherein OR is the odds ratio between both groups. 
The ratio between the treatment and placebo group sizes is 1:1 
The number of patients in each group could be calculated using the following formula [2]: 
 
(
)
(
)
2
1
/2
1
1
208
T
T
T
T
R
R
T
R
Z
Z
n
n
p
p
p
p
p
p
α
β
−
+


=
=
−
+
−
=





−


 
Thus, we obtain the minimum number of patients required for statistical analysis - 416 
(208 patients in each group). Given the 20% attrition rate, there is a necessity to randomize 
520 subjects (260 patients in each group). 
10.4 Applicable significance level of the clinical study 
All statistical tests in this study will be conducted at a 95% significance level (the threshold p value 
for confirming statistical significance is less than 0.05). Bilateral statistical criteria will be applied 
for all parameters studied. 
10.5 Clinical study termination criteria  
The study may be terminated subject to occurrence of terms and conditions set forth in section 5.8 
of this protocol. 
10.6 Missing, Suspect and Non-Amendable-To-Analysis Data Procedures  
During monitoring visits to the clinical center, Clinical Research Associates (Monitors) authorized 
by the Sponsor will analyze the CRF of the study subjects for the lack of necessary data. If there 
is any missing data in CRF and the relevant information is available in the source documentation, 
relevant queries to investigators shall be spelled out, as well as instructions for elimination of 
discrepancies. During check of the database, the Statistician, authorized by the Sponsor, and 
Managers for Data Control and Processing will determine whether there were any uncertain, 
missed, or non-amendable-to-analysis data, based on which queries to investigators can be defined. 
The investigators, if possible, eliminate the detected errors in CRF, and inform the Principal 
Investigator and authorized representatives of the Sponsor thereof. If the detected errors in the data 
cannot be eliminated after the completion of the patient’s participation in the study, sensitivity of 
the resulting parameters to the presence of suspected data will be analyzed during the statistical 
analysis of the data. Information on missing, suspected and non-amendable-to-analysis data will 
be presented in the final clinical study report. For the primary endpoint, the method of filling in 
the missing values will be applied on the basis of the maximum likelihood estimation (MLE), if 
necessary [64]. For all other types of endpoints and other parameters, the analysis will be carried 


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out only using actually available information, without data fulfillment, which is associated with a 
short duration of the clinical study.  
10.7 Procedures for reporting any deviations from the original statistical plan 
All deviations from the original statistical plan should be described and justified in an amendment 
to the protocol and / or the final study report (in the latter case, the statistical analysis plan 
developed prior to the initiation of the final statistical analysis should contain a list of these 
deviations with justification of reasons for deviating from statistical plan according to the 
Protocol).  
10.8 Selection of subjects for analysis  
For the analysis, the following data sets will be used: 
• Population of all included patients (intention-to-treat, ITT): all randomized subjects who 
administered at least one dose of the investigational medicinal product / placebo and completed 
at least one visit to evaluate the efficacy parameters (i.e. at least all procedures of visit 1). 
• Population of patients who completed the study according to the Protocol (per protocol, PP): 
all randomized subjects who completed participation in the study according to the Protocol 
(completed the prescribed period of treatment and follow-up without significant deviations 
from the Protocol). 
• Safety population: all randomized subjects who administered at least one dose of the 
investigational medicinal product / reference medicinal product and completed at least one visit 
to evaluate safety parameters (i.e. at least Visit 1). Unlike the ITT population, the safety 
population will be analyzed according to the actual treatment received rather than the prescribed 
treatment (if the differences are identified between the treatment prescribed and actually 
received). 
 
11. Description of activities concerning Quality Control and Quality Assurance 
11.1 Study Monitoring and Quality Control 
Regular visits of the Clinical Research Associate (Monitor), on behalf of the Sponsor and in 
accordance with standard operating procedures (SOPs), prior to, during and in the end of the study, 
contribute to the study success, guarantee the collection of accurate data and the timely detection 
of possible errors, documenting the clinical trial process and ensuring the protection of the study 


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subject rights and the study relevance to the principles of Good Clinical Practice (ICH GCP) and 
requirements of international law and applicable legislation of the Russian Federation. 
Routine study monitoring includes: 
• Confirmation of the proper conduction and documentation of the informed consent process, as 
well as screening and inclusion of subjects in the study; 
• Verification of CRF data and primary medical documentation of the study subjects;  
• Confirmation of documentation and timely reporting of information on AEs during the study; 
• Confirmation of compliance with the requirements for the implementation of diagnostic and 
therapeutic procedures of the study protocol by the personnel of the clinical center; 
• Confirmation of documentation on delivery, storage, distribution and destruction of the 
investigational medicinal product / reference medicinal product and study materials; 
• Confirmation of the personnel competencies of the clinical center, external laboratory, 
necessary for the study; 
• Confirmation of the conformity of diagnostic and laboratory equipment to the requirements of 
safe and adequate use during the study; 
• Confirmation of the Investigator's interactions with the local Ethics Committee on the study 
safety issues and the introduction of amendments to the study Protocol, approved by the 
Sponsor. 
Quality control of the study results is carried out by the Sponsor / Sponsor’s Qualified Person, 
maintaining an electronic study database, which determine inconsistencies, wrong data, missing 
data during the cross-validation of all CRFs. Should any questions or a need of clarification arise, 
a special form (request for data clarification) is sent to the Investigator in the eCRF system or by 
e-mail / fax, the request must be answered in written form within 7 days after its delivery. 
In accordance with legislative requirements, the Sponsor or authorized government authorities 
have the right to verify (audit) the material and technical support of the study and its 
documentation. The Investigator shall provide access to documentation and all necessary 
information to persons authorized to conduct an audit or inspection. 
Monitor visits can be carried out both face-to-face and remotely by agreement with the Sponsor. 
A detailed description and format of the visits will be provided in the Study Monitoring Plan. 
11.2 Protocol amendments 
The investigators' signatures on the Protocol signature page mean written confirmation of consent 
to conduct study in accordance with this Protocol. During the clinical study, amendments and 


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supplements may be made to the study materials. Such changes and supplements are considered 
as amendments. 
Amendment to the Protocol - a written description of the changes or a formal explanation of the 
text in the Clinical Trial Protocol. The amendments may be substantial and unsubstantial. Any 
amendment to the Protocol must be duly approved in accordance with the internal SOPs of the 
sponsoring company before it comes into effect, then approved by the regulatory authorities, the 
independent ethics committee and signed by the Investigator. 
In the Order of the Ministry of Health of the Russian Federation No. 775 “On Approval of the 
Procedure for Considering Reports on the Need to Amend the Clinical Trial Protocol of medicinal 
product for medical use” dated August 31, 2010, a list of substantial / unsubstantial amendments 
and the procedure for submitting materials for examination are defined. 
Amendments to the clinical trial materials are considered substantial if they can affect the goals, 
forms of organization, methodology, statistical methods for processing the clinical trial results and 
measures to ensure safety of patients participating in it. 
Amendments to the clinical trial materials are considered unsubstantial if they cannot affect the 
goals, forms of organization, methodology, statistical methods for processing the clinical trial 
results and measures to ensure safety of patients participating in it. 
If it is necessary to amend this Protocol, the study Sponsor reports to the Ministry of Health of the 
Russian Federation on the need to amend the Clinical Trial Protocol. The decision to introduce 
amendments or to refuse to introduce them is made by the Ministry of Health of the Russian 
Federation after examination of the provided updated materials. Amendments to the Protocol 
should be stored with the original version of the Protocol. The number and date of amendment 
shall be indicated on the title page of the Protocol. 
11.3 Protocol Deviations 
A deviation from the Protocol is an unintentional deviation from the approved study Protocol. 
A serious deviation from the Protocol is a deviation that may, according to the assessment of the 
Investigator or the Investigator’s Qualified Person, result in the subject dropping out from the 
study or his data being excluded from the bioanalytical and / or statistical part of the study. 
Deviations not classified as serious are considered minor deviations from the study Protocol. 
Serious deviations from the Protocol should be reported to the Sponsor as soon as possible by the 
clinical center and/or CRO personnel and Monitor (if present at the center). The Sponsor may 


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propose to re-classify the deviation from the Protocol (from minor to serious or vice versa) on the 
basis of the assessment. In such case, the classification made by the Sponsor shall prevail and shall 
be brought to the notice of CRO together with a written justification. 
The Sponsor must be informed of minor deviations from the Protocol within 10 working days, but 
before the start of the next study period / phase or before the start of the bioanalytic phase / 
statistical phase. 
The exceptions are the following minor deviations from the Protocol, which can be reported in the 
draft study report: 
• Logistical deviations (deviations in time from the scheduled plan of blood sampling; follow-up 
visits that moved out of the time frame established by the Protocol due to the subject's 
plans/schedule, etc.). 
• Administrative deviations (e.g. name change). 
In the case of enrollment of a smaller than planned number of volunteers, the CRO should contact 
the Sponsor, who may approve the dosing of a smaller than planned number of volunteers. This is 
not considered as deviation from the Protocol. 
Notices and reports about deviations from the Protocol shall be submitted to the Regulatory 
authorities and relevant Ethics Committees in accordance with applicable requirements / 
guidelines / laws. 
Procedure for documenting Protocol deviations 
The Investigator or the Investigator’s Responsible Person shall document and explain any Protocol 
deviation. Sponsor's notification of a deviation from the Protocol may be communicated verbally 
in exceptional cases (if immediate action / notification is required), followed by written 
notification (e.g., by e-mail; in the report on the study period). All deviations from the Protocol 
should be described in the final study report. 
12. Description of the clinical trial ethical aspects 
12.1 General provisions 
The study will be conducted in compliance with the principles and requirements set forth in the 
following documents: 
• WMA Declaration of Helsinki (adopted at the 18th WMA Assembly in Helsinki, June 1964, 
the latest edition was approved at the 64th Assembly in Fortaleza, October 2013),  


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• ICH E6 Harmonized Tripartite Guidelines for Good Clinical Practice (R2) dated November 9, 
2016  
• Rules of Good Clinical Practice of the Eurasian Economic Union (approved by Decision of the 
Council of the Eurasian Economic Commission No. 79 dated November 3, 2016); 
• Federal Law No 61-FZ “On Circulation of Medicines” (current edition) dated April 12, 2010; 
• Order of the Ministry of Health of the Russian Federation dated April 1, 2016 No. N 200n “On 
Good Clinical Practice Approval”; 
• National Standard of the Russian Federation GOST R 52379-2005 "Good Clinical Practice”; 
The study will be started in all research centers only after obtaining written permission to conduct 
the study and approval of the Ethics Council of the Ministry of Health of the Russian Federation 
and obtaining signatures on the Clinical Trial Protocol of each of the parties involved in the study. 
Investigators will be familiarized with study materials in a timely manner before its initiation. 
Qualification of investigators will meet the requirements necessary for conducting quality clinical 
study. 
The selection of prospective study subjects is voluntary.  
12.2 Procedure of obtaining informed consent 
Before being included in the study, the subject is provided with written information and an oral 
explanation of the goals, objectives and methods of the study, as well as the expected benefits and 
possible risks associated with participation in the study. Besides, subjects should be informed of 
the voluntary nature of participation in the study and that the subject has the right to refuse to 
participate in the study at any time and this refusal will not affect the quality of medical care 
provided for him. Although the subject does not have to report on the reasons that prompted him 
to interrupt participation in the study, the Investigator should try to find out these reasons without 
violating the subject’s rights. Subject consent must be obtained prior to any study procedures. 
The data processing collected during the study is carried out in compliance with the confidentiality 
of subjects. Subjects should be informed about the goals of the planned computer data processing 
and terms of publishing this data (e.g., for presentation at medical conferences, in journal articles 
and other open sources), presented only in an aggregated form that does not allow subject’s 
identification. 
Subjects should be informed that authorized representatives of the health authorities and the 
Sponsor will have access to their confidential medical information for monitoring, inspection and 


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audit purposes. At the same time, subjects must be guaranteed strict confidentiality of all 
information that allows to identify the study subject, and non-disclosure of such information. 
The Patient Information Leaflet with the informed consent form is to be completed in duplicate, 
signed and dated by the subject and Investigator in their own hands. The first copy of the signed 
Patient Information Leaflet with the informed consent form must be stored by the Investigator in 
the investigator’s file, the second copy must be given to the study subject. 
12.3 Confidentiality and identification of study subjects 
Confidentiality of records allowing for identification of the study subjects is ensured in compliance 
with the right of privacy and privacy protection in accordance with the regulatory requirements. 
Records concerning patient's identity are kept secret and can be disclosed only to the extent 
permitted by the legislation. The confidentiality of the subject personal data will be preserved 
when the study results are published. 
12.4 Selection of subjects from vulnerable and special groups 
Inclusion / non-inclusion criteria do not include participation of subjects from vulnerable groups 
in the study.  
Groups with special conditions in this study include women with preserved reproductive potential, 
who, according to inclusion and non-inclusion criteria, can participate in the study only if they 
consent to the use of effective contraceptive methods throughout the study, which is reflected in 
the Patient Information Leaflet and is confirmed through signing an informed consent form. 
 
 


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13. Description of working with data and recording 
All records and documents of the research center related to the clinical study, including those in 
the investigator’s file (including informed consent forms, logs, subject lists, etc.), as well as the 
source medical records of the subject must be stored for 15 years after the end of the study. The 
study Sponsor should control the preservation and availability of all materials in the clinical trial 
throughout the life cycle of the IMP. Archival data can be stored in the form of photocopies, as 
well as in optical and electronic media. The Principal Investigator must immediately inform the 
Sponsor of the facts of unintentional damage / destruction, as well as the change in the storage 
location of the archived materials concerning clinical trial. Wilful destruction of archived study 
materials is possible only with the written permission of the study Sponsor. 
As the subjects undergoes the planned visits and the Investigator completes eCRF, source 
documentation and eCRF will be verified by Sponsor’s authorized monitors. Should Manager for 
Data Control and / or Biostatistics at the stage of evaluating data in the eCRF have questions about 
the data, all updates and amendments to the eCRF data will be documented by creating request 
forms to clarify the data.  
The study should be conducted in accordance with the Protocol and applicable standard operating 
procedures of the Sponsor. If there is a need to amend the Protocol, one should follow the 
procedure described in section 11.2. 
For investigators, it is mandatory to fill out the source medical record and eCRFs of all subjects 
involved in the study. 
The Investigator is responsible for the full and accurate completion of the eCRF. All data recorded 
in the eCRF should also be reflected in the source medical record of the subject in printed form or 
in the form of records made by the Investigator or other Qualified Person of the clinical center. 
In eCRF, according to the source documentation, all significant information about the subject's 
participation in the study is recorded. The eCRF should also contain information on the subject's 
completion of participation in the study. The eCRF should be completed no later than 5 days after 
the subject’s visit to the research center.  
The Investigator has the right to convey the study information to persons not directly involved in 
the study, only with the permission of the Sponsor. 
The final report, consisting of a statistical and clinical report, is formed after the database is closed 
and the statistical processing of the study results is completed. 


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The final report is signed by the Principal Investigator of the clinical center, who confirms the 
results and conclusions of the study. 
Direct Access to the Source Data / Documents 
Source data is all information contained in the source medical records and certified copies, 
regarding the clinical data, follow-ups and other procedures within the framework of the study, 
and necessary for the reconstruction and evaluation of the study.  
The Investigator provides the opportunity to monitor study, audit(s), examination by the Ethics 
Council and regulatory authorities, provides direct access to source data / records. 
Source data should be stored in proper quality for the entire period provided by local and 
international legislation, as well as in written agreements with the company sponsoring the study. 
For each involved subject, the Investigator confirms in the source records the fact that the subject 
is participating in this study, and also records the following information: individual ID, personal 
data of patients (name, address), dates of medicinal product administration, vital signs, any AEs, 
study completion dates, and main reasons for discontinuing treatment (if applicable). 
It is the responsibility of the Investigator to provide direct access to source data and documentation 
for the Clinical Research Associate of the sponsoring company and / or its authorized 
representatives (CRO), the auditor of the competent authorities, representatives of the insurance 
company, and ethics committees. 
 
 


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14. Funding and Insurance 
14.1 Funding 
This study is funded by the sponsoring company through CRO. Prior to the study, appropriate 
agreements will be concluded between the CRO and each research center. 
14.2 Insurance 
Patient safety during this study is the responsibility of the Principal Investigator of the research 
center. If the patient experience an AE, the Principal Investigator and his staff will provide medical 
care and will do everything possible to treat the patient.  
If the patient agrees to participate in the study, his participation in this study will be insured by 
 in accordance with the Federal 
Law No. 61-FZ  “On Circulation of Medicines " dated April 12, 2010, Decree of the Government 
of the Russian Federation No. 714 "On Approval of Standard Rules for Compulsory Life and 
Health Insurance of a Patient Participating in Clinical Trials of a Medicinal Product" dated 
September 13, 2010 and Decree of the Government of the Russian Federation No. 393 "On 
Amendments to Standard Rules for Compulsory Life and Health Insurance of a Patient 
Participating in Clinical Trials of a Medicinal Product” dated May 18, 2011.  
According to the Decree of the Government of the Russian Federation No. 714 "On Approval of 
Standard Rules of Compulsory Life and Health Insurance of a Patient Participating in Clinical 
Trials of a Medicinal Product”, the amount of insurance payment under the contract is: 
a) in case of death of the insured person - 2 million rubles.  The insurance payment in the indicated 
amount is distributed among the beneficiaries in proportion to their number in equal shares; 
b) if the health of the insured person worsens, which entails: 
• group I disability confirmation - 1.5 million rubles; 
• group II disability confirmation - 1 million rubles; 
• group III disability confirmation - 500 thousand rubles; 
c) upon deterioration of the insured person health, which did not entail the disability confirmation 
- not more than 300 thousand rubles. 
Each patient will receive the original insurance policy and a memo with a description of the 
insurance terms and conditions provided for by the policy and the procedure for dealing with harm 
to health. In order to maintain anonymity, the personal data of each patient in the policy will be 


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replaced by the Individual Patient Identification Code, which is assigned during the study in the 
form established in the Russian Federation.  
In case of damage to the patient’s health associated with a clinical trial, 
 
Insurance Company shall compensate all costs for the necessary medical examination and 
treatment, the need for which will arise as a result of the direct effect of the investigational 
medicinal product and/or medical manipulations applied according to study Protocol. 
For more information, patients can contact the address of the Insurance Company: 
 
The study does not provide any additional types of voluntary insurance or other options for the 
provision of treatment and / or compensation in the event of the patient’s death or harm to the 
patient’s health as part of the study. 
The Sponsor is not responsible for any loss, harm and / or damage that may be caused to the patient 
in the event that such loss, harm and / or damage are caused by: 
• Administration of prohibited medicinal product during the study; 
• Deviations from the study Protocol, study requirements and / or any instructions or directions 
that the physician-investigator can provide, by the patient; 
• The action or inaction of a third party concerning adequate respond to an adverse event or 
reaction to the investigational medicinal product. 
 
 


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15. Publications 
The information contained in this document is the property of the Sponsor, and its transfer to third 
parties is permitted only with the written permission of the sponsoring company. Only the 
Investigator(s) and the research center(s) participating in the study, members of the independent 
ethics committee(s) and health officers authorized to control the clinical study have access to this 
information. Information on the study to the extent of making a decision on granting consent to 
participate is provided to subjects who can participate in the study. 
Exclusive rights to the study results belong to the Sponsor of the study. No data from this study 
may be presented or published without the prior written permission of the Sponsor. 


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fundamental and biomedical research. Appl Environ Microbiol. 74(16):4985–4996. 
 
Wang, Yuhua, Yanlong Liu, Irina Kirpich, Zhenhua Ma, Cuiling Wang, Min Zhang, Jill 
Suttles, Craig McClain, и Wenke Feng. «Lactobacillus Rhamnosus GG Reduces Hepatic 
TNFα Production and Inflammation in Chronic Alcohol-Induced Liver Injury». The Journal 
of Nutritional Biochemistry 24, вып. 9 (сентябрь 2013 г.): 1609–15.  
 
Young, Rosemary J., и Jon A. Vanderhoof. «Two Cases of Lactobacillus Bacteremia 
during Probiotic Treatment of Short Gut Syndrome». Journal of Pediatric Gastroenterology 
and Nutrition 39, вып. 4 (октябрь 2004 г.): 436–37; author reply 437. 
 
Zhang L, Li N, Caicedo R, Neu J. Alive and dead Lactobacillus rhamnosus GG decrease 
tumor necrosis factor-alpha-induced interleukin-8 production in Caco-2 cells. J 
Nutr. 2005 Jul;135(7):1752-6. 


Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
Page 198 of 253 
 
Zhou JS, Pillidge CJ, Gopal PK, Gill HS. Antibiotic susceptibility profiles of new probiotic 
Lactobacillus and Bifidobacterium strains. J Food Microbiol. 2005 Feb 1;98(2):211-7 
 
Zhou JS, Shu Q, Rutherfurd KJ, et al. Acute oral toxicity and bacterial translocation studies 
on potentially probiotic strains of lactic acid bacteria. Food Chem Toxicol. 2000a;38(2-3):153-
61.  
 
Zhou JS, Shu Q, Rutherfurd KJ, et al. Safety assessment of potential probiotic lactic acid 
bacterial strains Lactobacillus rhamnosus HN001, Lb. acidophilus HN017, and 
Bifidobacterium lactis HN019 in BALB/c mice. Int J Food Microbiol. 2000b;56(1):87-96.  
 


Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
Page 199 of 253 
17. Appendices 
17.1 Appendix 1. Prohibited Therapy List 
Pharmaceutical groups 
Active substance 
Systemic glucocorticosteroids 
hydrocortisone, cortisone, prednisone, 
methylprednisone, prednisone, triamcynolone, 
dexamethasone, betamethasone and their 
analogues and/or combinations and derivatives 
thereof 
Antibacterial agents 
aminoglycosides, amphenycols, ansamicines, 
glycopeptides, carbapenemes, lincosamides, 
macrolides and azalides, penicillins, 
tetracyclines, cephalosporins - in monotherapy 
and/or combinations 
Probiotics, including dietary supplements 
acidophilic lactobacteria, kefir fungi, 
bifidobacteria bifidum, Escherichia coli, 
lactobacteria, lysozyme, enterococcus fecium, 
longum bifidobacteria, animalis bifidobacteria, 
lactulose, plantharum lactobacteria, product 
Broncho-munal® - as monotherapy and as part of 
the drug / dietary supplement in any combination 
Adsorbents 
activated carbon, aluminium oxide, attapulgite, 
colloidal silicon dioxide, lactulose, lignin 
hydrolised, povidone, polymethylsiloxane 
polyhydrate, dioctahedral smectite - as 
monotherapy and as a part of the drug / dietary 
supplements in any combination 
Calcium preparations 
calcium glubionate, calcium lactobionate, 
calcium carbonate, calcium lactogluconate - as 
monotherapy and as part of the drug / dietary 
supplement in any combination 
Anti-diarrheal medications 
attapulgite, bergenia rhizome, bacillus subtilis, 
bifidobacteria bifidum, snakeweed rhizome, 
burnet rhizome with roots, 
loperamide+symeticone, loperamide, oval 
plantain seed coating, racecadotryl, dioctahedral 
smectite, hackberry fruit, blueberry fruit - as 
monotherapy and as part of the drug / dietary 
supplements in any combination 
Myotropic spasmolytics 
bendazole, metamizole, papaverine, drotaverine, 
theobromine, bencyclane, darifenacin, 
dicyclovenerine, codeine, camylophin, 
mecloxamine, propyphenazole, ergotamine, 
mebeverine, oxybutynin, otilonium bromide, 
platyphylline, pynaverium bromide, trimebutine, 
as well as plant spasmolytics - as monotherapy 
and as part of the drug / dietary supplements in 
any combination  


Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
Page 200 of 253 
Antiemetics and drugs that affect 
gastrointestinal motility 
pyridostigmine, neostigmine, itoprid, cisapride, 
aprepitant, bromopride, granisetron, 
dimenhydrinate, domperidone, levomenthol 
solution in menthyl isovalerate, meclozine, 
moxastine, ondansetron, palonosetron, 
perphenazine, thiethylperazine, trifluoperazine, 
tropisetron, fosaprepitant, as well as medications 
of plant origin - as monotherapy and as part of 
the drug / dietary supplements in any 
combination  
 


Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
Page 201 of 253 
17.2.Appendix 2. Prescribing on stool sample collection for patient 
In case of diarrhea, collect samples of the stool according to the following instructions:  
Container 1 (sterile container with spoon and lid). 
Collect a stool sample of no more than 1/3 of the container volume (from several places). During 
collection, try to avoid impurities of urine and urethral and vaginal discharge. Close the container, 
place it to the fridge (NOT to the freezer). 
 
Container 2 (sterile container with spoon and lid). 
 Collect a stool sample of no more than 1/3 of the container volume (from several places). During 
collection, try to avoid impurities of urine and urethral and vaginal discharge. Close the container, 
place it to the fridge (NOT to the freezer). 
 
Container 3 (transport kit consisting of a Cary-Blair liquid tube with a green lid and a swab 
on the applicator) 
Collect the sample by immersion of the tampon in the feces alternately in several places, then place 
the swab to the tube and break off the surplus of applicator on the red mark. 
Screw the lid tightly to prevent material from leaking. Close the container, place it in the fridge 
(NOT in the freezer). 
 
Contact the research center within 1 hour of collecting the samples and notify it on the need 
to transport the containers to the laboratory. Keep samples in the fridge (NOT in the 
freezer!) before the employee arrives. 


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1 7. 3.  A p pe n di x  3. P atie nt di ar y 
Fille d b y t he p atie nt: Da y N o.  1  
  
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nc e of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h air  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
 
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 0 3  of 2 5 3  
 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore ti mes a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or.  
4.  B o d y te m per at ure  
M eas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 0 4  of 2 5 3  
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s): 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 0 5  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  2  
  
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri b e d it?   
  
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h air  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
 
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or more ti mes a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or.  


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 0 6  of 2 5 3  
 
4.  B o d y te m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 0 7  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 0 8  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  3  
  
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?   
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a  d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h air  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
 
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore ti mes a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 0 9  of 2 5 3  
 
4.  B o d y te m per at ure  
Me as ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 0  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 1  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  4  
  
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h air  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y p e  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore ti mes a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 2  of 2 5 3  
 
4.   B o d y te m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 3  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 4  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  5  
  
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
  
 Ye s          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h a ir  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see   
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore times a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 5  of 2 5 3  
 
4.  B o d y t e m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 6  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 7  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  6  
  
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
  
  Ye s          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h a ir  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _  
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _  
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore times a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 8  of 2 5 3  
 
4.  B o d y t e m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 1 9  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 0  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  7  
  
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
  
 Ye s          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h a ir  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore times a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 1  of 2 5 3  
 
4.  B o d y t e m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 2  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 3  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  8  
  
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
  
 Ye s          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h a ir  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore times a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 4  of 2 5 3  
 
4.  B o d y t e m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 5  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts a n d 
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 6  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  9  
  
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
  
  Ye s          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h a ir  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore times a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 7  of 2 5 3  
 
4.  B o d y t e m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 8  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts a n d 
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 2 9  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  1 0    
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it?  
  Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
  
  Ye s          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h a ir  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore times a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 0  of 2 5 3  
 
4.  B o d y t e m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 1  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts a n d 
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 2  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  1 1    
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it? 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
 
 Yes           N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h ai r  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore times a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 3  of 2 5 3  
 
4.  B o d y t e m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 4  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts a n d 
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 5  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  1 2    
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it? 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
 
 Yes           N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h ai r  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore times a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 6  of 2 5 3  
 
4.  B o d y t e m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 7  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 8  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  1 3    
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it? 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h air  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y p e  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore ti mes a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 3 9  of 2 5 3  
 
4.  B o d y te m per at ure 
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 0  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o   
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 1  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  1 4    
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it? 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h air  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y p e  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore ti mes a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 2  of 2 5 3  
 
4.  B o d y te m per at ure  
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 3  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 4  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  1 5    
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it? 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h air  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore ti mes a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 5  of 2 5 3  
 
4.  B o d y te m per at ure  
Me as ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 6  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 7  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  1 6    
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it? 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
 
 Yes           N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h ai r  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore times a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 8  of 2 5 3  
 
4.  B o d y te m per at ure 
Meas ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 4 9  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 5 0  of 2 5 3  
 
Fille d b y t he p atie nt:  Da y N o.  1 7    
  
  
  
  
Date _ _/ _ _/ _ _ _ _ _ 
1.  D osi n g re gi me n of i n vesti g ati o n al me dici n al pr o d ucts  
Di d y o u ta ke y o ur r esear c h dr u g t he w a y y o ur d oct or prescri b e d it? 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
2.  A nti b acteri al t her a p y re gi me n  
Di d y o u ta ke t he a nti bi otic t he wa y y o ur d oct or prescri be d it?  
 
 Yes          N o:  
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
3.  Occ urre nce of st o ol a d a y; c o nsiste nc y of st o ol 
Mar k  t he  ti me  eac h  c h air  e pis o de  occ urre d  t o da y  a n d  i n dicate  t he  t y pe  of  c o nsiste nc y  (see  
Fi g ure 1).  
1.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
2.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
3.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567 
4.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
5.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567          
6.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567    
7.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
8.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
9.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
1 0.  Ti me: _ _ _ _ _ _ _ _ _ _ _ 
T y pe 1234567   
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
If y o u n otice a l o ose st o ol or water y s ha peless st o ol wit h a fre q ue nc y of 3 or m ore ti mes a da y, 
y o u s h o ul d call a n d i nf or m y o ur d oct or. Y o ur d oct or will rec o m me n d t he dr u gs a p pr o ve d f or us e 
i n t his st u d y t o eli mi nate s y m pt o ms of y o ur c o n diti o n.  
Please re me m b er t hat t he decisi o n t o ta ke a d diti o nal dr u gs ca n o nl y be m a d e b y a d oct or. 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 5 1  of 2 5 3  
 
4.  B o d y te m per at ure  
Me as ure t he b o d y te m perat ure i n t he a xillar y ca vit y wit h a merc ur y t her m o meter a n d rec or d t he 
res ult: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
5.  G astr oi ntesti n al s y m pt o ms  
Mar k t he occ urre n ce of eac h of t hese s y m pt o ms d uri n g t he da y a n d rate t he se verit y of s y m pt o ms 
o n a 5- p oi nt ver bal scale ( 0 t o 4):  
Na usea:                    Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
V o miti n g:                          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Flat ule nce:                Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
 
 


Pr ot oc ol N o. C T _ 0 0 2 _ L R G _ C A P  
Versi o n: 3. 0 date d J u ne  2 3,  2 0 2 0  
C o nfi de nti al!  
Pa ge 2 5 2  of 2 5 3  
 
A b d o mi nal pai n:          Yes          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
Decr ease d a p petite:  Y es          N o  
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
○ 
 
 
 
 
 
 
 
 
 
 
0   
1   
2   
3  
4  
a bse nce  
mil d  
m a nifest ati o ns  
severe 
very severe 
m a nifest ati o ns  
pr o n o u nce d  
me di u m  
m a nifest ati o ns  
m a nifest ati o ns  
 
 
m a nifest ati o ns  
i nte nsity 
 
 
 
C o m me nts
 a n d
c o m plai nts: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
6.  S y m pt o m atic t her a p y  
Ha ve y o u ta ke n a n y me di cati o n t o eli mi nate s y m pt o ms of t he u n derl yi n g disease a n d/ or s y m pt o ms 
of diarr hea?    
 Yes          N o:  
If
 yes,
 pr o vi de
 t h e
 na me,
 d os e,
 ti me
 a n d
 fre q ue n c y
 of
 t he
 me dicati o n(s):
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _
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Protocol No. CT_002_LRG_CAP 
Version: 3.0 dated June 23, 2020 
Confidential! 
Page 253 of 253 
 
17.4. Appendix 4. Bristol Stool Form Scale (according to Lewis S. J. Et al, 1997, adapt. by 
Kharchenko et al. 2007)  
Type of consistency 
Parameter 
Figure 
Type 1 
individual hard lumps like nuts (passageway 
is difficult) 
 
Type 2 
sausage like stool, but lumpy 
 
Type 3 
sausage shaped feces with cracks in the 
surface 
 
Type 4 
smooth and soft sausage or snake shaped 
feces 
 
Type 5 
Soft blobs with clear-cut edges 
 
Type 6 
loose pieces with ragged edges 
 
Type 7 
loose stool 
 
 

SAP_001.pdf: 
Official Title: 
Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel-group 
Efficacy and Safety Study of LRG-002 Hard capsules (Lek d.d., 
Slovenia), Used in the Prophylaxis of Antibiotic-associated Diarrhea in Adults 
NCT Number: 
NCT04321460 
Document Date: 
Statistical Analysis Plan version 1.0: 11 March 2021 


Перевод с русского языка на английский язык 
Translation from Russian into English 
 
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STATISTICAL ANALYSIS PLAN 
 
Page 1 of 40 
Statistical Analysis Plan 
 
Sponsor 
Sandoz JSC 
Protocol title 
Multicenter, double-blind, randomized, placebo-
controlled, parallel-group study of the efficacy and 
safety of LRG-002, hard capsules (Lek d.d., 
Slovenia), in the prophylaxis of antibiotic-associated 
diarrhea in adults 
Protocol No. 
CT_002_LRG_CAP, version 3.0 dated June 23, 2020 
 
Author 
 
Statistical Analysis Plan version 
1.0 
Date of version 
March 11, 2021 
 
 


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Approved by 
Full name 
Position 
Signature 
Date 
/Signature/ 
March 22, 2021 
/Signature/ 
March 22, 2021 
/Signature/ 
March 22, 2021 
/Signature/ 
March 22, 2021 
 
Document history 
Version 
Reason for change 
Date 
1.0 
Original document 
March 11, 2021 
  
 


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Table of contents 
 
1. 
Introduction ............................................................................................................................................. 13 
2. 
Study objectives and design..................................................................................................................... 13 
2.1. 
Study objective ................................................................................................................................ 13 
2.2. 
Study design .................................................................................................................................... 13 
2.2.1. 
Study design flowchart ........................................................................................................... 14 
2.2.2. 
Study duration ......................................................................................................................... 14 
2.2.3. 
Study stages ............................................................................................................................ 15 
2.3. 
Sample size ..................................................................................................................................... 18 
3. 
General analysis values ........................................................................................................................... 20 
3.1. 
Clinical and statistical significance ................................................................................................. 20 
3.2. 
Procedure for missing, unanalyzable, and questionable data  ......................................................... 20 
4. 
Study participants .................................................................................................................................... 21 
4.1. 
Patient distribution .......................................................................................................................... 21 
4.2. 
Study population ............................................................................................................................. 21 
4.2.1. 
Safety population .................................................................................................................... 21 
4.2.2. 
ITT population receiving treatment ........................................................................................ 22 
4.2.3. 
Per protocol set ....................................................................................................................... 22 
5. 
Demographics and baseline characteristics ............................................................................................. 22 
6. 
Concomitant therapy ................................................................................................................................ 23 
6.1. 
Permitted concomitant therapy ........................................................................................................ 23 
6.2. 
Prohibited concomitant therapy ...................................................................................................... 24 
7. 
Efficacy analysis ...................................................................................................................................... 26 
 
Analysis of efficacy endpoints will be carried out in accordance with Section V of the Recommendations of 
the Board of the Eurasian Economic Commission On Guidelines on the Principles of Applying Biostatistics 
in Clinical Trials of Medicines No. 19 dated November 3, 2020. The main analysis tool will be the R 
programming language, version 3.7. ....................................................................................................... 26 
7.1. 
Primary endpoint analysis ............................................................................................................... 26 
7.2. 
Analysis of secondary endpoints ..................................................................................................... 28 
8. 
Safety analysis ......................................................................................................................................... 30 
8.1. 
Adverse events ................................................................................................................................ 31 
8.2. 
Other safety endpoints ..................................................................................................................... 32 
9. 
Exploratory analysis ................................................................................................................................ 32 
10. Interim analysis ....................................................................................................................................... 32 
Appendix 1. Table layouts ............................................................................................................................... 33 
Table No. 1. Example of a statistical table for a quantitative variable ....................................................... 33 
Table No. 2. Example of a group comparison table for a quantitative variable ......................................... 34 
Table No. 3. Example of a repeated comparison table for a quantitative variable  .................................... 35  
Table No. 4. Example of a statistical table for a categorical variable ......................................................... 37 
Table No. 5. Example of a table of adverse events for calculating the number of all adverse events ........ 38 
Table No. 6. Example of a table of adverse events for calculating the number of adverse events  
in the context .............................................................................................................................................. 38 


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List of abbreviations and definitions of terms 
AAD 
Antibiotic-associated diarrhea 
AB 
Antibiotics 
AB-therapy 
Antibiotic therapy 
ARLD 
Alcohol-related liver disease 
BP 
Blood pressure 
GA 
Gastric adenocarcinoma 
ALT 
Alanine aminotransferase 
JSC 
Joint-stock company 
ASH 
Alcoholic steatohepatitis 
AST 
Aspartate aminotransferase 
ATP 
Adenosine triphosphate 
ATPase 
Adenosine triphosphatase 
ATC 
Anatomical Therapeutic Chemical (classification system) 
ROS 
Reactive oxygen species 
DS 
Dietary supplement 
BSS 
Bristol Stool Scale 
IM 
Intramuscular 
IV 
Intravenous 
ULN 
Upper limit of normal 
HIV 
Human immunodeficiency virus 
IBD 
Inflammatory bowel disease 
WMA 
World Medical Association 
IUS 
Intrauterine system 
IUD 
Intrauterine device 
RSC 
Russian Society of Cardiology 
WHO 
World Health Organization 
HPLC 
High-performance liquid chromatography 
g 
Gram 
GOST 
State standard 
GC 
Gas chromatography 
 
 


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d.d. 
"d.d." or "delniška družba," Slovenian, public limited 
company 
DBP 
Diastolic blood pressure 
CI 
Confidence interval 
DMH 
Dimethylhydrazine 
DNA 
Deoxyribonucleic acid 
TD 
Traveler's diarrhea 
ADI 
Acceptable daily intake 
GI tract 
Gastrointestinal tract 
CJSC 
Closed joint-stock company 
EU 
European Union 
IAAD 
Idiopathic antibiotic-associated diarrhea 
CF 
Case form 
IL 
Interleukin 
PI 
Prescribing information 
Full name 
First Name, Patronymic, Last Name 
eCRF 
Electronic case record form 
ELISA 
Enzyme-linked immunosorbent assay 
IFN 
Interferon 
IFN-γ 
Interferon gamma 
CRO 
Contract research organization 
kg 
Kilogram(s) 
NDI 
Numbers of days of illness 
CFU 
Colony-forming units 
CPS 
Capsular polysaccharides 
CRC 
Colorectal cancer 
L 
liter(s) 
LGG 
Lactobacillus rhamnosus GG 
LD50 
Half-lethal dose 
LPS 
Lipopolysaccharides 
CF 
Cystic fibrosis 
mg 
Milligrams 
 
 


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MDA 
Malondialdehyde 
MoH 
Ministry of health 
 
min 
Minutes 
ICD 
International Classification of Diseases 
μg 
Micrograms 
mL 
Milliliters 
mm 
Millimeters 
PBMC 
Peripheral blood mononuclear cells 
INN 
International nonproprietary name 
MNNG 
Methylnitronitrosoguanidine 
MIC 
Minimum inhibitory concentration 
NPE 
Number of polychromatophilic erythrocytes 
NAFLD 
Non-alcoholic fatty liver disease 
e.g. 
For example 
NEC 
Necrotizing enterocolitis 
AR 
Adverse reaction 
IEC 
Independent Ethics Committee 
AE 
Adverse event 
AWD 
Acute watery diarrhea 
AGE 
Acute gastroenteritis 
SCS 
Spent culture supernatant 
LLC 
Limited liability company 
RR 
Relative risk 
ARD 
Acute respiratory disease 
ICU 
Intensive care unit 
FEV 
Forced expiratory volume 
OR 
Odds ratio 
PVC 
Polyvinyl chloride 
TJ 
Tight junctions 
PCTFE 
Polychlorotrifluoroethylene 
PCA 
Pyrrole-2-carboxylic acid 
PCR 
Polymerase chain reaction 
 
 


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times/day 
Times a day 
WG 
Working group 
RIGT 
Radiation-induced gastrointestinal toxicity 
RCS 
Randomized clinical studies 
BC 
Breast cancer 
RMSAH 
The Russian Medical Society on Arterial Hypertension  
RNA 
Ribonucleic acid 
ORS 
Oral rehydration solution 
RD 
Risk difference 
MA 
Marketing authorization 
RF 
Russian Federation 
SBP 
Systolic blood pressure 
SAR 
Serious adverse reaction 
SAE 
Serious adverse event 
et al. 
And other authors 
SOP 
Standard operating procedure 
ESR 
Erythrocyte sedimentation rate 
MD 
Mean difference 
IBS 
Irritable bowel syndrome 
day 
day 
i.e. 
That is 
TCID50 
Tissue culture infectious dose 
TEER 
Transepithelial electrical resistance 
FAP 
Functional abdominal pain 
FD 
Functional dyspepsia 
FL 
Federal law 
Full name 
First name, Patronymic, Last name 
TNF 
Tumor necrosis factor 
FSH 
Follicle-stimulating hormone 
BU 
Bread unit 
CIGT 
Chemotherapy-induced gastrointestinal toxicity 
 
 


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h 
Hours 
NNT 
Number needed to treat 
RR 
Respiration rate 
HR 
Heart rate 
ECG 
Electrocardiography, electrocardiogram 
EPS 
Exopolysaccharides 
AFB 
Acid-fast bacilli 
AGRICOLA 
Agricultural Online Access 
AMED 
Allied and Complementary Medicine Database 
АТСС 
АТСС 53103, strain L. rhamnosus 
AUC 
Area under the curve 
AUC0–∞ 
Concentration–time curve from time zero to infinity 
BALB 
A laboratory-bred strain of albino house mouse widely used 
in clinical studies 
BG2FO 
One of the strains of Lactobacillus spp. 
С 
Degree Celsius 
С. difficile 
Clostridium difficile 
C57BJ 
Inbred strain of laboratory mice widely used as models of 
human diseases 
C57BL 
Inbred strain of laboratory mice widely used as models of 
human diseases 
CaH 
Calcium hydride 
СВА 
Inbred strain of laboratory mice 
CCL 
С-С 
Motif Chemokine Ligand 11: chemokine 11 containing a 
C-C motif 
 
 


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CD 
Cluster of differentiation 
CD62p 
Markers of platelet activation 
CdAD 
Clostridium difficile-associated diarrhea 
CdD 
Clostridium difficile-associated diarrhea 
CHСС 
One of the strains of Lactobacillus spp. 
СНО 
Chinese hamster ovary 
СINAHL 
Cumulative Index to Nursing and Allied Health Literature 
CMPG 5153 
Mutant L. rhamnosus GG strain 
СР 
Organophosphate pesticides parathion and chlorpyrifos 
СТМ 
Clinical Trial Manager 
CXCL 
Interleukin-8 
CYP 
Cytochrome P450 
CYP2E 
Cytochrome P450 
GCP 
Good clinical practice 
DN-114001 
One of the strains of Lactobacillus casei 
DOI 
Digital object (article) identifier 
Е. cloacae 
Escherichia cloacae 
Е. coli 
Escherichia coli 
EFSA 
European Food Safety Agency 
EMBASE 
Biomedical and pharmacological bibliographic database 
ЕРЕС 
Enteropathogenic Escherichia coli 
ERK 
Protein kinase signaling pathway 
ESPGHAN 
European Society of Pediatric Gastroenterology, Hepatology, 
and Nutrition 
et al. 
And others 
ETEC 
Enterotoxigenic E. coli 
F0F1- 
Structural complex of ATP synthase 
 
 


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FAO 
Food and Agriculture Organization of the United Nations 
FDA 
Food and Drug Administration 
GAPDH 
Glyceraldehyde-3-phosphate dehydrogenase 
GR 
One of the L. rhamnosus strains 
GRAS 
Generally Regarded As Safe – FDA 
GSH 
Glutathione 
H. pylori 
Helicobacter pylori 
HCI 
Hydrochloric acid 
HIF 
Hypoxia-inducible factors 
HIV 
Human immunodeficiency viruses 
HNOO 1-DR20 
One of the probiotic Lactobacillus rhamnosus 
HN001 
One of the L. rhamnosus strains 
HN019 
One of the L. rhamnosus strains 
HNOO 
One of the L. rhamnosus strains 
HNO1 
One of the L. rhamnosus strains 
ICH 
The International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use 
ITT 
Intention-To-Treat 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin М 
IkВ 
Inhibitory protein 
JAMA 
Journal of the American Medical Association 
L. 
Lactobacillus 
LCR 
Lactobacillus casei subsp. rhamnosus strain 
LGG 
One of the L. rhamnosus strains 
LGR 
One of the L. rhamnosus strains 
 
 


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LPPV 
Local Person for Pharmacovigilance 
LPXTG 
Binding protein 
MANTIS 
Manual, Alternative, and Natural Therapy Index System 
MAMP 
Microbe-associated molecular patterns 
МАРК 
Mitogen-activated protein kinase 
MedDRA 
The Medical Dictionary for Drug Regulatory Affairs 
MRS 
Liquid medium for the isolation of lactobacilli, according to 
the prescription recommended by Man, Rogosa, and Sharpe 
as well as according to ISO standards 
mTg 
Murine thyroglobulin 
NNT 
Number needed to treat 
OTA 
Ochratoxin А 
PECD62p 
Marker of platelet activation 
PJS 
Propionibacterium freudenreichii ssp. shermanii JS 
PP 
Per-Protocol 
PROSAFE 
Collection of probiotic and human strains 
PRR 
Pattern recognition receptor 
QPS 
Qualified Presumption of Safety 
RC 
One of the L. rhamnosus strains 
RR 
Risk ratio 
S. boulardii 
Saccharomyces boulardii 
SF68 
Enterococcus faecium SF68 
spp. 
Species 
subsp. 
Subspecies 
 
 


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SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TGF 
Transforming growth factor 
TLR 
Toll-like receptor 
TOXLINE 
Toxicology Literature Online 
TY21A 
Salmonella typhimurium 
ToxFILE 
Bibliographic database of biochemical, pharmacological, 
physiological, and toxicological effects of drugs and other 
chemicals 
VRE 
Vancomycin-resistant enterococci 
ZO-1 
Zonula occludens-1 
 
 


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1. Introduction 
This clinical study is conducted to investigate the efficacy and safety of the investigational 
medicinal product LRG-002, capsules, versus placebo to LRG-002, capsules, against the 
background of standard antibiotic therapy in patients with acute respiratory disease for the 
prevention of AAD. Based on the results of this clinical study of the medicinal product, the 
state registration (authorization) of LRG-002, capsules, is planned. 
Statistical analysis for this study will be carried out using the R programming language, 
version 3.7. 
2. Study objectives and design 
2.1. Study objective 
The objective of this study is to investigate the efficacy and safety of using the 
investigational medicinal product LRG-002, capsules (Lek d.d., Slovenia), versus placebo in 
addition to standard antibiotic therapy in patients with acute respiratory diseases (ARD) as an 
auxiliary therapy for the prevention of AAD. 
2.2. Study design 
A prospective, multicenter, double-blind, randomized, parallel-group clinical study. 
Patients will be included by applying stratified randomization in two strata: 
• Age < 50 years 
• Age ≥ 50 years 
Each treatment group will be balanced as 1:1 in each stratum. 
In this study, neither the investigator nor the patient shall be aware of whether the 
investigational medicinal product or placebo is being administered to the patient. 
The investigational medicinal product LRG-002 is used according to the following scheme: 
a single dose of 1 capsule for oral administration with a meal and a little water; the medicinal 
product will be taken orally 2 times a day for 14 days. 
Placebo is administered under the following scheme: a single dose of 1 capsule for oral 
administration with a meal and a little water; the medicinal product will be taken orally 2 times 
a day for 14 days. 
 


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If the prescription is received in the afternoon, the protocol allows only one capsule to be 
taken on Day 1. The interval between taking the oral antibiotic and the investigational medicinal 
product shall be at least 3 hours. 
The study design is depicted in Figure 1. 
2.2.1. Study design flowchart 
 
Figure 1. Study design flowchart 
 
2.2.2. Study duration 
The duration of the study will be no more than 17 days for patients. 
1) Screening/randomization/initiation of therapy: Day 1 
2) Interim observation visit: Day 7 ± 2 
3) Final visit: Day 15 ± 2 
4) Total enrollment duration: about 8 months 
 
Visit 1 
Visit 2 
Visit 3 
Screening 
Randomization, n = 520 
Antibacterial therapy + 
LRG-002, n = 260 
Antibacterial therapy + 
Placebo, n = 260 
LRG-002, n = 260 
Placebo 
n = 260 
Day 1 
Day 7 ± 2 
Day 15 ± 2 


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2.2.3. Study stages 
It is allowed to conduct visits in the form of outpatient visits by a doctor and a nurse at the 
patient's home. 
Screening/randomization/therapy initiation (Visit 1) 
Visit 1 is scheduled for Day 1. At this visit, the doctor evaluates the patient's eligibility for 
the study. If non-inclusion criteria are not identified, randomization is carried out, the patient is 
given the investigational/reference product, a laboratory kit for collecting stool samples with 
appropriate instructions, a patient diary, and training on filling out the patient diary 
(Appendix 3). 
Procedures at Visit 1: 
Visit 1 (Day 1) 
• Collection of demographic data (year of birth, sex, age); 
• Measurement of weight and height; 
• Anamnesis collection; 
• Registration of concomitant therapy (including other medications, dietary supplements, 
and the use of medical devices); 
• Collection of complaints, actualization of anamnesis; 
• Physical examination; 
• Assessment of vital signs (heart rate, respiration rate, blood pressure, temperature); 
• Hematology; 
• Biochemistry; 
• Express test for the qualitative detection of immunoglobulin G (IgG) and 
immunoglobulin M (IgM) antibodies to COVID-19; 
• Urine pregnancy test; 
• 12-lead ECG; 
• Evaluation of inclusion/non-inclusion criteria; 
• Randomization; 
• Dispensing of an investigational medicinal product (IMP)/ placebo; 
• Issuance of a patient diary, mercury thermometer, and appropriate instructions; 
• Issuance of a laboratory kit with the necessary consumables for collecting stool samples; 


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• Evaluation of adverse events. 
Visit 2 (Day 7 ± 2) 
Procedures performed at Visit 2 in each treatment group: 
• Collection of complaints, actualization of anamnesis; 
• Records on the concomitant therapy; 
• Weight measurement; 
• Physical examination; 
• Measurement of vital signs; 
• Hematology; 
• Biochemistry; 
• Adverse events registration; 
• Evaluation of exclusion criteria; 
• Issuance of a laboratory kit with the necessary consumables for collecting stool samples 
(if necessary); 
• Compliance evaluation (diary completion, administration of the investigational medicinal 
products); 
• Assessment of diarrhea based on patient diary entries and face-to-face interviews in 
relation to antibiotic use (AAD or non-AAD) according to the investigator's opinion (in 
the absence of stool analysis results at the time of the visit, the assessment is carried out 
after the investigator receives the results from the laboratory). 
Treatment completion visit (Visit 3, Day 15 ± 2) 
Visit 3 is conducted on Day 15 ± 2; the patient must visit the trial site in the fasted state and 
bring the filled-in diary and unused medicinal product. 
• Collection of complaints, actualization of anamnesis; 
• Body weight measurement; 
• Records on the concomitant therapy; 
• Physical examination; 
• Measurement of vital signs; 
• Adverse events registration; 
• Evaluation of exclusion criteria; 
 


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• Compliance evaluation (diary completion, administration of the investigational medicinal 
products); 
• Hematology; 
• Biochemistry; 
• 12-lead ECG; 
• Assessment of diarrhea based on patient diary entries and face-to-face interviews for 
classification as AAD according to the doctor's opinion (in the absence of stool analysis 
results at the time of the visit, the assessment is carried out after the investigator receives 
the results from the laboratory); 
• Return of the unused investigational medicinal product; 
• Return of the unused laboratory stool collection kit; 
• Return of the patient's diary. 
 
Unscheduled visits 
The unscheduled visits will be conducted when necessary, e.g., in case of the index disease 
deterioration, AEs, or intolerability of IMPs (LRG-002 or placebo). 
Every unscheduled visit, irrespective of its cause, must include the procedures listed below 
with completion of the relevant eCRF pages (Unscheduled visit): 
 
• Physical examination; 
 
• Measurement of vital signs (blood pressure, heart rate, respiration rate, body 
temperature); 
• 12-lead ECG; 
• Evaluation of adverse events; 
• Evaluation of the concomitant therapy. 
 
In case of indications, any of the study procedures may be additionally performed upon the 
decision of the Principal Investigator. 
Taking into account the frequency of visits, unscheduled visits may be conducted on the 
same days as scheduled ones but at a different time (e.g., in case of worsening, the patient may 
visit the trial site in the afternoon). 
Procedures for planned clinical study visits are the same in each treatment group during each 
study period. 
 


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Early study termination 
The Sponsor has the right to terminate the study, and the Investigator has the right to stop 
recruiting patients at any time. In the event of early closure of the site/study, all completed and 
unused CRFs (including unused pages of partially completed CRFs) and other documentation 
(with the exception of documentation that must be kept at the site) must be returned to the 
Sponsor. Study materials can be destroyed only with the consent of the Sponsor. 
 
2.3. Sample size 
Calculation of the sample size is based on the following works: 
1. Efficacy of probiotics in prevention of acute diarrhea: a meta-analysis of masked, 
randomized, placebo-controlled trials. Sazawal S, Hiremath G, Dhingra U, Malik P, Deb S, 
Black RE. Lancet Infect Dis. 2006 Jun; 6(6):374-82. Review. PMID: 16728323. 
DOI:10.1016/S1473- 3099(06)70495-9. 
2. Chow S, Shao J, Wang H. Sample Size Calculations in Clinical Research. 2nd Ed. 
Chapman & Hall/CRC Biostatistics Series, 2008. 
3. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated 
diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 
2006 Apr;101(4):812-22. 
4. Videlock EJ, Cremonini F. Meta-analysis: probiotics in antibiotic-associated diarrhoea. 
Aliment Pharmacol Ther. 2012 Jun;35(12): 1355-69. doi: 10.1111/j.1365-2036.2012.05104.x. 
Epub 2012 Apr 24. 
5. H. Szajewska, M. Kolodziej. Systematic review with meta-analysis: Lactobacillus 
rhamnosus GG in the prevention of antibiotic-associated diarrhoea in children and adults. 
AP&T, Volume 42, Issue 10, November 2015, Pages 1149–1157. 
The primary endpoint is an assessment of the incidence of AAD from Day 1 to the last day 
of the course of LRG-002 use vs. placebo in ARD patients receiving standard antimicrobial 
therapy. The primary efficacy criterion will be considered met if the odds ratio for AAD 
between the two groups is statistically significantly greater than 1 (i.e., the incidence of AAD 
in the LRG-002 group is lower than in the placebo group). 
A test based on the odds ratio was used to calculate the sample size. 
 


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The following data were obtained from Figure 2 in a meta-analysis [1] (only data for AAD 
were used): 
Using only data for AAD studies in adults from the cited publication, the rate for the control 
group is 0.24 and for the treatment group 0.14. 
Using only data for LGG studies in adults and children, the rate for the control group is 0.26 
and for the treatment group 0.15. 
In meta-analysis [14], figures from Table 1 give a rate of 0.196 for a treatment group and 
0.29 for a placebo group (only studies for adults with LGG were taken into consideration). 
In meta-analysis [15], figures from Table 2 give a rate of 0.188 for a treatment group and 
0.269 for a placebo group (only studies for adults with LGG were taken into consideration). 
The consideration of AAD studies for LGG from [16], concerning infections in adults 
(including H. pylori), gives 0.14 for a probiotic group and 0.22 for a control group. 
Combining all the strains, we obtain an incidence of 0.26 for the placebo and 0.15 for the 
probiotic group. 
The following indicators were used for calculations: 
1. The difference of absolute risks of AAD in the placebo group and the treatment group is 
expected to be positive. 
The incidence of AAD = 0.26 is assumed for the placebo and 0.15 for the treatment group. 
Possibility of type I error: 0.05 
Power of the study is 80%, which corresponds to the type II error: 0.20. 
Statistical hypothesis is the evidence of superior efficacy: 
Н0:OR = 1 
Н1:OR ≠ 1, 
where OR is the odds ratio between both groups. 
The ratio between the treatment and placebo group sizes is 1:1. 
Amount of the patient in each group could be calculated using the following formula [2]: 
 
 


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Thus, the minimum number of patients required for statistical analysis is 416 (208 patients 
per group). Taking into account a 20% withdrawal rate, one needs to randomize 520 subjects 
(260 patients per group). 
3. General analysis values 
3.1. Clinical and statistical significance 
All the statistical tests within this study will be performed at 95% confidence level (threshold 
value p to confirm statistical significance is less than 0.05). The two-sided statistical criteria 
will be used for all other studied parameters. 
3.2. Procedure for missing, unanalyzable, and questionable data 
During the monitoring visits to the study sites, the clinical study specialists (monitors) 
authorized by the Sponsor will analyze CRFs for data completeness. In the absence of data on 
CRFs and the availability of relevant information in the primary documentation, questions for 
investigators and regulations to address inconsistencies will be formulated. At the database 
check, the expert in statistics authorized by the Sponsor, the Data Control and Processing 
managers will analyze the study results for questionable, missing, and unanalyzable data, which 
might be the basis for the questions for investigators. If possible, the investigators will eliminate 
the errors identified in CRFs and inform the Principal Investigator and authorized 
representatives of the Sponsor hereof. In case the identified data errors cannot be eliminated 
after the completion of the patients' participation in the study, the analysis of the resulting 
parameter sensitivity to questionable data will be conducted in the statistical analysis. 
Information on missing, questionable, and unanalyzable data will be summarized in the final 
clinical study report. A method of filling in the missing data based on maximum likelihood 
estimation (MLE) for the primary endpoint will be applied if needed. The analysis of the rest 
of endpoint types and other parameters will be performed only on the basis of the available 
information without filling in the missing data in view of the short duration of the clinical study. 
 
 


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4. Study participants 
4.1. Patient distribution 
It will be a double-blind, randomized study. 
Patients will be included by applying stratified randomization in two strata: 
Age < 50 years 
Age ≥ 50 years 
Each treatment group will be balanced as 1:1 in each stratum. 
Stratified randomization is a two-stage procedure in which patients who enter a clinical study 
are first grouped into strata. Within each stratum, patients are then assigned to treatment 
according to separate randomization schedules. The randomization module of EDC system 
assigns patient unique randomization code based on a treatment group and stratum. 
Randomization schedules will be hidden from medical personnel and all other persons involved 
in the study (monitors, data management, biometry, sponsor, etc.), except for the specialists 
responsible for IMP labeling and emergency unblinding. 
4.2. Study population 
4.2.1. Safety population 
The safety population (safety): All randomized subjects who received at least one dose of 
the investigational/reference product and have completed at least one visit aimed at the 
evaluation of safety parameters (i.e., at least Visit 1). As distinct from ITT population, the safety 
population will be analyzed depending on actually received treatment (not only prescribed) (in 
case of difference between the prescribed and received therapies). 
 


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4.2.2. ITT population receiving treatment 
The intention-to-treat (ITT) population: All randomized subjects who received at least one 
dose of the investigational medicinal product/placebo and have completed at least one visit 
aimed at the evaluation of efficacy parameters (i.e., at least all the procedures of Visit 1). 
4.2.3. Per protocol set 
The per protocol (PP) population: All randomized subjects who completed participation in 
the study in accordance with the protocol (have completed the prescribed period of treatment 
and follow-up without significant deviations from the protocol). 
5. Demographics and baseline characteristics 
All the data obtained in the groups before the study therapy initiation (demographic, 
laboratory, instrumental, and physical examinations data, vital signs, etc.) will be compared to 
determine the groups' comparability for analysis. 
For quantitative characteristics, it is planned to calculate the following statistics: 
 
1) Quantity 
2) Number of missing values 
3) Median 
4) 95% CI for the mean 
5) Standard deviation 
6) Median 
7) Minimum 
8) Maximum 
9) First quartile 
10) Third quartile 
11) Interquartile range 
 
For categorical variables, it is planned to calculate the following characteristics: 
 
1) Absolute number by the group 
2) Percentage relative to groups 
 


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3) Percentage of visits by group 
Quantitative variables will be checked for compliance with the normal distribution using the 
Shapiro–Wilk test. 
To compare quantitative data distributed according to the normal distribution, it is planned 
to use parametric criteria: Student's t-test for dependent/independent samples, analysis of 
variance (ANOVA) for repeated measurements to compare more than two stages. 
To compare quantitative data distributed according to a principle other than normal 
distribution, it is planned to use standard nonparametric tests: Mann–Whitney U test, Wilcoxon 
T test for dependent samples, and Friedman test for dependent samples. 
Comparison of the frequencies of indicators between treatment groups will be carried out 
using Pearson's chi-square test if the number of points in each cell of the crosstab is ≥ 5, or 
Fisher's exact test if at least one of the crosstab cells contains < 5 points. 
In the event that any of the initial data reveal the incomparability of the study groups 
(statistically significant differences in demographic and other initial data between the groups), 
an analysis of the parameters of efficacy and safety will be additionally carried out together 
with the primary planned analysis using multivariate statistics (ANCOVA or logistic regression 
depending on the type of parameter under study), adjusted for the initial indicator(s), according 
to which the groups initially differed. 
6. Concomitant therapy 
6.1. Permitted concomitant therapy 
Oral beta-lactam antibiotic (for example, amoxicillin, amoxicillin + clavulanic acid, 
cefixime, etc.) (see Background Antibacterial Therapy) as per inclusion criterion No. 3, in the 
same dosage regimen as at the study initiation. 
Medicinal products for the treatment of comorbidities that were used prior to registration 
without violating any non-inclusion criteria. Female patients that take oral contraceptives may 
continue taking them during the study. 
 


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Standard symptomatic treatment agents used to treat acute respiratory infections (in case of 
medical need), including anilides, triazole derivatives, with the exception of medicinal products 
that can have a laxative effect (for example, throat lozenges with sugar substitutes). 
Agents for relieving symptoms of acute diarrhea (in case of medical need), including 
electrolyte solutions, with the exception of sorbents. 
The prescription of therapy for acute diarrhea and symptomatic therapy for acute respiratory 
infections is possible only by the decision of the investigator. 
6.2. Prohibited concomitant therapy 
1. Systemic glucocorticosteroids within the last 8 weeks prior to and during the study; 
2. Any antibacterial agents in the last 3 months before the study and during the study, with 
the exception of antibacterial medicinal products provided for in inclusion criterion No. 3 
during the study; 
3. The use of any proton pump inhibitors within 3 months prior to the study; 
4. Other probiotics (bacteria or yeast, medicinal products, food supplements, fermented 
products) and Broncho-munal® within 2 weeks prior to and during the study; 
Any therapy (including medicinal products, medical devices, and dietary supplements) that 
may affect stool consistency, in the opinion of the investigator, shall not be used within 14 days 
prior to Visit 1 (with the exception of the medicinal products specified in items 3 and 4 of the 
Permitted Concomitant Therapy section). 
 
Pharmacotherapeutic groups 
Active substance 
Systemic glucocorticosteroids 
Hydrocortisone, cortisone, prednisolone, 
methylprednisolone, prednisone, triamcinolone, 
dexamethasone, betamethasone and their 
analogs, and/or combinations and derivatives 
Antibacterial agents 
Aminoglycosides, amphenicols, ansamycins, 
glycopeptides, carbapenems, lincosamides, 
macrolides and azalides, penicillins, 
 
 


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tetracyclines, cephalosporins – as monotherapy 
and/or combinations 
Probiotics, incl. dietary supplements 
Lactobacillus acidophilus, kefir fungi, 
Bifidobacterium bifidum, Escherichia coli, 
lactobacillus, lysozyme, Enterococcus faecium, 
Bifidobacterium longum, Bifidobacterium 
animalis, lactulose, Lactobacillus plantarum, 
Broncho-munal® – as monotherapy and as part 
of a medicinal product/ dietary supplement in 
any combination 
Adsorbents 
Activated carbon, aluminum oxide, attapulgite, 
colloidal silicon dioxide, lactulose, hydrolytic 
lignin, povidone, polymethylsiloxane 
polyhydrate, dioctahedral smectite – as 
monotherapy and as part of a medicinal product/ 
dietary supplement in any combination 
Calcium products 
Calcium glubionate, calcium lactobionate, 
calcium carbonate, calcium lactogluconate – as 
monotherapy and as part of a medicinal product/ 
dietary supplement in any combination 
Antidiarrheal medicinal products 
Attapulgite, Bergenia rhizoma, Bacillus subtilis, 
Bifidobacterium bifidum, Snakeweed rhizoma, 
burnet rhizomes with roots, loperamide + 
simethicone, loperamide, plantain oval seed 
coat, Racecadotril, Dioctahedral smectite, fruits 
of bird cherry, fruits of common blueberries – 
as monotherapy and as part of a medicinal 
product/ dietary supplement in any combination 
 
 


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Myotropic antispasmodics 
Bendazole, metamizole, papaverine, drotaverine, 
theobromine, bencyclan, darifenacin, 
dicycloverine, codeine, camilofin, mecloxamine, 
propyphenazone, ergotamine, mebeverine, 
oxybutynin, otilonium bromide, platyphylline, 
pinaverium bromide, trimebutine as well as 
herbal antispasmodics – as monotherapy and as 
part of a medicinal product/ dietary supplement 
in any combination 
Antiemetics and medicinal products 
affecting gastrointestinal motility 
Pyridostigmine, neostigmine, itopride, cisapride, 
aprepitant, bromopride, granisetron, 
dimenhydrinate, domperidone, levomenthol 
solution in menthyl isovalerate, meclozine, 
moxastine, ondansetron, palonosetron, 
perphenazine, thiethylperazine, trifluoperazine, 
tropisetron, fosaprepitant as well as herbal 
medicinal products – as monotherapy and as part 
of a medicinal product/ dietary supplement in 
any combination 
 
7. Efficacy analysis 
 
Analysis of efficacy endpoints will be carried out in accordance with Section V of the 
Recommendations of the Board of the Eurasian Economic Commission On Guidelines on 
the Principles of Applying Biostatistics in Clinical Trials of Medicines No. 19 dated 
November 3, 2020. The main analysis tool will be the R programming language, 
version 3.7. 
7.1. Primary endpoint analysis 
Assessment of the incidence of AAD from Day 1 to the last day of the course of LRG-002 
use vs. placebo in ARD patients receiving standard antimicrobial therapy. The primary efficacy 
criterion will be considered met if the odds ratio for AAD between the two groups is statistically 
significantly greater than 1 (i.e., the incidence of AAD in the LRG-002 group is lower than in 
the placebo group). 
 
 


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The primary efficacy endpoint will be analyzed using a fixed-factor logistic regression 
model for the treatment group and age group. The treatment effect will be displayed using the 
adjusted odds ratio and the corresponding two-sided 95% confidence interval. 
PCT will be calculated using the following set of functions of the R language: 
• glm – building a logistic regression model; 
• summary – displays the regression coefficients with an indication of the statistical 
significance; 
• confint – displays confidence intervals for regression coefficients. 
 
An example of a planned way of using these functions is shown in Figure 2. In the figure, 
the Outcome variable encodes the outcome (AAD – yes/no), Treatment encodes belonging to a 
particular study group, the Age variable encodes the age category (over or under 50 years old). 
The p-value is highlighted in red, the two-sided confidence interval is highlighted in blue, 
according to which the decision on reaching the PCT will be made. 
 
> model_out <- glm(Outcome ~ Treatment + Age, data = df, family = "binomial") 
> summary (model_out) 
Call: 
glm(formula = Outcome ~ Treatment + Age, family = "binomial", data = df) 
Deviance Residuals: 
Min 
1Q 
Median 
3Q 
Max 
−0.3327 −0.3327 −0.1635 −0.1635 2.9402 
 
Coefficients: 
 
Estimate 
Std. Error z value 
Pr(>|z|) 
(Intercept) 
−4.3090 
0.5949 
−7.243 
4.4e-13*** 
Treatment2 
1.4427 
0.6520 
2.213 
0.0269* 
Ageage >=50 
−0.5368 
0.6558 
−0.819 
0.4130 
 
 
 
 
 
 
  
 


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Signif. codes: 0 '***' 0.001 '**' 0.01 '*' 0.05 '.' 0.1 ' ' 1 
 
(Dispersion parameter for binomial family taken to be 1) 
 
Null deviance: 135.35 on 509 degrees of freedom Residual deviance: 128.52 on 
507 degrees of freedom 
AIC: 134.52 
 
Number of Fisher Scoring iterations: 7 
 
> confint(model_out) 
Waiting for profiling to be done... 
 
2.5% 
97.5% 
(Intercept) −5.7259968 −3.3150721 
Treatment2 0.2808742 
2.9311963 
Age >=50 
−2.0306660 0.6338301 
 
 
 
Figure 2. Running functions for calculating PCT 
7.2. Analysis of secondary endpoints 
The whole secondary efficiency analysis will be considered investigational, therefore 
multiplicity correction will not be performed; for test results, no formal capacity calculation 
will be provided. 
Secondary efficiency points are classified into three groups: 
1. 
Points characterizing the likelihood of a particular clinically significant event: 
• The occurrence rate of any diarrhea in the treatment group as compared to the placebo group; 
• The occurrence rate of C. difficile-associated AAD in the treatment group as compared to 
the placebo group; 
• The incidence of AAD not associated with C. difficile in the treatment group as compared 
to the placebo group; 
 


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• Frequency of gastrointestinal symptoms, including nausea, vomiting, flatulence, abdominal 
pain, and decreased appetite (according to the diary data), in the treatment group as compared 
to the placebo group; 
• Number (share) of patients using standard symptomatic therapy to relieve symptoms of acute 
diarrhea in the treatment group as compared to the placebo group; 
• The hospitalization rate in the treatment group as compared to the placebo group. 
 
For these types of ВКТ, contingency tables 2×2 will be generated where the rows will show the 
groups, the columns will show the facts of the presence or absence of a particular event, the 
elements of the table are the patients included in the analysis. The contingency table data will 
be analyzed using Fisher's test (using the fisher.test function) or the chi-square test (using 
the chisq.test function) depending on the number of observations per cell (< 5 or ≥ 5). 
 
2. 
Points characterizing the severity (or duration) of a particular clinical manifestation: 
 
• Occurrence of bowel movements per day (according to the diary data) in the treatment group 
as compared to the placebo group; 
• Duration of AAD (the time from the onset of AAD to the normalization of stool form 
according to BSS (types 1, 2, 3, and 4) and the presence of normal stool within 48 hours)) in 
the treatment group as compared to the placebo group; 
• Duration of any diarrhea (time from diarrhea onset to normalization of stool form according 
to BSS (type 1, 2, 3, and 4) and presence of normal stool for 48 hours) in the treatment group 
as compared to the placebo group; 
• Severity of the gastrointestinal symptoms, including nausea, vomiting, flatulence, abdominal 
pain, and decreased appetite (according to the diary data); 
• A number of days of using symptomatic therapy to relieve symptoms of acute diarrhea in 
the treatment group as compared to the placebo group. 
 
Due to the obvious difference between the distribution of these indicators from the normal (they 
have a discrete distribution), the nonparametric Mann–Whitney–Wilcoxon test implemented in 
the wilcox.test function will be used for intergroup comparison. 
 


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3. Other secondary endpoints: 
• Weight change at Visit 3 compared with Visit 1 in the placebo group as compared to the 
treatment group. This BKT can have a distribution close to normal. Accordingly, at the first 
stage, the normality of the distribution will be assessed (using the Shapiro–Wilk test 
implemented in the shapiro.test function), at the second stage, either the t-test (t.test function) 
or the Mann–Whitney–Wilcoxon test (wilcox.test function) will be used. 
• Stool consistency change (according to Bristol Stool Scale) (according to the diary) in the 
treatment group as compared to the placebo group; any individual changes in stool 
consistency will be classified as improved/unchanged/worsened, and the difference between 
the groups will be analyzed using chi-square criterion (chisq.test function). 
8. Safety analysis 
Safety parameters will be evaluated at every planned or unscheduled visit. 
The safety assessment will be based on the following indicators (between Visits 
1 and 3) compared between the investigational medicinal product and placebo: 
 
• 
Changes in the vital signs over time and the incidence of pathological abnormalities 
revealed during the physical examination will be summarized by the group; a comparison will 
be made between the groups using appropriate tests for quantitative and qualitative data. 
The data will be checked for compliance with the normal distribution law using the Shapiro–
Wilk test. 
Intergroup comparison of secondary endpoints related to quantitative scales will be 
performed using Student's t-test for independent samples if the data correspond to the normal 
distribution law; otherwise, the Mann–Whitney U test will be applied to independent samples. 
Intergroup comparisons of secondary endpoints related to categorical scales will be 
performed using Pearson's chi-square test if the number of points in each cell of the crosstab is 
≥ 5, or Fisher's exact test if at least one of the crosstab cells contains < 5 points. 


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The dynamics will be assessed using ANOVA methods with repeated measurements if the 
data correspond to the normal distribution, otherwise, the Friedman test will be applied. 
8.1. Adverse events 
Safety assessment will also be based on the following parameters (between Visits 1 and 3) 
compared between the investigational medicinal product and placebo: 
Incidence of adverse events (AEs) and/or serious adverse events (SAEs) in the treatment 
groups including: 
• Overall AE rate as compared to placebo; 
• AE rate according to the results of physical examinations during each visit compared with 
placebo; 
• AE incidence according to the assessment of the vital signs (HR, BP, BT, RR) at each 
visit as compared to placebo; 
• AE incidence according to the ECG results on Day 15 (± 2) in comparison with placebo; 
• AE incidence according to the results of laboratory examinations on Days 7 (± 2) and 
15 (± 2) as compared to placebo; 
• AE incidence according to the results of daily self-examination of the state of health 
recorded in Self-Observation Diary. 
The study doctor will review the entries in the Self-Observation Diary. If the study doctor 
believes that the information in the Diary complies with the AE criteria, they will ask the patient 
about this event and document all information about the AE (including the causality 
assessment). 
 
The AEs will be described according to the scheme given below: 
 
• AE description 
• Severity of the adverse event (meeting the severity criteria) 
• AE severity 
• AE duration 
• Relation to the IMP 
• Measures taken in relation to the investigational medicinal product 
• Measures taken in relation to the patient 
 


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• Outcome 
Adverse events will be coded according to the MedDRA 
 
Methods of descriptive statistics will be used to represent the results. A comparison of the 
incidence of new AE cases in the study groups will be performed using the Fisher's exact test 
or the chi-square test, depending on the number of proposed observations in one cell (< 5 or 
≥ 5), and a comparison of the severity (and the possible causality between the administered 
medicinal product and AE) will be conducted using the Cochran–Armitage test for linear trends 
for ordered categorical data. 
8.2. Other safety endpoints 
 
No other safety endpoints are foreseen in this study. 
 
9. Exploratory analysis 
 
In the course of this study, exploratory analysis is not envisaged. 
 
10. Interim analysis 
 
Interim data analysis is not planned for this study. 
 


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Appendix 1. Table layouts 
 
Table No. 1. Example of a statistical table for a quantitative variable 
 
Visit 
Group 
Parameter 
Variable 
name 
Visit 
number 
Group 1 
N 
 
Missed 
 
Mean 
 
95% CI 
 
SD 
 
Median 
 
Min 
 
Max 
 
Q1 
 
Q3 
 
IQR 
 
Group 2 
N 
 
Missed 
 
 
 


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Visit 
Group 
Parameter 
Variable 
name 
 
 
Mean 
 
95% CI 
 
SD 
 
Median 
 
Min 
 
Max 
 
Q1 
 
Q3 
 
IQR 
 
 
Table No. 2. Example of a group comparison table for a quantitative variable 
 
Visit 
No. 
No. 
No. 
No. 
Variable 
variable name 
 
 


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Shapiro–
Wilk 
test, p-
value 
Group 1 
 
 
 
 
Group 2 
 
 
 
 
Student's t-test, p-
value 
 
 
 
 
Mann–Whitney test, 
p-value 
 
 
 
 
 
Table No. 3. Example of a repeated comparison table for a quantitative variable 
Variable 
Group 
Visit 
Friedman test/ 
ANOVA for 
repeated 
measurements 
Wilcoxon test/ 
Student's t-test 
for repeated 
measurements 
variable name 
Group 1 
Comparison of 
visits 
 
 
No. vs. No. 
 
 
 
 


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Variable 
Group 
Visit 
Friedman test/ 
ANOVA for 
repeated 
measurements 
Wilcoxon test/ 
Student's t-test 
for repeated 
measurements 
 
 
No. vs. No. 
 
 
No. vs. No. 
 
No. vs. No. 
 
No. vs. No. 
 
No. vs. No. 
 
Group 2 
Comparison of 
visits 
 
 
No. vs. No. 
 
 
No. vs. No. 
 
No. vs. No. 
 
No. vs. No. 
 
 
 


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Variable 
Group 
Visit 
Friedman test/ 
ANOVA for 
repeated 
measurements 
Wilcoxon test/ 
Student's t-test 
for repeated 
measurements 
 
 
No. vs. No. 
 
 
No. vs. No. 
 
 
Table No. 4. Example of a statistical table for a categorical variable 
Variable 
Visit 
Group 
Variable 
value 
Amount 
% by group % by groups 
for visit 
Fisher's test, 
p-value 
variable 
name 
No. 
Group 1 
value 
 
 
 
 
value 
 
 
 
Group 2 
value 
 
 
 
value 
 
 
 
 
 


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Table No. 5. Example of a table of adverse events for calculating the number of all adverse events 
Adverse 
events 
Group 
Amount 
% of the 
number of 
AEs in the 
group 
% of the total 
number of 
AEs 
Binomial test, 
p-value 
All adverse 
events 
Group 1 
 
 
 
 
Group 2 
 
 
 
SOC 
Group 1 
 
 
 
 
Group 2 
 
 
 
РТ 
Group 1 
 
 
 
 
Group 2 
 
 
 
 
Table No. 6. Example of a table of adverse events for calculating the number of adverse events in the context 
Adverse 
events 
Group 
variable 
name 
Amount 
% of the 
number of 
AEs in the 
group 
% of the total 
number of 
AEs 
Fisher's test, 
p-value 
 
Group 1 
value 
 
 
 
 
 
value 
 
 
 
 
 
 


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Adverse 
events 
Group 
Variable 
name 
Amount 
% of the 
number of 
AEs in the 
group 
% of the total 
number of 
AEs 
Fisher's test, 
p-value 
All adverse 
events 
 
value 
 
 
 
 
Group 2 
value 
 
 
 
value 
 
 
 
value 
 
 
 
SOC 
Group 1 
value 
 
 
 
 
value 
 
 
 
value 
 
 
 
Group 2 
value 
 
 
 
value 
 
 
 
value 
 
 
 
РТ 
Group 1 
value 
 
 
 
 
value 
 
 
 
value 
 
 
 
Group 2 
value 
 
 
 
value 
 
 
 
 
 


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Adverse 
events 
Group 
variable name 
Amount 
% of the 
number of 
AEs in the 
group 
% of the total 
number of 
AEs 
Fisher's test, 
p-value 
 
 
value