Conditions: Diarrhoea;Acute
Keywords: Diarrhoea Carbowhite Colloidal silicon dioxide
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 145
Healthy volunteers: no

Brief summary:
The purpose of the study is to demonstrate the antidiarrheal efficacy of colloidal silicon dioxide in tablet dosage form (Carbowhite) in patients with acute diarrhea.

Detailed description:
Background: Diarrhea is a medical condition characterized by frequent stool, more than 3 times (and more than 5-7 times in newborns) within the last 24 hours, and/or loose stool. The fecal matter is liquid, its daily mass exceeds 200 g per day, and water content reaches 95%.

Objectives: To demonstrate the antidiarrheal efficacy of colloidal silicon dioxide in tablet dosage form (Carbowhite) in patients with acute diarrhea.

Methods: A randomized clinical trial, double-blind, placebo-controlled, multi-center.

Arms:
arm 1: 3 tablets as a single dose (210 mg х 3 = 630 mg) TID (630 mg х 3 = 1,890 mg) arm 2: 3 tablets as a single dose (210 mg х 3 = 630 mg) TID (630 mg х 3 = 1,890 mg)

Interventions: intervention 1: Carbowhite intervention 2: Carbowhite placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_ICF_000.pdf: 
1 
 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
 
RANDOMIZED, DOUBLE-BLIND,  
PLACEBO-CONTROLLED, MULTI-CENTER STUDY 
OF EFFICACY OF THE ADMINISTRATION OF COLLOIDAL SILICON 
DIOXIDE IN TABLET DOSAGE FORM (CARBOWHITE)  
IN PATIENTS WITH ACUTE DIARRHEA 
 
 
 
Sponsor:  
Limited Liability Company “OmniFarma Kiev” 
 
 
Sponsor’s representative  
responsible for CS: O.V.Kurchenko, Candidate of Medical Science 
 
 
Sponsor’s Medical and  
Scientific Adviser: V.A.Tereshin, Post-doctoral Degree in Medicine, Professor  
 
 
Protocol ID: CRID CODE-7-180 
 
 
Version No: 1 
 
Date: 08.06.2015 
 
 
 
 
 
 
 
 
 


2 
 
1. ABBREVIATIONS  
 
DS – diarrheal syndrome  
DBP – diastolic blood pressure  
IP – investigational product  
CS – clinical study 
UE – undesirable effects 
AR – adverse reaction 
AE – adverse effect 
SBP – systolic blood pressure 
SUE – serious undesirable effects 
HR – heart rate 
 
 


3 
 
2. CLINICAL STUDY REVIEW 
 
ACTIVE INGREDIENT  
Colloidal silicon dioxide (Aerosil 300 Pharma) 
TITLE 
Randomized, double-blind, placebo-controlled, 
multi-center study of efficacy of the administration 
of colloidal silicon dioxide in tablet dosage form 
(Carbowhite) in patients with acute diarrhea 
Study objective 
To demonstrate the antidiarrheal efficacy of 
colloidal silicon dioxide in tablet dosage form 
(Carbowhite) in patients with acute diarrhea. 
Duration of study 
participation 
- duration of study participation – 7 days. 
- study points: days 0, 1, 2, 3, 4, 5, 6, 7 of study. 
Total expected number of 
patients  
Expected number of sites 
Approx. 144 enrolled patients. 
 
3-5 sites 
STUDY THERAPY 
Dosage form and 
composition of 
investigational product (IP) 
1 tablet contains colloidal silicon dioxide with 
active sorption surface area of minimum 300 sq.m 
per 1 gram of the substance – 210 mg 
Method of administration 
Orally 
Primary inclusion criteria 
 
 
- signed Informed Consent Form for patient's study 
participation; 
- male and female patients at the ages from 18 to 55 
years; 
- acute diarrhea (more than three episodes of liquid 
stool a day) within 48 hours or less in patients with 
usually normal stool*; 
- body temperature of ≤ 38oС; 
- patient’s ability to adequately cooperate in the 
process of study. 
Primary exclusion criteria 
 
- aged of <18 or >55 years; 
- blood or pus in stool; 
- body temperature of >38oС; 
- episodes of acute diarrhea for the last 30 days; 
- administration of antidiarrheal products for the last 
24 hours; 
- salmonellosis (Salmonella of any serotype 
different from S. typhi and S. paratyphi; ICD-10: 
A02.0), dysentery (Shigella dysenteriae, Shigella 
flexneri, Shigella boydii; ICD-10: A03.0-A03.3), 
colibacillosis (Escherichia coli; ICD-10: A04.0-
A04.4) which require administration of 
antimicrobial products; 
- pregnancy, lactation; 
- concomitant decompensated diseases or acute 
conditions which, according to an investigator, may 


4 
 
affect study results; 
- alcoholism and drug abuse; 
- participation in any other clinical study. 
DOSAGE REGIMEN: 
Initial dose**:  
IP/placebo is prescribed on Day 0 at a dose of: 3 
tablets as a single dose (210 mg х 3 = 630 mg) t.i.d. 
(630 mg х 3 = 1,890 mg); 
IP/placebo dose escalation**: 
The IP/placebo dose escalation may be made on 
Days 1, 2, 3 and 4 in case of insufficient 
antidiarrheal efficacy (see Criteria of insufficient 
antidiarrheal therapy efficacy). 
IP/placebo dose escalation procedure: 
The IP/placebo dose escalation shall be made in two 
stages: 
 Stage 1: 3 tablets as a single dose (210 mg х 
3 = 630 mg) q.i.d. (630 mg х 4 = 2,520 mg); 
Stage 1 can start on Day 1 or Day 2. 
 Stage 2: 4 as a single dose (210 mg х 4=840 
mg) q.i.d. (840 mg х 4 = 3,360 mg). 
Stage 2 shall be implemented after Stage 1 only.  
For example, if a physician-investigator escalated 
the dose on Day 1 (Stage 1), Stage 2 can be 
implemented on Days 2, 3 or 4.  
If Stage 1 was implemented on Day 2, Stage 2 can 
be implemented on Days 3 or 4. 
In case of sufficient antidiarrheal efficacy 
(reduction in stool frequency per day) after dose 
escalation at Stage 1, Stage 2 may not be 
implemented. 
Dose reduction to the initial dose**: 
After the IP/placebo dose escalation according to p. 
11.2, it may be reduced to the initial dose (see p. 
11.1) in case of change in stool frequency to 3-4 
times a day. The physician-investigator shall make 
such a decision in each particular case. 
Criteria of insufficient antidiarrheal efficacy: 
 No reduction in stool frequency (per day) 
from the initiation of treatment with 
IP/placebo. 
The physician-investigator may discontinue 
treatment with IP/placebo in case of any treatment 
failure criteria: 
Criteria of treatment failure: 


5 
 
 Increase in stool frequency (per day) from the 
initiation of treatment with IP/placebo.  
 No reduction or increase in stool frequency 
within a day after the IP/placebo initial dose 
escalation to a maximum daily dose (Stage 
2). 
Criteria of the end of treatment: 
 Reduction in stool frequency to 3 times a day 
or less. 
 Verification of bacteriologic diagnosis with 
subsequent initiation of antibacterial therapy.  
 In case of any side effects associated, 
according to the physician-investigator, with 
the administration of IP/placebo. 
SCHEDULE OF 
ASSESSMENTS 
Efficacy:  
see Study Schedule in Section 25.1. 
Safety:  
see Study Schedule in Section 25.2. 
Tolerance:  
see Study Schedule in Section 25.3. 
FORBIDDEN 
CONCOMITANT 
THERAPY 
Sorbents: 
 Silicon dioxide containing products;  
 Activated carbon containing products; 
 Dioctahedral smectite; 
 Methyl-silicic acid hydrogel; 
 Lignin hydrolised 
 Combined sorbents. 
Probiotics: 
 L. Plantarum or L. Fermentum containing 
products; 
 Bifidobacterium Bifidum I containing 
products; 
 Other monoprobiotics, polyprobiotics and 
combined probiotics.  
Prokinetics: 
 Domperidone, metoclopramide, sulpiride. 
Antimicrobial medicinal products (antibiotics, 
synthetic chemotherapeutic medicinal products) 
in cases when it is allowed for acute diarrhea – for 
example, bacterial foodborne intoxication, 
unspecified (ICD-10 A05.9), in mild and moderate 
disease. 
**the diagnosis of the disease associated with diarrhea shall be formulated by the physician-
investigator as required by the Statistics Department of the medical institution (for example, bacterial 
foodborne intoxication, unspecified (ICD-10 A05.9), in mild and moderate disease). 
** in all cases, IP/placebo shall be administered between meals (in 2 hours after or before meals). 


6 
 
 
 
3. STUDY SCHEDULE 
DAYS 
Screening 
0 
0 
1 
2 
3 
4 
5 
6 
7 
Inclusion/exclusion criteria  
Х 
Х 
 
 
 
 
 
 
 
Informed Consent 
Х 
 
 
 
 
 
 
 
 
Randomization (IWRS) 
 
Х 
 
 
 
 
 
 
 
Demographic determinants 
(gender, age) of the patient 
 
Х 
 
 
 
 
 
 
 
Life history and medical history 
 
Х 
 
 
 
 
 
 
 
Prior medical therapy  
 
Х 
 
 
 
 
 
 
 
Physical examination 
 
Х 
 
 
 
 
Х 
 
 
Vital signs (HR, SBP, DBP) 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Body temperature 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Body weight 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Body height 
 
Х 
 
 
 
 
 
 
 
Fecal mass sampling for 
bacterial examination (if 
necessary) 
 
Х 
 
 
 
 
 
 
 
Handing-over of IP 
 
Х 
Х 
Х 
Х 
Х 
 
 
 
Records of concomitant medical 
therapy 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
EFFICACY 
 
 
 
 
 
 
 
 
 
Check of records in the Patient’s 
Stool Quantity and 
Characteristics Diary  
 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
TOLERANCE 
 
 
 
 
 
 
 
 
 
Recording of AR/AE 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
SAFETY 
 
 
 
 
 
 
 
 
 
Recording of AE/SUE 
 
 
Х 
Х 
Х 
Х 
Х 
Х 
Х 
Hematology, biochemistry of 
serum  
 
Х 
 
 
 
 
Х* 
 
 
Clinical urine examination 
 
Х 
 
 
 
 
Х* 
 
 
Urine pregnancy test (for 
women of child-bearing age)** 
 
Х 
 
 
 
 
 
 
 
* - if the patient was excluded on Days 1, 2, 3 or 4, safety assessment procedures for Day 5 shall be 
performed. 
** - postmenopausal (over 2-year menopause) or women after surgical sterilization shall not take the 
pregnancy test. 
 
4. INTRODUCTION AND JUSTIFICAION OF STUDY 
 
Diarrhea is a medical condition characterized by frequent stool, more than 3 times (and 
more than 5-7 times in newborns) within the last 24 hours, and/or loose stool. The fecal 
matter is liquid, its daily mass exceeds 200 g per day, and water content reaches 95%. 
Diarrheal diseases are one of the main causes of mortality in developing countries [5, 
6]. The largest economies show relatively low rate of mortality due to diarrheal diseases, 
but nonetheless, they are significant cause of morbidity and represent a material item of 
expenditure of the budget of public health service [6-8]. Traveller’s diarrhea should be 
particularly noted as it is a specific group of diarrheal diseases that is becoming more 


7 
 
relevant and associated with permanent increase in the number of travellers [15, 18-20]. 
In a wide range of travelers’ diseases, diarrhea takes the leading role – in average, it 
occurs in 20-60% of tourists [12]. The relevance of acute diarrhea is also associated with 
the necessity to solve a number of key issues arising during treatment, namely with 
patients’ preference of self-arresting this medical condition [7, 13, 16]. 
In spite of the disease pattern, it is usually difficult to find out the cause of diarrhea in 
each particular case only based on symptoms and signs. There are acute (with the 
duration not exceeding 2-3 weeks) and chronic (with the duration of more than 3 weeks) 
diarrhea. There is also a notion of diarrheal syndrome (DS), i.e. diarrhea-induced 
symptomatology. DS means not only the diarrhea as itself but also abdominal pain, 
dehydration, fluid-and-electrolyte imbalance, intoxication and asthenia. Control of each 
such symptoms needs individual self-medication [7, 9, 13]. 
Causal treatment is optimal for any disease. To define etiology of diarrhea, plenty of 
time is required and a physician usually does not have it.  
In view of this, treatment of any type of diarrhea includes two basic stages: 
 
symptomatic therapy to arrest the main signs of DS (frequent and bulky stool, pain 
syndrome, dehydration, intoxication); 
 
selection of causal treatment (it is possible only after laboratory verification of the 
pathogens of disease). 
 
At conduction of symptomatic therapy of diarrhea, the administration of medicinal 
products not absorbed in the intestinal tract, i.e. locally acting (in the intestine lumen), 
is preferable [18]. Systemic effect on organism is excluded in this case. Quick 
antidiarrheal action of the product, as well as its high efficacy that allows its 
administration for a short period of time is critical issue [8].  
Siliceous enterosorbent Carbowhite (IP) that has been developed on the basis of 
colloidal silicone dioxide (SiO2) with active sorption surface area no less than 300 sq.m 
per 1 gram of a substance pertains these features to a large extent. It is suggested that 
silicone dioxide blocks the adhesion factors and causes denaturation of adhesive proteins 
on the bacterial cell surface, disturbing the functional activity and adhesive properties 
of the pathogenic microorganisms. Antimicrobial activity of silicon dioxide against 
enteric pathogens defines its antidiarrheal effect; three-dimensional structure of the 
sorbent increases viscosity of the liquid media, causing antidiarrheal and coating effect.  
Experiments on animals showed antidiarrheal effects of silicone dioxide (0.5-3% 
suspension) due to its ability to cause small bowel decontamination with a small bowel 
bacterial overgrowth syndrome; dose-dependent by 1.5-27 times, it reduced mediator-
induced (cAMP, sodium desoxylate, serotonin) liquid accumulation in the intestinal tract 
of rats and stimulate ex vivo electrolyte and glucose absorption via the mucous 
membrane of small bowel of rats. During the oral administration of silicone dioxide (50-
1,000 mg/kg), dose-dependent, it reduced frequency of defecation in case of non-
infectious diarrhea in rats (castor oil; 0.5 ml/100 g, intragastrically); had therapeutic 
action in case of dyspepsia in calves; at a dose of 10 mg/kg, it reduced mortality due to 
diarrhea in piglets.  
Single oral administration of silicone dioxide (300-1,000 mg/kg) does not affect the 
blood cell composition and causes minor transient changes in biochemical values. Long-


8 
 
term administration of silicone dioxide at a therapeutic dose (150 mg/kg) does not affect 
the general state of pigs and metabolic values by increasing the body weight and 
reducing the quantity of triglycerides and cholesterol.    
At its intake by animals, less than 1% of inorganic silicone is absorbed. After repeated 
30-day intragastrical administration of silicone dioxide (100 and 1,500 mg/kg), no 
silicone accumulation is observed in organs and tissues of rats. Silicon dioxide in animal 
organisms is not subject to metabolic changes. After oral administration by rats and 
rabbits, more than 99% of silicone dioxide transits the intestinal tract and is excreted 
with fecal mass; small quantity of the absorbed silicone (less than 1%) is quickly 
excreted with urine. Silicon dioxide blocks the receptors of mucous membrane which 
are responsible for adhesion of microorganisms and toxin binding, thus, accelerating the 
absorption of medicinal products in the intestinal tract.      
During assessment of its effect in human organism, it can be noted that silicone dioxide, 
like any other enterosorbents, has no systemic pharmacokinetics as its bioavailability 
makes less than 1%.  
In various controlled clinical studies, in case of acute intestinal infection, infectious 
toxicosis syndrome, diarrhea and epigastric pain time reduction, quick remission, and 
inpatient stay term reduction were demonstrated with the administration of silicone 
dioxide for 3-5 days; at a dose of 0.5-0.75 g (per os, 4-6 times daily, 3-5 days), it 
promoted positive dynamics of disease pattern and complete eradication of the pathogen 
(according to bacteriological examination results), improved “average mass” molecule 
content in blood and immune complex level, inhibited abnormal activation of free-
radical processes (according to biochemical examination results) against the background 
of diarrheal syndrome and epigastric pain time reduction by 2.1 days, post infectious 
asthenia signs time reduction by 4.8 days as compared to conventional therapy.   
In the randomized controlled study of efficacy and safety of silicone dioxide (0.63-0.84 
g, per os, 3-4 times daily, 15-20 days) in patients with drug-induced liver injury, high 
tolerability of the sorbent Carbowhite (tablets) and no undesirable reactions were 
observed. 
That is why it is offered to conduct a randomized, double-blind, placebo-controlled, 
multi-center study of efficacy of the administration and safety of the sorbent Carbowhite 
(colloidal silicone dioxide) in patients with acute diarrhea.  
 
4.1. Name and description of investigational product 
 
Name: Carbowhite. 
Composition: 
active ingredient: colloidal silicone dioxide. 
1 tablet contains 210 mg silicone dioxide; 
excipients: microcrystalline cellulose, sorbite, potato starch, croscarmellose sodium, 
magnesium stearate. 
Dosage form: tablets. 
Method of administration: orally. 
Pharmacologic class: sorbents. ATC code: А07В. 
 
5. STUDY OBJECTIVE 


9 
 
 
To demonstrate the antidiarrheal efficacy of colloidal silicon dioxide in tablet dosage 
form (Carbowhite) in patients with acute diarrhea. 
 
6. STUDY DESIGN 
 
This clinical study is a randomized, double-blind, placebo-controlled, multi-center study 
where the colloidal silicon dioxide (Carbowhite) will be prescribed for the patients with 
acute diarrhea.   
This study is conducted in compliance with requirements of the current legislation of 
Ukraine. 
About 144 male and female subjects, age from 18 to 55 years old, for whom the 
enterosorbents were prescribed due to acute diarrhea will participate in the study.  
Duration of study participation for each patient does not exceed 8 days. 
 
7. PATIENT SELECTION 
 
7.1. Patients’ inclusion criteria: 
-  signed Informed Consent Form (Participant Information Sheet) for patient's clinical 
study; 
-  male and female subjects, age from 18 to 55 years old; 
-  acute diarrhea (more than 3 episodes of watery stool a day) during 48 hours or less in 
patients with normal stool usually*; 
-  body temperature ≤ 38oС; 
-  patient’s ability to adequately cooperate during the study  
*the diagnosis of the disease associated with diarrhea shall be formulated by the physician-investigator 
as required by the Statistics Department of the medical institution (for example, bacterial foodborne 
intoxication, unspecified (ICD-10 A05.9), in mild and moderate disease). 
 
7.2. Patients’ exclusion criteria: 
-  age <18 or >55 years old; 
-  the blood or pus in stool; 
-  body temperature >38oС; 
-  the episodes of acute diarrhea for the last 30 days; 
-  the administration of anti-diarrheal medicinal products during 24 hours; 
-  salmonellosis (Salmonella of any serotype, different from S. typhi and S. paratyphi; 
ICD-10 code: A02.0), dysentery (Shigella dysenteriae, Shigella flexneri, Shigella 
boydii; ICD-10 code: A03.0-A03.3), escherichiosis (Escherichia coli; ICD-10 code: 
A04.0-A04.4) requiring prescription of antibacterial medicines; 
-  pregnancy, lactation; 
-  concomitant decompensated diseases or acute conditions, in Investigator’s opinion, 
are able to effect on the study results; 
-  alcoholism and drug abuse; 
-  participation in any other clinical study. 
 
8. STUDY PROCEDURES BY VISITS  


10 
 
 
Section 2 describes the general study procedure schedule. The detailed list of procedures 
conducted at each visit is given bellow. 
 
Day 0 (SCREENING AND RANDOMIZATION)  
After a patient is admitted to Department of Infectious Disease, the physician-
investigator shall estimate: 
 the patient’s possibility (provisional diagnosis, age) to participate in the study and 
shall offer him/her to participate; 
 shall explain the essence of study participation to the patient.   
Having received a preliminary consent for study participation, the patient shall be 
offered to familiarize himself/herself with the Patient Information. The physician-
investigator must provide comprehensive answers to all questions the patient is 
interested in. After the consent is obtained, the patient shall sign an Informed Consent 
Form.   
If at the moment of admission, it is not possible for the patient to familiarize 
himself/herself with a full version of the Patient Information in quiet atmosphere and 
get comprehensive answers to all questions in interest due to the patient’s condition 
(frequent loose stool, asthenia, fever), he/she will sign the Patient Information Sheet (a 
brief version of the Patient Information). In this case, the physician-investigator shall 
provide an opportunity for the patient to familiarize himself/herself with the full version 
of the Patient Information and re-sign the Informed Consent Form within the first 24 
hours of the study participation. If the patient refuses to sign the Informed Consent Form 
after his/her familiarization with the full version of the Patient Information, he/she will 
be excluded from the study as a consent withdrawn person.  
The physician-investigator shall estimate all inclusion/exclusion criteria in whole (see 
subp. 7.1 and 7.2). The patient shall be interviewed (complaints, medical and life 
history) and his/her organs and systems shall be examined (general examination, skin 
and mucosae, respiratory, gastrointestinal, cardiovascular, and urogenital systems).  
The following shall be recorded: patient’s body weight, heart rate (HR), systolic and 
diastolic blood pressure (SBP and DBP). In case of compliance with inclusion criteria 
and no exclusion criteria, the patient shall be enrolled into the study. 
The patient shall be randomized (via IWRS) in a study group. Thus, 
 about 120 subjects will administer colloidal silicon dioxide (Carbowhite, IP);  
 and about 24 subjects will administer placebo, i.e. at the ratio 5:1. 
Prior to initiate treatment, the patient shall get a Patient’s Stool Quantity and 
Characteristics Diary (see Annex 25.1). During Visit 1, the patient shall record data a 
day before admission. The physician-investigator must explain the correct filling in the 
diary to the patient. 
The patient shall fill in the Patient’s Stool Quantity and Characteristics Diary on a daily 
basis before the administration of a new daily dose of IP/placebo. 
Before the patient receives any medical treatment, including IP/placebo, in the hospital 
department, he/she must have all necessary samples taken as provided by the Protocol 
(see Annex 25.2), as well as fecal matter taken for bacterial examination (if necessary). 
The female subjects of child-bearing age must take urine pregnancy test. 


11 
 
Postmenopausal (over 2-year menopause) or women after surgical sterilization shall not 
take the pregnancy test. 
After all laboratory tests have been made, the physician-investigator shall prescribe an 
initial dose of IP/placebo for the patient as per p. 11.1. All necessary medical treatment 
(rehydration and other symptomatic therapy) shall be also prescribed for the patient.  
If the patient receives the medical treatment related to any other somatic diseases, these 
medicinal products must be administered not earlier than in 3 hours after the 
administration of IP/placebo. 
The patient shall get the Patient’s Stool Quantity and Characteristics Diary for Day 1 of 
treatment. 
 
Day 1 
The physician shall interview the patient (complaints) and examine him/her.  
The following shall be recorded: patient’s body temperature, HR, SBP and DBP.  
The Patient’s Stool Quantity and Characteristics Diary records shall be checked. 
After the administration of the IP/placebo initial dose (see p. 11.1) within a day, the 
physician-investigator shall make a decision of the dosage regimen change, if necessary, 
as per p. 11.2. The decision of the dosage regimen change shall be taken by the 
investigator based on the assessment of the Patient’s Stool Quantity and Characteristics 
Diary filled in by the patient after Day 1 of treatment.    
UE/SUE recording. 
The patient shall get the Patient’s Stool Quantity and Characteristics Diary for Day 3 of 
treatment. 
 
Day 2 
The physician shall interview the patient (complaints) and examine him/her.  
The following shall be recorded: patient’s body temperature, HR, SBP and DBP.  
The Patient’s Stool Quantity and Characteristics Diary records shall be checked. 
IP/placebo shall be further prescribed at the dosage regimen that was determined on Day 
0 or 1 of study participation or escalated as per p. 11.2.  
UE/SUE recording. 
The patient shall get the Patient’s Stool Quantity and Characteristics Diary for Day 3 of 
treatment. 
 
Day 3 
The physician shall interview the patient (complaints) and examine him/her.  
The following shall be recorded: patient’s body temperature, HR, SBP and DBP.  
The Patient’s Stool Quantity and Characteristics Diary records shall be checked. 
In case of bacteriologic diagnosis verification, the physician shall make a decision 
whether a causal treatment is necessary. If it is necessary and the patient administers 
antimicrobial products, he/she shall discontinue study participation (see p. 12.2.). The 
patient’s treatment with IP/placebo shall be discontinued.  
The treatment can be also discontinued as required by other provisions of p. 12.2. 
Laboratory examinations shall be made to estimate the IP/placebo treatment safety (see 
Annex 24.2.).  


12 
 
In case when the antimicrobial products are not prescribed, the patient shall continue 
study participation, IP/placebo shall be further prescribed in the following possible 
dosage regimen:  
 till the end of the study the patient shall continue treatment in the dosage regimen 
that was determined on Day 0, 1 or 2 of treatment, or the physician-investigator 
shall make a decision of the dosage regimen change, if necessary, as per p. 11.2. 
 the dose can be reduced to the initial dose (see p. 11.1.). 
UE/SUE recording. 
The patient shall get the Patient’s Stool Quantity and Characteristics Diary for Day 4 of 
treatment. 
 
Day 4 
The physician shall interview the patient (complaints) and examine him/her.  
The following shall be recorded: patient’s body temperature, HR, SBP and DBP.  
The Patient’s Stool Quantity and Characteristics Diary records shall be checked. 
The patient shall continue study participation, IP/placebo shall be further prescribed in 
the following possible dosage regimen:  
 till the end of the study the patient shall continue treatment in the dosage regimen 
that was determined on Day 0, 1, 2 or 3 of treatment, or the physician-investigator 
shall take a decision of the dosage regimen change, if necessary, as per p. 11.2. 
 the dose can be reduced to the initial dose (see p. 11.1.). 
UE/SUE recording. 
The patient shall get the Patient’s Stool Quantity and Characteristics Diary for Day 5 of 
treatment. 
 
Day 5 
The physician shall interview the patient (complaints) and examine him/her.  
The following shall be recorded: patient’s body temperature, HR, SBP and DBP. 
The Patient’s Stool Quantity and Characteristics Diary records shall be checked. 
The patient’s treatment with IP/placebo shall be discontinued.  
Laboratory examinations shall be made to assess the IP/placebo treatment safety (see 
Annex 25.2.).  
UE/SUE recording. 
The patient shall get the Patient’s Stool Quantity and Characteristics Diary for Day 6 of 
treatment. 
 
Day 6 
The physician shall interview the patient (complaints) and examine him/her.  
The following shall be recorded: patient’s body temperature, HR, SBP and DBP. 
The Patient’s Stool Quantity and Characteristics Diary records shall be checked. 
UE/SUE recording. 
The patient shall get the Patient’s Stool Quantity and Characteristics Diary for Day 7 of 
treatment. 
 
Day 7 
The physician shall interview the patient (complaints) and examine him/her.  


13 
 
The following shall be recorded: patient’s body temperature, HR, SBP and DBP. 
The Patient’s Stool Quantity and Characteristics Diary records shall be checked. 
Safety assessment according to laboratory parameters (hematology and biochemistry). 
UE/SUE recording. 
Study participation shall be discontinued. 
 
9. CONCOMITANT THERAPY 
 
Concomitant therapy is any therapy prescribed for the patient simultaneously with the 
administration of IP. The concomitant therapy should be minimal during the CS period. 
If the concomitant therapy is considered necessary for the patient and it is unlikely to 
interfere the IP therapy, it may be prescribed at the discretion of the investigator, with 
the stable dose preferable.   
If the patient receives the medical treatment of other somatic diseases and administers 
symptomatic medicinal products (analgesics-antipyretics, etc.), these products should be 
administered no less than in 3 hours after the administration of IP/placebo.  
Any concomitant therapy initiated before the CS and/or prescribed or changed during 
the CS should be indicated in the source documentation. 
 
9.1. Forbidden concomitant therapy 
 
The following products shall be forbidden during the clinical study participation due to 
their effect on stool frequency and characteristics: 
 
Sorbents: 
 Silicon dioxide containing products; 
 Activated carbon containing products; 
 Dioctahedral smectite; 
 Methyl-silicic acid hydrogel; 
 Lignin hydrolyzed; 
 Combined sorbents. 
 
Probiotics: 
 L. Plantarum or L. Fermentum containing products; 
 Bifidobacterium Bifidum I containing products; 
 Other monoprobiotics, polyprobiotics and combined probiotics.  
 
Prokinetics: 
 Domperidone, metoclopramide, sulpiride. 
 
Antimicrobial medicinal products (antibiotics, synthetic chemotherapeutic 
medicinal products) 
in cases when it is allowed for acute diarrhea – for example, bacterial foodborne 
intoxication, unspecified (ICD-10 A05.9), in mild and moderate disease. 
 
9.2 Permitted concomitant therapy 


14 
 
The investigator shall prescribe the medicinal products which are set out by standards 
of care of acute diarrhea (rehydration therapy), as well as symptomatic medicinal 
products (analgesics-antipyretics, etc.). The patient shall continue administering the 
medicinal products he/she administered due to concomitant somatic diseases. 
 
10. INVESTIGATIONAL PRODUCT 
 
10.1 Description of investigational product 
The investigational product (IP) and placebo will be supplied by the Limited Liability 
Company “OmniFarma Kiev”. 
The IP/placebo delivery frequency will depend on its availability, site potential for 
patients’ inclusion and IP shelf-life.  
The investigational product (IP) and placebo are white biconvex tablets, 12 mm 
diameter.  
 
10.2 Packaging 
The IP and placebo are packed and labelled according to the Good Manufacturing 
Practice (GMP) and applied laws and provisions. The IP and placebo are packed to 
prevent their deterioration during transportation and storage. 
All packages will be similar to observe double-blind study design. Each package will 
contain 80 tablets of the IP or placebo in total and will be intended for the administration 
by one patient for the whole treatment period.   
 
 
10.3 Product accountability and storage 
The Investigator shall record the IP/placebo dosage regimen administered by the patient 
in the source documentation (see below) on a daily basis. At the end of the last day of 
IP/placebo treatment (after the last administration), the physician-investigator shall 
count and record in the accounting form the total quantity of tablets administered during 
treatment period and the quantity of remaining IP/placebo tablets. The unused 
IP/placebo shall be kept in the site until returned to the Sponsor.  
The Investigator shall be obliged to ensure proper storage of partially used and unused 
IP/placebo. Storage temperature requirements are from 0 to 25oC. 
 
10.4 Product administration procedure (randomization procedure) 
Centralized fixed block randomization is applied in the study.  
To solve the given task, client-server architecture is used. The Sponsor of the study shall 
organize the central server (hereinafter – CS) operation both from hardware and software 
part. All the used software is provided with rightsholder’s’ licenses and approvals. Study 
Accounting Computer System (hereinafter – SACS) is server-based, and the sites shall 
have access to the SACS in the client mode, 24 hours a day. Hardware and software 
tools available at the site shall be used to ensure access. The Sponsor shall provide access 
to the SACS and technical support. In case of any technical malfunctions, the Sponsor 
shall resolve the problems arisen and restore the SACS normal operation.  
The fixed block randomization is applied within the framework of the clinical study. 
The sites are the natural blocks. In terms of a block (a site), this method makes it 
possible, with a specified probability (at the ratio 5:1 in our case) to enroll a patient in a 


15 
 
real treatment or a placebo treatment group, with proportional ratio of these groups. The 
patient shall be enrolled in any of the groups on the basis of random numbers generated 
by the computer program. 
 
Product (placebo or real) definition algorithm for a patient in the SACS: 
1. Entering the source data in the SACS. At the stage of entering the patient’s source 
data, the SACS monitors the patient’s suitability for the study according to the 
parameters described in the Protocol. If the patient does not fit according to the key 
parameters, the SACS will not allow the patient’s inclusion.    
2. If the patient fits according to the key parameters, his/her data shall be entered in the 
SACS database, as well as the patient’s anonymity and confidentiality shall be ensured. 
In this case, the SACS provides access to randomized product definition for the patient.   
3. The randomized product definition for the patient consists of two stages:  
3.1 a set of available products is defined in terms of the site. The set numbering begins 
with 0.   
3.2 by means of random number generator with a range from 0 to the number of available 
products minus one, the SACS defines the index of the set of available products. The 
product with a defined index is assigned to the patient, and this product is excluded from 
the set of available products. The product is identified by the product batch labelling. 
The Sponsor shall provide labelling at the production stage considering that it should 
not be evident to define the kind of the product (placebo or IP).    
Disclosure of randomization codes at the client level is not provided in the SACS.  
 
10.5 Randomization code disclosure procedure 
Randomization code disclosure takes place in case of serious AR/AE and when the 
physician considers that the future management of the patient can be determined only if 
the previous treatment (IP or placebo) of the patient is known.  
Each product package with individual number will have the enclosed sealed envelope 
with information on tablet content (IP or placebo). The envelopes should be kept in at 
the site. The decision on envelope opening shall be taken by the physician-investigator 
who must inform the Sponsor on code disclosure within 24 hours. Upon study 
completion, the monitor checks the integrity of all envelopes whereof the appropriate 
report is drawn up.  
The patient with the disclosed randomization code shall not be included into statistical 
processing of efficacy estimation but shall be included into treatment safety assessment.  
 
10.6 Product return and disposal 
The Sponsor shall be responsible for return and disposal of all the partially used or 
unused IP/placebo. The Returned IP/placebo Log will be given to the Investigator and 
then signed by the Investigator and monitoring group.  
The Investigator shall not dispose the partially used or unused IP/placebo without the 
Sponsor’s written authorization. 
 
11. PRESCRIBED TREATMENT REGIMEN  
 
The subjects will be randomized in 2 groups at the ratio 5:1: 


16 
 
1st group – about 120 subjects who will administer tablets containing colloidal silicon 
dioxide (Carbowhite - IP); 
2nd group – about 24 subjects who will administer placebo. 
 
In any case, the physician-investigator shall initiate treatment with an initial dose of 
IP/placebo that may remain unchanged till the end of the study or may change (see 
below). 
 
11.1 Initial dose 
On Day 0, IP/placebo is prescribed at the initial dose of: 3 tablets as a single dose (210 
mg х 3 = 630 mg) t.i.d. (630 mg х 3 = 1,890 mg); 
In all cases, IP/placebo is administered between meals (in 2 hours after or before meals). 
 
11.2 Dose escalation to a maximum daily dose 
IP/placebo dose escalation: 
The IP/placebo dose escalation may be made on Days 1, 2, 3 and 4 in case of insufficient 
antidiarrheal efficacy (see Criteria of insufficient antidiarrheal therapy efficacy). 
IP/placebo dose escalation procedure: 
The IP/placebo dose escalation shall be made in two stages: 
 Stage 1: 3 tablets as a single dose (210 mg х 3 = 630 mg) q.i.d. (630 mg х 4 = 
2,520 mg); 
Stage 1 can begin on Day 1 or Day 2. 
 Stage 2: 4 as a single dose (210 mg х 4 = 840 mg) q.i.d. (840 mg х 4 = 3,360 mg). 
Stage 2 shall be implemented after Stage 1 only. 
For example, if the physician-investigator escalated the dose on Day 1 (Stage 1), Stage 
2 can be implemented on Days 2, 3 or 4. If Stage 1 was implemented on Day 2, Stage 2 
can be implemented on Days 3 or 4. 
In case of sufficient antidiarrheal efficacy (reduction in stool frequency per day) after 
dose escalation at Stage 1, Stage 2 may not be implemented. 
 
11.3 Dose reduction to the initial dose 
After the IP/placebo dose escalation according to p. 11.2, it may be reduced to the initial 
dose (see p. 11.1) in case of change in stool frequency to 3-4 times a day.  
The physician-investigator makes such a decision individually in each particular case. 
 
12. END OF TREATMENT WITH INVESTIGATIONAL 
PRODUCT/PLACEBO 
 
The physician-investigator may discontinue treatment with IP/placebo in case of the 
following criteria: 
 
12.1 Insufficient antidiarrheal efficacy and treatment failure criteria 
 No reduction of stool frequency (per day) from the initiation of treatment with 
IP/placebo. 
 


17 
 
The physician-investigator may discontinue treatment with IP/placebo in case of any 
treatment failure criteria (premature treatment discontinuation): 
 
Treatment failure criteria: 
 Increase of stool frequency (per day) from the initiation of treatment with 
IP/placebo. 
 No reduction or increase of stool frequency within a day after the IP/placebo 
initial dose escalation to a maximum daily dose (Stage 2). 
 
12.2 Treatment end criteria 
 Reduction of stool frequency to 3 and less times a day, no loose stool. 
 Bacteriological diagnosis verification with the consequent antibacterial therapy 
beginning. 
 Development of adverse reactions associated, in the opinion of the physician-
investigator, with the administration of IP/placebo. 
 
12.3 CS participation premature discontinuation criteria  
 The patient withdraws his/her signature under the Informed Consent Form. 
 The patient refuses to sign the Informed Consent Form after familiarization with 
a full version of the Patient Information (when the patient familiarized with the 
Patient Information Sheet during screening and signed the Informed Consent 
Form). 
 The patient refuses to be examined and follow the physician’s instructions. 
 The patient has the SUE associated, in the opinion of the physician-investigator, 
with the administration of IP. 
 
13. DEFINITION OF SOURCE DOCUMENTATION 
 
Data entered into the Case Report Forms (CRF) should be confirmed in the indentified 
and signed source documentation including, but not limited to, the following: 
 Patient Information and Informed Consent Form; 
 Patient Information Sheet and Informed Consent Form; 
 Patient Identification Information (copies of outpatient medical records, case 
records, expert opinions, laboratory reports, etc.), last clinical study participation, 
medical history, concurrent diseases, and investigated disorder data; 
 Previous and concomitant treatment; 
 Date of the investigational product administration and dosage regimen; 
 Date and time of visits and assessments, including the examination report; 
 Vital signs (HR, SBP, DBP), body temperature, height, and weight; 
 Laboratory reports; 
 Undesirable effects (AR/AE) and follow-up control (in case of SUE, copies of 
epicrisis and examination reports evidencing the follow-up control must be 
included into the documentation); 
 Date and reason for premature discontinuation (if any). 
 


18 
 
The source documentation may be as follows: 
 Medical record; 
 Photocopies of Patient Identification Information; 
 Physician’s documentation; 
 Patient’s Diary. 
 
The Investigator must keep all the study documentation confidential for at least fifteen 
years and take measures to prevent its early destruction. If the Investigator’s conditions 
do not guarantee the source documentation archiving, he/she must inform the Sponsor 
hereof and the documentation must be handed over to a third party (as mutually agreed). 
The Investigator shall enter the accurate data the CRF (according to the Sponsor 
developed technology) to register all observations and other CS related data (as 
instructed by the Sponsor). 
The data computer processing by the Sponsor may result in additional requests (DCF) 
the Investigator must respond to. These requests and responses will add to CRF available 
by the Investigator and Sponsor.  
 
14. STATISCTICAL ASPECTS 
 
14.1. DETERMINATION OF SAMPLE SIZE 
 
At clinical study conduction, a minimum sample size that is sufficient to achieve study 
objectives is determined at the planning stage. 
The minimum sample size shall be determined by a clinical effect value which presence 
(absence) is supposed to be found out and by a confidence level of the obtained 
conclusion which is defined with type I error probability ( – consumer’s risk) and type 
II error probability ( – producer’s risk). 
Based on the placebo-controlled study objectives, one may come to a conclusion that to 
solve the formulated tasks it is necessary to estimate the percent of patients administered 
the investigational product who achieved the efficacy endpoint such as reduction in 
frequency of defecation to 3 times per day, absence of loose stool, on Day 5 or earlier 
(Pproduct). Based on preliminary studies, it is supposed that the expected probability of 
effect during the administration of the product will make Pproduct=0.9.  
To estimate the minimum sample size that is sufficient for solving the formulated tasks, 
we used G*Power 3.1.5 (Heinrich-Heine-Universität Düsseldorf, 1992-2013) [3]. 
To verify statistical hypotheses, frequency comparison method for one group, Fisher 
exact test, two-sided critical range are used. When estimating the sample size, the 
standard levels of type I error probability =0.05 and type II error probability =0.2 
were chosen, 5% estimation error was chosen. 
The protocol of calculations for this case is given in Table 1. 
 
Thus, to solve the formulated task with the “consumer’s risk” probability of =0.05 and 
“producer’s risk” probability of =0.2, 107 subjects will be sufficient.  
Solving the safety assessment will require the calculation of percent of patients 
administered the investigational product who had undesirable effects. During the sample 


19 
 
size determination, the standard levels of type I error probability =0.05 and type II 
error probability =0.2 were chosen, 5% estimation error was chosen. The calculations 
made for this case show that to solve this task with the “consumer’s risk” probability of 
=0.05 and “producer’s risk” probability of =0.2, 32 subjects will be sufficient.   
Comparison of medicinal product efficacy vs placebo effect will require statistical 
hypotheses verification: 
H0: Pplacebo = Pproduct 
Hα: Pplacebo  Pproduct 
where Pplacebo is a probability (incidence, %) of clinical effect achievement during the 
administration of placebo, and Pproduct is a probability (incidence, %) of clinical effect 
achievement during the administration of the investigational product. 
 
To verify statistical hypotheses, incidence comparison method for two independent 
groups, Fisher exact test, two-sided critical range are used. When estimating the sample 
size, the standard levels of type I error probability =0.05 and type II error probability 
=0.2 were chosen. 
Considering the prognostic significance of diarrhea which may lead to significant liquid 
loss as well as the patient’s psychoemotional and physical discomfort, the placebo 
control group should be minimum allowed. Such approach will be ethically justified. 
Thus, the assessment was conducted at the assumption of lesser quantity of subjects in 
placebo group, Nproduct/Nplacebo= 5. According to the literature [1,2,4], the mean time for 
diarrheal syndrome arresting was 3 days during the administration of placebo, therefore, 
it can be accepted for this group that the expected probability of effect on Day 5 will 
make Pplacebo= 0.6, and the expected probability of effect during the administration of the 
product will make Pproduct= 0.9. Hence, in the planned study it is suggested to find out 
the efficacy difference (if any) in 30%. The protocol of calculations for this case is given 
in Table 1. 
 
Thus, to compare the investigational product efficacy vs placebo effect with the 
“consumer’s risk” probability of =0.05 and “producer’s risk” probability of =0.2, 108 
subjects will be sufficient (90 subjects in study group and 18 subjects in control group). 
Summarizing the obtained results (considering the probability of subjects’ 
discontinuation), we will find out that a minimum group of 144 subjects (120 subjects 
in study group and 24 subjects in control group) will be sufficient to: 
1) estimate the percent of patients administered the investigational product who 
achieved the efficacy endpoint – reduction of defecation to 3 times a day, absence of 
loose stool, on Day 5 and earlier; 
2) estimate the percent of patients administered the investigational product who had 
undesirable effects;  
3) compare the medicinal product efficacy vs placebo effect, – with the level of type I 
error probability of =0.05 and type II error probability of =0.2.  
To obtain the representative sampling, it is planned to conduct study in 4 sites (30 
subjects in study group and 6 subjects in control group for each site) and combine the 
obtained results using meta-analysis elements. 
 
14.2 ANALYSIS ENDPOINTS 


20 
 
 
14.2.1. Demographic and initial characteristics  
 Demographic determinants: gender, age 
 Medical history; 
 Prior medical therapy; 
 Vital signs (HR, SBP, DBP); 
 Body temperature; 
 Physical examination (including body height and weight); 
 Laboratory data. 
 
14.2.2. Efficacy endpoints 
Efficacy endpoint is the reduction in frequency of defecation to 3 or less times a day, 
absence of loose stool.   
 
Primary efficacy parameters of investigational product 
1. Percent of patients administered the investigational production who achieved the 
efficacy endpoint (reduction in frequency of defecation to 3 times per day, absence of 
loose stool) on Day 5 or earlier. 
 
Secondary efficacy parameters of investigational product 
1. Percent of patients administered the investigational production who discontinued the 
study. 
2. Mean duration of treatment. 
3. Mean quantity of tablets per treatment course. 
 
14.2.3. Safety endpoints 
Safety analysis shall be based on the following: 
 Undesirable effects (adverse reaction / adverse effect – AR/AE); 
 Vital signs (SBP, DBP, HR); 
 Body weight; 
 Laboratory test results: clinical and biochemical blood test, fluid-and-electrolyte 
balance, clinical urine test and urine pregnancy test. 
 
Primary safety parameters of investigational product 
1. Percent of patients administered the investigational production who had undesirable 
effects. 
 
Secondary safety parameters of investigational product 
1. Dynamics of vital sign change (SBP, DBP, HR).  
2. Dynamics of body weight change 
3. Laboratory test values: clinical and biochemical blood test, fluid-and-electrolyte 
balance, clinical urine test and urine pregnancy test. 
 
14.3. STATISTICAL METHODS OF ANALYSIS 
 


21 
 
At primary and secondary variables analysis, the methods of descriptive statistics will 
be applied: at qualitative characteristics analysis the incidence rate (%) and standard 
error (m%) will be calculated; for quantitative characteristics in case of the normal 
statistical law the arithmetic mean value ( X) and standard deviation (SD) will be 
calculated; if statistical law differed from the normal one, the median value (Me), and 
the first and third quartile value (QI and QIII, respectively) will be calculated. For 
assessment of the primary efficacy and safety parameters of the treatment, 95% 
confidence interval (95% CI) will be calculated. The Chi-squared test will be used at 
comparison of efficacy of medicinal product vs. placebo effect. During analysis the 
significance threshold has been chosen equal to 0.05. 
 
To combine the results of 4 sites, meta-analysis elements will be used.  
During parameters change dynamics analysis, ANOVA methods for the repeated 
measurements (or their non-parametric analogue) will be used. 
The method of construction and analysis of the logistic regression models will be used 
for standardization of the potential risk factors for treatment failure.  
 
In the course of analysis “Medstat” (Y.E.Lyach, V.G.Guryanov, 2004-2011) “MedCalc 
15.6” (MedCalc Software, 1993-2015), G*Power 3.1.5 (Heinrich-Heine-Universität 
Düsseldorf, 1992-2013) statistical software will be used. 
 
14.4 EFFICACY AND TOLERANCE/SAFETY STATISTICAL ANALYSIS 
PLAN 
 
14.4.1 Initial homogeneity analysis 
Initial homogeneity analysis is conducted by the age, gender, body weight and height, 
body mass index, physical examination factors, clinical and laboratory values.    
To do this, 
1) Use the methods of descriptive statistics to describe the baseline of each of two study 
groups (for quantitative variables in case of the normal statistical law: n, the arithmetic 
mean value (X) and standard deviation (SD), minimum and maximum values; for 
quantitative variables if statistical law differs from the normal one: n, the median value 
(Me), and the first and third quartile value (QI and QIII, respectively), minimum and 
maximum values; for categorical characteristics: n, incidence and percentage and 
standard error (m%).  
2) For homogeneity estimation according to quantitative variables, compare the groups 
using the Student’s t-test for independent samples in case of normally distributed data 
or the Wilcoxon-W-test, if statistical law differs from the normal one, verify the two-
sided hypothesis. Verify the normality of distribution using the D'Agostino-Pearson 
Test.  
3) For homogeneity estimation according to categorical variables, compare the groups 
using the Chi-squared test with Yates correction (verify the two-sided hypothesis). 
4) Make statistical conclusions on initial homogeneity of the compared groups according 
to the specified variables. 


22 
 
 
14.4.2 Tolerance/safety analysis 
Tolerance/safety analysis will be performed for each of the variables according to the 
following scheme. 
1) Dichotomous variables describing presence of AR/AE/SUE.  
The values of descriptive statistics (incidence and percentage) will be defined for each 
study group for Days 1-5 of the study. Analyze the trend presence using the Chi-squared 
test.  
2) Quantitative variables describing the vital signs (HR, SBP, DBP, body temperature, 
body weight).  
In each study group, for each BP, Ps and thermometry parameter measured on Day 0 at 
the admission, and on Days 1-5, conduct one-way ANOVA test with repeated 
measurements (if statistical law differs from the normal one, use its non-parametric 
analogue, the Friedman test).   
3) Quantitative variables describing the biochemical blood test parameters, fluid-and-
electrolyte balance values, clinical urine test.  
Define the values of descriptive statistics at study baseline and endpoint for each group.  
To find out the changes, compare the groups using the Student’s t-test for linked samples 
in case of normally distributed data or the Wilcoxon-T-test, if statistical law differs from 
the normal one, verify the two-sided hypothesis.  
 
14.4.3 Between-groups tolerance/safety comparison  
1) Dichotomous variables describing presence of AR/AE/SUE.  
The values of descriptive statistics (incidence and percentage) will be defined for each 
study group for 1-5 days of the study. Compare the percentage in each period for Days 
1 and 5 using the Chi-square Test with Yates’ correction and define if their difference is 
statistically significant.  
2) Quantitative variables describing the vital signs (HR, SBP, DBP, body temperature, 
body weight).  
In each study group, for each BP, Ps and thermometry parameter measured on Day 0 at 
the admission, and on Days 1-5. To find out the differences, compare two groups of 
patients in each period for Days 1 and 5. To compare, use the Student’s t-test for 
independent samples in case of normally distributed data or the Wilcoxon-W-test, if 
statistical law differs from the normal one, verify the two-sided hypothesis. 
3) Quantitative variables describing the biochemical blood test parameters, fluid-and-
electrolyte balance values, clinical urine test.  
Define the values of descriptive statistics at the study endpoint for each group. To find 
out the differences, compare the groups using the SUE’s t-test for independent samples 
in case of normally distributed data or the Wilcoxon-T-test, if statistical law differs from 
the normal one, verify the two-sided hypothesis at the study endpoint.    
4) Based on comparative analysis, make general conclusions on tolerance/safety. 
 
14.4.4 Efficacy analysis 
The product efficacy will be estimated for each group of variables according to the 
following scheme. 


23 
 
1) Dichotomous variable representing a percentage of patients administered the 
investigational product who achieved the efficacy endpoint – reduction in frequency of 
defecation to 3 times a day, absence of loose stool, on Day 5 and earlier. 
Define the values of descriptive statistics (incidence and percentage) at the study 
endpoint for each group. The efficacy value is estimated in each group, its 95% CI is 
estimated.   
2) Quantitative variables: mean duration of treatment and mean quantity of tablets per 
treatment course.  
Define the values of descriptive statistics (Me, QI, QIII, minimum and maximum values) 
at the study endpoint for each group.  
 
14.4.5 Between-groups efficacy comparison  
1) Dichotomous variable representing a percentage of patients administered the 
investigational product who achieved the efficacy endpoint – reduction in frequency of 
defecation to 3 times a day, absence of loose stool, on Day 5 and earlier. 
The values of descriptive statistics (incidence and percentage) shall be defined at the 
study endpoint for each group. Compare the failure risks using the Chi-squared test with 
Yates correction and define if their difference is statistically significant. For quantitative 
estimation of the clinical effect, calculate the relative failure risk (RFR), Number-
Needed-to-Treat, and estimate their 95% CI. 
The method of construction and analysis of the logistic regression models shall be used 
for standardization of the potential risk factors for treatment failure. During the analysis, 
use the primary efficacy value as the output variable Y. For patients who achieved the 
efficacy endpoint – reduction in frequency of defecation to 3 times a day, absence of 
loose stool, on Day 5 and earlier, the value is Y=0, otherwise, Y=1. As the factorial 
features, conduct the analysis specified for gender, weight, height, body mass index, 
physical examination parameters, clinical and laboratory test values at baseline, as well 
as treatment procedure (IP/placebo). To select the treatment failure risk factors, use the 
inclusion/exclusion stepwise method (Stepwise, p<0.1 for inclusion, p>0.3 for 
exclusion). Based on model analysis, estimate the effect of the specified factorial 
features on the treatment failure risk (calculate the OR, 95% CI).  
2) Quantitative variables: mean duration of treatment and mean quantity of tablets per 
treatment course. 
Define the values of descriptive statistics at the study endpoint for each group. To find 
out the differences, compare the groups using the Wilcoxon-T-test at the study endpoint.   
Make the general conclusion on efficacy estimation, provide the efficacy value for the 
IP group (%, 95% CI), provide the efficacy value for the IP group vs. placebo group 
(RR, 95% CI, and NNT, 95% CI), provide the value of standardized (by other risk 
factors) failure risk for the IP group vs. placebo group (OR, 95%). 
In all cases, during the analysis, select the significance threshold αcritical=0.05.  
 
15. UNDESIRABLE EFFECTS MONITORING 
 
All undesirable effects (AR/AE) will be recorded in the source documentation from the 
date of patients’ signing the Informed Consent Form until the expiration of 2 days after 


24 
 
the administration of the last IP dose. They will be reported as set forth by the applied 
instructions and will be included into the CS final report. 
 
15.1 UNDESIRABLE EFFECTS DEFINITIONS  
 
15.1.1 Undesirable effects  
Adverse reaction (AR) means all negative and unexpected responses to the introduction 
of medicinal product at any dose.  
Adverse effect (AE) may be any undesirable and unexpected sign (including laboratory 
data change), symptom or disease which are concurrent with the administration of 
(investigational) medicinal product irrespective whether it is associated with the 
administration of (investigational) medicinal product or not.   
 
15.1.2 Serious undesirable effect 
Serious undesirable effect (SUE) is adverse clinical sign that, irrespective of a dose of 
the product, leads to:  
 death;  
 admission or admission prolongation; 
 persistent or substantial disability and (or) incapacity;  
 or is a congenial anomaly/ developmental disease. 
 
15.2. INVESTIGATOR’S OBLIGATION AS TO THE UE (AR/AE) AND SUE 
REPORTING  
 
15.2.1 General instruction for undesirable effects reporting  
 All UE (AR/AE), starting from the date of signing the Informed Consent Form and 
until the CS completion, and irrespective of severity level and relation to the IP 
administration should be recorded on the relevant CRF pages. 
 The Investigator, as soon as possible, shall inform of the diagnosis (or syndrome) 
stating from the first day, intensity, measures taken with regard to IP, prescribed 
therapy, additional examinations conducted, outcome, and his/her own opinion as 
to whether there is a reasonable possibility that the UE (AR/AE) was caused by the 
IP administration.  
 
15.2.2 Instructions for serious undesirable effects reporting  
 
In case of SUE, the physician-investigator shall immediately:  
 Within the first working day, send the signed and dated CRF pages to the Sponsor’s 
monitoring team representative by fax or e-mail (name, fax number, e-mail address 
is given in the CS Protocol). 
 Enclose scan (photo) copies of all conducted examinations (with examination dates 
stated). The Investigator shall ensure the patient personal protection and properly 
specify the patient’s ID in CS.  
 All additional information should be sent to the Sponsor’s monitoring team within 
the 1st working day from the date of its receipt.   
 


25 
 
15.3 SPONSOR’S OBLIGATION AS TO THE UE AND SUE REPORTING  
 
In the course of CS, the Sponsor shall:  
 Ensure compliance with regulatory requirements on UE (AR/AE) and SUE 
reporting set forth by the State Expert Centre of the Ministry of Health of Ukraine. 
 Report, in an expedited manner, of all SUE unexpected or reasonably associated 
with the IP to the State Expert Centre of the Ministry of Health of Ukraine. 
 
16. CONFIDENTIALITY 
 
All the information provided by the Sponsor as well as received during the CS, namely 
CS Protocol, source documentation, CRF, Investigator’s Brochure, and CS results shall 
be kept confidential till results publication. The Investigator and co-investigators shall 
respect confidentiality and do not disclose the CS information to the third party without 
the Sponsor’s prior written consent. 
This CS Protocol as well as other required documentation can be submitted to the 
Independent Ethics Committee, and the members of the Independent Ethics Committee 
must respect confidentiality. 
The Sponsor and Investigator have agreed to respect confidentiality with regard to 
personal data of patients, investigator and employees involved in this CS. 
 
17. PROPRIETARY RIGHTS 
 
All information, documents and IP provided by the Sponsor shall be a Sponsor’s sole 
property. 
The Investigator may not refer to any information or IP in any patent applications or any 
other intellectual property rights applications. 
The Sponsor may use or apply all the results at his own discretion without any limitations 
of his property rights. The Sponsor shall have no obligations on patenting, marketing or 
any other utilization of the CS results. 
 
18. DATA PROTECTION 
 
The patient’s personal data to be entered into the Sponsor’s database shall be protected 
in accordance with all applied laws and regulations. 
The Sponsor shall take all necessary measures for patients’ and investigator’s (co-
investigators’) personal data protection to prevent access by the third parties.  
 
19. INSURANCE INDEMNITY 
 
The Sponsor shall prove the availability of the Certificate of Insurance covering the 
insured events related to the study participated.   
If necessary, the Certificate of Insurance will be provided to the Ethics Committee.   
 
20. SPONSOR AUDITS AND COMPETENT AUTHORITIES’ INSPECTIONS  
 


26 
 
To adhere to the CS Protocol, Good Clinical Practice (GCP) and relevant regulatory 
requirements, the Investigator shall allow audits by the Sponsor and inspections by the 
relevant competent authorities. 
The Investigator shall assist in audits/inspections providing access to all necessary 
documents and rooms which were used for CS anyway. 
The Investigator shall agree that the auditors/inspectors get full access to the CS 
documentation for the purposes of analysis. The Investigator shall understand that these 
persons must keep professional secrecy and shall not disclose any CS related 
information.   
The Investigator shall take all measures to solve the problems that were revealed during 
the audit/inspection. 
 
21. CLINICAL STUDY RESULTS 
 
The Sponsor shall be responsible for CS report preparation as well as for CS summary 
provision to the Investigator.  
 
22. PUBLICATIONS AND REPORTS 
 
The Investigator shall undertake not to disclose the CS and its results without the 
Sponsor’s prior written approval. The Sponsor shall undertake not to limit publications 
without apparent causes. 
Considering that this CS is conducted in several sites, the first publication will be made 
in the form of publication in all the sites involved in this Protocol fulfillment.  
During the publication (report) preparation, the Investigator shall provide a script 
(presentation) for analysis at least 30 days before the publication submission (public 
speech).  
The Investigator shall not use the Sponsor name in the publications (reports) without the 
Sponsor’s prior written consent.  
The Sponsor shall not use the Investigator (co-investigators) name(s) in advertising 
materials or publications without his/her (their) prior written consent. 
Any publication (presentation) can be delayed for no more than 90 days in order the 
Sponsor could submit patent application or take other measures to prove his property 
rights.  
The Sponsor shall have the right to publish the study results at any time.  
 
23. ANNEXES AND AMENDMENTS TO CLINICAL STUDY PROTOCOL  
 
All annexes to this Protocol referred to in the body of the Protocol shall be integral parts 
of the CS Protocol. 
The Investigator cannot make amendments to the CS Protocol or allow for any departure 
from it without prior review and approval (or favorable opinion) by the Ethics 
Committee of the health care institution where the CS is conducted, except for the cases 
when it needs to be immediately done to avoid the risk to patient. Any agreed changes 
will be recorded in a written form. The written change will be signed by the Investigator 
and Sponsor as well as enclosed to the CS Protocol.    


27 
 
Any amendment to the CS Protocol needs to have approval (or favorable opinion) of the 
National Ethics Committee prior to be implemented if there are no safety reasons 
requiring to omit it. 
 
24. LITERATURE REFERENCES 
 
1. S.S. Vialov. Use of foodborne intoxication enterosorption therapy at pre-hospital 
stage / S.S. Vialov // Meditsynskii Sovet. - 2012. - No 3. - PP. 38–41. 
2. Efficacy of up-to-date enterosorbent “Carbowhite” in patients with opportunistic 
acute intestinal infections / V.M. Frolov, T.P. Harnyk, O.V. Kruhlova [et al.] // 
Phytotherapy. Chasopys. – 2011. - No 4. – PP. 17-22. 
3. Efficacy of enterosorption in complex therapy of patients with acute intestinal 
infections / V.O. Terioshyn, N.I. Khomutianska, O.V. Kruhlova, I.V. Dekaliuk // 
All-Ukrainian Research and Practice Conference “Feral Herd Infections” 
(Uzhhorod, May 17-18, 2012). – P. 101. 
4. S.O. Kramarev Enterosorption for acute intestinal infections in children / S.O. 
Kramarev, O.A. Dmitrieva // Zdorovye Rebenka. – 2011. – No 2 (29). – PP. 77-80. 
5. Batz M.B. Long-term consequences of foodborne infections / M.B. Batz, E. Henke 
// Infect Dis Clin North Am. – 2013. – Vol. 27(3). – P. 599-616.  
6. Bicer S. A retrospective analysis of acute gastroenteritis agents in children admitted 
to a university hospital pediatric emergency unit / S. Bicer, D. Col, G.C. Erdag // 
Jundishapur J Microbiol. – 2014. - Vol. 7 (4). – Р. 9148. 
7. Burgmann K. Acute diarrhea / К. Burgmann, А. Schoepfer // Ther Umsch. – 2014. 
- Vol. 71 (9). – Р. 529-535.  
8. Dickinson B. Infectious diarrhea: an overview / В. Dickinson, С.М. Surawicz // Curr 
Gastroenterol Rep. – 2014. – Vol. 16 (8). - Р. 399. 
9. Efficacy of diosmectite (Smecta) in the treatment of acute watery diarrhoea in adults: 
A multicentre, randomized, double-blind, placebo-controlled, parallel group study / 
F.Khediri, A.I. Mrad, M. Azzouz, H. Doughi // Gastroenterology Research and 
Practice. – 2011. - http://dx.doi.org/10.1155/2011/783196 
10. 2. Evaluation of diosmectite in acute diarrhea in children / C. Milocco, A. Bolis, V. 
Rizzo, T.Suprani // Pediatria medicae chirurgica. – 1999. – Vol. 21, Issue 3. – Р. 
129-133.  
11. G*Power 3: A flexible statistical power analysis program for the social, behavioral, 
and biomedical sciences / F. Faul, E. Erdfelder, A. Lang / 2007. Behavior Research 
Methods. – 2007. - P. 175-191. 
12. Hill D.R. Travelers' diarrhea / D.R. Hill, N.J. Beeching  // Curr Opin Infect Dis. – 
2010. – Vol. 23 (5). – P. 481-487.  
13. Kocoshis S.A. Medical management of pediatric intestinal failure / S.A. Kocoshis // 
Semin Pediatr Surg. – 2010. – Vol. 19 (1). – P. 20-26. 
14. Lloyd R. Travellers' diarrhoea: causes, prevention and treatment / R. Lloyd, C. 
Bennett C. // Nurs Stand. – 2012. - Vol. 26(40). – P. 51-56. 
15. McGregor A.C. Geographic, symptomatic and laboratory predictors of parasitic and 
bacterial causes of diarrhoea in travellers / A.C. McGregor, C. Whitty // Trans R Soc 
Trop Med Hyg. – 2012. – Vol. 106 (9). – P. 549-553. 


28 
 
16. Nothdurft H.D. Common forms of infectious diarrhea after trips abroad--what is 
proven and what is actually done? / H.D. Nothdurft, T. Löscher // Dtsch Med 
Wochenschr. – 2001. - Vol. 126. - Р. 38-43. 
17. Pozio E. Foodborne and waterborne parasites / E. Pozio // Acta Microbiol Pol. – 
2003. - Vol. 52. – Р. 83-96. 
18.  Rifaximin treatment of pathogen-negative travelers'diarrhea / H.L. DuPont , R. 
Haake, D.N. Taylor et al. // J Travel Med. – 2007. - Vol. 14. – Р. 16-19. 
19. Zaidi D. An update on travelers' diarrhea / D. Zaidi, Е. Wine // Curr. Opin. 
Gastroenterol. – 2015. – Vol. 31 (1). – Р. 7-13.  
20. Zboromyrska Y. Aetiology of traveller's diarrhoea: evaluation of a multiplex PCR 
tool to detect different enteropathogens / Zboromyrska Y., Hurtado J.C., Salvador 
P. // Clin Microbiol Infect. – 2014. - Vol. 20(10). – P. 753-759.  
 
 
 


29 
 
25. ANNEXES 
 
25.1 Efficacy assessment is conducted according to the Stool Quantity and 
Characteristics questionnaire. 
 
Patient’s Stool Quantity and Characteristics Diary 
 
Date of issue of the Diary______________ 
Patient ID________ 
 
Please fill in the Patient’s Stool Quantity and Characteristics Diary. You should record 
the information on stool quantity and characteristics in this Diary*, ** 
 
Annex 25.1 
Patient’s Stool Quantity and Characteristics Diary 
 
Frequency of 
defecation  
(specify the 
number) 
Morning  
(06.00 a.m. till  
12.00 a.m.) 
Daytime 
(12.00 a.m. till 
06.00 p.m.) 
Evening 
(06.00 p.m till  
12.00 p.m.) 
Night  
(12.00 p.m. till  
06.00 a.m.) 
 
 
 
 
 
Total number of 
defecation a day 
 
Stool characteristics 
(put “X”) 
 
 
 
 
Formed 
 
 
 
 
Unformed 
 
 
 
 
Soft  
 
 
 
 
Loose 
 
 
 
 
Mucous  
 
 
 
 
Bloody  
 
 
 
 
Other characteristics (to 
be specified) 
 
 
 
 
* at the date of admission, you shall fill in the information on stool quantity and characteristics observed 
during a day before hospitalization; 
** on Days (0, 1, 2, 3, 4, 5 and 6) you shall record the information on stool quantity and characteristics 
for the previous day in the Diary and submit it to your attending physician on Days 1, 2, 3, 4, 5, 6 and 
7, respectively. 
 
 
 


30 
 
25.2 Safety assessment is conducted according to the patients’ laboratory test values 
(clinical and biochemical blood examination, fluid-and-electrolyte balance values, 
clinical urine examination), AE/SUE recording. 
 
Annex 25.2. 
Patients’ Laboratory Test Values by Visits 
  
Visits 
Visit 1 
(Day 0) 
Visit 6  
(Day 7±1) 
(Visit 3 or 4 in case of the 
patient’s premature 
exclusion) 
Clinical Blood Examination 
Erythrocytes (RBCs) , х1012/L 
* 
* 
Hemoglobin, g/L 
* 
* 
Color index, units 
* 
* 
Hematocrit 
* 
* 
Leukocytes (WBC), х109/L 
* 
* 
Stab cells, % 
* 
* 
Segmentated cells, % 
* 
* 
Lymphocytes, % 
* 
* 
Monocytes, % 
* 
* 
Eosinophils, % 
* 
* 
Basophils, % 
* 
* 
Platelets, х109/L 
* 
* 
ESR, mm/h 
* 
* 
Clinical Urine Examination 
Specific gravity, g/L 
* 
* 
pH, units 
* 
* 
Protein, g/L 
* 
* 
Glucose, g/L 
* 
* 
Leukocytes, number per field of view 
* 
* 
Erythrocytes, number per field of view 
* 
* 
Epithelial cells, number per field of view 
* 
* 
Biochemical Blood Examination 
Total protein, g/L 
* 
* 
ALT, μmol/Lh 
* 
* 
AST, μmol/Lh 
* 
* 
Bilirubin (total), μmol/L 
* 
* 
Creatinine, μmol/L 
* 
* 
Urea, mmol/L 
* 
* 
Blood glucose, mmol/L 
* 
* 
Fluid-and-Electrolyte balance Values  
Sodium, mmol/L 
* 
* 
Potassium, mmol/L 
* 
* 


31 
 
25.3 Tolerance assessment is conducted according to AR recording. 
 
 
 
PATIENT INFORMATION AND INFORMED CONSENT FORM  
(ACCORDING TO GCP 4.8 AND 
PERSONAL DATA PROTECTION REQUIREMENTS) 
 
 
Randomized, Double-Blind,  
Placebo-Controlled, Multi-Center Study 
of Efficacy and Safety of the Administration of Colloidal Silicon Dioxide  
in Tablet Dosage Form (Carbowhite)  
in Patients with Acute Diarrhea 
 
 
 
 
Version No: 1 
Date: ____________ 
 
Principal Investigator: ___________________________________________ 
 
Patient ID: __________________________________________________ 
 
Address and telephone number of Ethics Committee in: 
________________________________________________ 
 
 
 
INTRODUCTION 
We kindly invite you to take part in the clinical study. According to the physician-
investigator, you meet the study basic requirements. Prior to give your consent to study 
participation, it is important for you to read and understand the information given in this 
document. It describes the purpose, procedures, advantages, potential risks and 
inconveniences related to this study, as well as your obligations as a study participant. 
It also describes alternative procedures available for you and your rights for study 
participation discontinuation at any time. No warranties and statements are made with 
regard to the study results. After you familiarize yourself with this document and receive 
all answers to the questions you are interested in, you will be offered to sign the Consent 
Form. 
 
You can do harm yourself if you fail to give true and realistic answers concerning your 
medical history, administration of prescription and non-prescription medicinal products 
before and at the present time to your physician-investigator. 
 


32 
 
STUDY OBJECTIVE 
 
Diarrhea is a medical condition characterized by frequent stool, more than 3 times (and 
more than 5-7 times in newborns) within the last 24 hours, and/or loose stool. The fecal 
matter is liquid, its daily mass exceeds 200 g per day, and water content reaches 95%. 
Diarrheal diseases are one of the main causes of mortality in developing countries. The 
largest economies show relatively low rate of mortality due to diarrheal diseases, but 
nonetheless, they are significant cause of morbidity and represent a material item of 
expenditure of the budget of public health service.  
In spite of the disease pattern, it is usually difficult to find out the cause of diarrhea in 
each particular case only based on symptoms and signs. There are acute (with the 
duration not exceeding 2-3 weeks) and chronic (with the duration of more than 3 weeks) 
diarrhea. There is also a notion of diarrheal syndrome (DS), i.e. diarrhea-induced 
symptomatology. DS means not only the diarrhea as itself but also abdominal pain, 
dehydration, fluid-and-electrolyte imbalance, intoxication and asthenia. Control of each 
such symptoms needs individual self-medication. 
Causal treatment, i.e. the treatment addressing the causes of the disease, is optimal for 
any disease. To define etiology of diarrhea, plenty of time is required and a physician 
usually does not have it.  
In view of this, treatment of any type of diarrhea includes two basic stages: 
 
symptomatic therapy to arrest the main signs of DS (frequent and bulky stool, pain 
syndrome, dehydration, intoxication); 
 
selection of causal treatment (it is possible only after laboratory verification of the 
pathogens of disease). 
 
At conduction of symptomatic therapy of diarrhea, the administration of medicinal 
products not absorbed in the intestinal tract, i.e. locally acting (in the entodermal canal 
lumen), is preferable. Systemic effect on human body is excluded in this case. Quick 
antidiarrheal action of the product, as well as its high efficacy that allows its 
administration for a short period of time is critical issue.  
Silica-based eneterosorbent developed on the basis of colloidal silicone dioxide (SiO2) 
Carbowhite (IP) fits these properties to a great extent. The product has a large sorption 
surface (active sorption surface area) is no less than 300 sq.m per 1 gram of the 
substance) as well as high binding rate of bacteria and their toxins that provides for quick 
therapeutic (antidiarrheal) effect. In addition, the colloidal silicone dioxide 
pharmacological profile is associated with its good safety profile. 
Silicone dioxide is produced in the form of powder for suspension that is not always 
easy to administer. The Carbowhite product is of tablet dosage form containing 210 mg 
of colloidal silicone dioxide. Tablets are more suitable for consumers.  
This study objective is to estimate the antidiarrheal efficacy and safety of the 
administration of tablet dosage form of colloidal silicone dioxide (Carbowhite) in 
patients with acute diarrhea. 


33 
 
If you meet the inclusion criteria, the IP/placebo treatment will be prescribed for you. 
By its appearance, placebo does not differ from the colloidal silicon dioxide tablets, but 
it does not contain active ingredient.  
The IP/placebo dose initially prescribed for you will be 3 tablets as a single dose (210 
mg х 3 = 630 mg) t.i.d. (630 mg х 3 = 1,890 mg). This dose may be escalated to 3 tablets 
as a single dose (210 mg х 3 = 630 mg) q.i.d. (630 mg х 4 = 2,520 mg) on Day 1 or Day 
2 if the product antidiarrheal efficacy is insufficient. On Day 3 and Day 4, the IP/placebo 
dose may be escalated to 4 as a single dose (210 mg х 4 = 840 mg) q.i.d . (840 mg х 4 = 
3,360 mg) if the IP/placebo dose was escalated on Day 1 or Day 2. 
In case of IP/placebo treatment failure (stool frequency increase) you can be excluded 
and another treatment will be prescribed for you.  
After the bacteriological diagnosis verification (in 3 days, usually), if the physician-
investigator considers it necessary to prescribe antimicrobial products, your IP/placebo 
treatment will be discontinued. If the antimicrobial products are not prescribed, the 
IP/placebo treatment can be prolonged up to 5 days. 
In the course of treatment, other products provided by the standards of care of patients 
with bacterial foodborne intoxication will be prescribed for you. The physician-
investigator shall define the prescription of these products. 
 
STUDY DESCRIPTION 
 
This study shall be conducted in several hospitals of infectious diseases of Ukraine.  
About 140 adult patients with acute diarrhea will participate in the study. Your study 
participation will last about 7 days.   
If you agree to participate in this study and meet all the participation requirements, you 
will be offered to do the following depending on the study period. 
 
Day 0 
Screening period 
Screening period starts after the patient was admitted to the Department of Infectious 
Disease and the diagnosis of bacterial foodborne intoxication unspecified (moderate). 
Then the physician-investigator shall: 
 estimate your possibility to participate in the study and offer you to participate; 
 explain the essence of study participation to you.  
 
Having received a preliminary consent for study participation, you will be offered to 
familiarize yourself with the Patient Information. The physician-investigator must 
provide comprehensive answers to all questions you are interested in. After the consent 
is obtained, you will be offered to sign the Informed Consent Form. 
 
You will be asked about your birth date, gender, complaints, medical history, prior and 
concurrent diseases, medicinal products you administer due to other diseases.  It is very 
important to give accurate and full information on these questions. Provision of untrue, 
incomplete or false information about your medical history, including information about 
medicinal products administered at the moment or before, can lead to negative 
consequences for your health.  


34 
 
You will take physical examination with the measurement of the body height and 
weight, as well as body temperature, blood pressure and pulse. 
You will be explained how to fill in the Patient’s Stool Quantity and Characteristics 
Diary and asked to fill it in. In this Diary, you will have to record the information on 
stool quantity and characteristics, gastrointestinal tract conditions a day before 
hospitalization. 
 
Blood sampling will be made for the purposes of the following examinations: 
 clinical examination – erythrocytes, hemoglobin, hematocrit, leucocytes, 
monocytes, erythrocyte sedimentation rate; 
 biochemistry 
– 
total 
protein, 
aspartate 
aminotransferase, 
alanine 
aminotransferase, bilirubin, creatinine, urea, glucose; 
 fluid-and-electrolyte balance values – sodium, potassium. 
The blood is sampled from the vein, at least twice (before treatment and during the final 
visit), approx. by 10 mL. In total, up to 20 mL of blood will be sampled that corresponds 
to 4 tea spoons. 
Urine sampling will be made for the purposes of the clinical examinations to define 
specific gravity, pH, protein, glucose, erythrocytes, leucocytes, epithelial cells and salts.    
Also, fecal masses will be sampled for bacteriological examination.  
For women of child-bearing age, urine pregnancy test will be made as the pregnant 
women must not participate in this clinical study. 
During the screening period that lasts for up to 3-4 hours you will not administer 
IP/placebo.    
 
Randomization and treatment initiation 
Upon the screening period completion, you will be randomized, i.e. by random sampling 
technique included into one of the groups:  
Group 1 – patients administering colloidal silicon dioxide (Carbowhite, IP); 
Group 2 – patients administering placebo. 
By its appearance, placebo does not differ from the colloidal silicon dioxide tablets 
(Carbowhite) but it does not contain active ingredient. The assignment by groups at the 
ratio 5:1 will be done, i.e. about 120 patients will administer colloidal silicon dioxide 
(Carbowhite, IP), and 24 – placebo.     
After randomization, an initial dose of IP/placebo will be prescribed for you:  
IP/placebo is prescribed at a dose of: 3 tablets as a single dose (210 mg х 3 = 630 mg) 
t.i.d. (630 mg х 3 = 1,890 mg). 
You be will be given the Patient’s Stool Quantity and Characteristics Diary to record 
necessary information during the next day. The Patient’s Stool Quantity and 
Characteristics Diary is given on each next day of treatment (1, 2, 3, 4, 5 and 6). 
 
 
 
 
Day 1 


35 
 
The physician-investigator will ask you about the complaints. Your body temperature, 
blood pressure and pulse will be measured. These procedures are taken at the beginning 
of each next day of treatment (2, 3, 4, 5, 6 and 7). 
The physician-investigator will check your Patient’s Stool Quantity and Characteristics 
Diary records. This is made at the beginning of each next day of treatment (2, 3, 4, 5, 6 
and 7). Based on these data, the physician-investigator shall make a decision whether to 
remain the prescribed IP/placebo dose or escalate it: 3 tablets as a single dose (210 mg 
х 3 = 630 mg) q.i.d. (630 mg х 4 = 2,520 mg). 
 
Day 2 
The physician-investigator will check your Patient’s Stool Quantity and Characteristics 
Diary records.  
Based on the data you stated in the Patient’s Diary, the physician-investigator shall make 
a decision whether to continue treatment with the dosage regimen that was determined 
on Day 0 or escalate it: 3 tablets as a single dose (210 mg х 3 = 630 mg) q.i.d. (630 mg 
х 4 = 2,520 mg).  
The decision on your discontinuation shall be taken in case of insufficient antidiarrheal 
efficacy of the treatment conducted. 
In case of IP/placebo treatment discontinuation, you will have your blood sampled for 
examinations (clinical and biochemical examinations, fluid-and-electrolyte balance 
values), as well as urine sampled for clinical examination.   
In case of discontinuation, another treatment will be prescribed for you.  
 
Day 3 
Based on the fecal mass bacteriological examination results, the pathogen can be 
determined. The physician-investigator can make a decision on prescription of 
antimicrobial products for you. In this case, you will be excluded from the study.    
The physician-investigator can make a decision on your IP/placebo treatment 
discontinuation if: 
 diarrhea stopped (stool frequency does not exceed 3 times a day, formed stool); 
 antidiarrheal efficacy of the conducted IP/placebo treatment is insufficient. 
In case of exclusion from the study, your will have your blood and urine sampled for 
examinations as described in the procedures (Day 2). 
Irrespective of the fecal mass bacteriological examination results, the physician-
investigator may take a decision on your further study participation. In this case, 
treatment with IP/placebo shall continue with the dosage regimen determined by the 
physician-investigator:   
 the dose that was determined on Day 1 or Day 2; 
 the dose can be escalated to 4 tablets as a single dose (210 mg х 4 = 840 mg) q.i.d. 
(840 mg х 4 = 3,360 mg) if it was escalated on Day 1 or Day 2; 
 the dose that was determined on Day 0 (initial dose). 
 
Day 4 
Your treatment with IP/placebo can be discontinued if the diarrhea stopped (stool 
frequency does not exceed 3 times a day, formed stool). 


36 
 
In case of IP/Placebo treatment discontinuation, your will have your blood and urine 
sampled for examinations as described in the procedures (Day 2). 
In case of IP/Placebo treatment discontinuation on Day 2, the physician-investigator 
shall inform you about the blood and urine examination results.  
If the treatment with IP/placebo continues, the dosage regimen shall be determined by 
the physician-investigator described in the procedures (Day 3). 
 
Day 5 
Treatment with IP/placebo stops.  
Your will have your blood sampled for examinations (clinical and biochemical 
examinations, fluid-and-electrolyte balance values), as well as urine sampled for clinical 
examination. 
In case of IP/Placebo treatment discontinuation on Day 3, the physician-investigator 
shall inform you about the blood and urine examination results. 
 
Day 6 
The above procedures are taken. In case of IP/Placebo treatment discontinuation on Day 
4, the physician-investigator shall inform you about the blood and urine examination 
results. 
 
Day 7 
The physical examination and above procedures are taken. The physician-investigator 
shall inform you about the blood and urine examination results obtained on Day 5. 
Study participation is stopped. 
 
POTENTIAL EXPECTED BENEFITS  
Colloidal silicone dioxide (Carbowhite) may help you recover from diarrhea. In the 
course of this study, you can benefit from medical supervision that will be performed 
during visits. We hope the information obtained from this study will provide valuable 
data and help improve treatment of patients with diarrhea in case of bacterial foodborne 
intoxication.  
 
POTENTIAL RISKS 
Like any other medicinal product, colloidal silicone dioxide (Carbowhite) can cause 
adverse reactions. Nevertheless, this does not mean that you will have the adverse 
reactions for sure. The literature data demonstrate that usually the product is well-
tolerated by patients. Potential long-term adverse effects and serious risks associated 
with the administration of colloidal silicone dioxide (Carbowhite) are not expected to 
occur.   
You can experience some short-term and/or minor discomfort during blood sampling: 
pain caused by a needle entering the vein or dizziness. In case of the mentioned 
symptoms, report to medical staff who make such manipulation hereof. 
 
ALTERNATIVE TREATMENT  
This study participation is not a prerequisite for your treatment. There are other 
treatment methods available. If you decide not to participate in this study, please ask you 


37 
 
physician-investigator about alternative treatment. You and your physician-investigator 
can decide what treatment is better for you. 
 
STUDY PARTICIPANT’S OBLIGATIONS  
In the course of study participation, you must not administer any other antidiarrheal 
products. The physician-investigator will discuss with you which treatment is allowed 
before inclusion. If you administer any medicinal products due to concurrent diseases, 
changing the mode of their administration may be necessary. The physician-investigator 
will inform you hereof. 
 
EXPENSES AND PAYMENT FOR STUDY PARTICIPATION  
In the frameworks of the study, you will get the investigational product and take all tests 
and procedures free of charge. 
Your study participation will not imply any extra material costs. 
Payment to the patient for study participation is not provided. 
 
INSURANCE 
The Certificate of Insurance for this clinical study as required by the current legislation 
was received in the insurance company 
“______________________________________________”,  
with legal address ____________________________________ 
Tel:________________.  
Insurance Contract No_______________________________. 
This Certificate of Insurance shall cover the responsibility of possible harmful effect 
caused to life and health of the patients by the clinical study.  
 
CONFIDENTIALITY 
Only the physician-investigator, medical staff, Sponsor and his legal representatives, the 
Ministry of Health of Ukraine and its authorized bodies, governmental agencies of other 
countries where colloidal silicone dioxide (Carbowhite) is planned for approval and the 
local ethics committee shall have access to medical documentation and medical data 
obtained in the course of the clinical study.  
Your personal data shall be kept by the physician-investigator and his/her medical staff 
and shall not be disclosed, including the study data publications. 
The Sponsor and physician-investigator shall guarantee confidentiality of your personal 
medical data in accordance with the current legislation of Ukraine. 
 
 
 
 
 
 
 
 
 
 


38 
 
 
DISCONTINUATION OF STUDY PARTICIPATION 
 
You may voluntarily discontinue your participation at any time. If you decided to refuse 
from study participation, you should inform the physician-investigator hereof. The 
physician-investigator shall discuss further treatment with you. 
 
The physician-investigator can discontinue your participation due to many reasons even 
if you do not wish. These reasons may include such circumstances as unwillingness to 
undergo examination or follow the physician’s instructions. In this case, the 
administration of the investigational product will be stopped. The physician-investigator 
shall discuss further treatment with you. 
 
Even if you discontinued study participation, you may be asked to stay for further 
supervision for safety purposes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


39 
 
 
 
INFORMED CONSENT FORM 
 
Study title: randomized, double-blind, placebo-controlled, multi-center study of 
efficacy and safety of the administration of colloidal silicon dioxide in tablet dosage 
form (Carbowhite) in patients with acute diarrhea.  
 
Sponsor: Limited Liability Company “OmniFarma Kiev” 
 
Full name of the responsible investigator: ________________________________ 
Address: _____________________________________________________________ 
 
Patient ID: ________________________________ 
 
By signing this document, I shall confirm that:  
1. 
I have read this Patient Information and Informed Consent Form in an 
understandable language and got answers to all interested questions concerning 
this study.   
2. 
I have had sufficient time to make a decision. 
3. 
I voluntarily agree to participate in the study described in this Patient Information 
and Informed Consent Form.  
4. 
I was informed of the names of study team members whom I can contact. 
5. 
I agree that the Sponsor, medical staff of the study and other persons will have 
access to my medical history as described in this Patient Information and 
Informed Consent Form. 
6. 
I have got the secondary original of this Patient Information and Informed 
Consent Form to be kept by me.  
 
 
Patient’s signature                    
 
Date (dd/mm/yyyy) 
 
 
Full name of the patient (please print with your own hand) 
 
 
 
Physician-investigator’s signature         Date (dd/mm/yyyy) 
 
 
Full name of the physician-investigator (please print with your own hand) 
 
 
 


40 
 
PATIENT INFORMATION AND INFORMED CONSENT FORM  
(ACCORDING TO GCP 4.8 AND 
PERSONAL DATA PROTECTION REQUIREMENTS) 
 
 
 
 
 
 
Randomized, Double-Blind,  
Placebo-Controlled, Multi-Center Study 
of Efficacy and Safety of the Administration of Colloidal Silicon Dioxide  
in Tablet Dosage Form (Carbowhite)  
in Patients with Acute Diarrhea 
 
 
 
 
 
 
 
Version No: 1 
Date: ____________ 
 
Principal Investigator: ___________________________________________ 
 
Patient ID: __________________________________________________ 
 
Address and telephone number of Ethics Committee in: 
________________________________________________ 
 
 
Due to your condition, it is not possible for you to familiarize yourself with a full version 
of the Patient Information, that’s why you are offered to read brief information about 
the clinical study (CS) and participate in it. If you agree to participate in the CS, you 
should familiarize yourself with the full version of the Patient Information in the nearest 
time, but not later than in a day. According to the physician-investigator’s opinion, you 
meet the initial requirements of this study.  
 
Diarrhea is a medical condition characterized by increase in stool frequency more than 
3 times for the last 24 hours and/or stool softening.   
The medicinal products not absorbed in the intestinal tract are usually used in the course 
of diarrhea symptomatic therapy. Silica-based enterosorbent Carbowhite (IP) developed 
on the basis of colloidal silicone dioxide (SiO2) fits these properties. The product has a 
large sorption surface as well as high binding rate of bacteria and their toxins that 
provides for quick therapeutic (antidiarrheal) effect.   


41 
 
The study objective is to estimate the antidiarrheal efficacy of the administration of 
colloidal silicon dioxide in tablet dosage form (Carbowhite) in patients with acute 
diarrhea. 
During the screening period, the inclusion/exclusion criteria will be estimated to define 
the possibility of your participation in the CS. Upon screening period completion, you 
will be randomized, i.e. by random sampling technique included into one of the groups: 
Group 1 – patients administering tablets containing the IP; Group 2 - patients 
administering placebo. By its appearance, placebo does not differ from the colloidal 
silicon dioxide tablets (Carbowhite), but it does not contain active ingredient. 
After randomization, an initial dose of IP/placebo will be prescribed for you at a dose 
of: 3 tablets as a single dose (210 mg х 3 = 630 mg) t.i.d. (630 mg х 3 = 1,890 mg). 
During the treatment the IP/placebo dose can vary at the physician-investigator’s 
discretion or depending on your condition.  
 
Treatment with IP/placebo will last for no more than 5 days. You may terminate CS 
participation at any of its stages. In this case, the physician shall discuss further treatment 
with you. Participation in this CS is not a prerequisite for your treatment. 
 
 
 
 
 
 
 
 
 
 


42 
 
INFORMED CONSENT FORM 
 
Study title: randomized, double-blind, placebo-controlled, multi-center study of 
efficacy and safety of the administration of colloidal silicon dioxide in tablet dosage 
form (Carbowhite) in patients with acute diarrhea.  
 
Sponsor: Limited Liability Company “OmniFarma Kiev” 
 
Full name of the responsible investigator: ________________________________ 
Address: _____________________________________________________________ 
 
Patient ID: ________________________________ 
 
By signing this document, I shall confirm that:  
1. 
I have read this Patient Information and Informed Consent Form in an 
understandable language and got answers to all interested questions concerning 
this study.   
2. 
I have had sufficient time to make a decision. 
3. 
I voluntarily agree to participate in the study described in this Patient Information 
and Informed Consent Form.  
4. 
I was informed of the names of study team members whom I can contact. 
5. 
I agree that the Sponsor, medical staff of the study and other persons will have 
access to my medical history as described in this Patient Information and 
Informed Consent Form. 
6. 
I have got the secondary original of this Patient Information and Informed 
Consent Form to be kept by me.  
 
 
Patient’s signature                    
 
Date (dd/mm/yyyy) 
 
 
Full name of the patient (please print with your own hand) 
 
 
 
Physician-investigator’s signature         Date (dd/mm/yyyy) 
 
 
Full name of the physician-investigator (please print with your own hand) 
 


43 
 
TABLES 
 
Table 1. Protocol of sample size estimation at frequency comparison for two independent groups, 
Fisher’s exact test, two-sided critical zone (G*Power 3.1.5). 
 
Exact - Proportion: Difference from constant (binomial test, one sample case) 
Options: 
α balancing: α/2 on each side 
Analysis: 
A priori: Compute required sample size  
Input: 
Tail(s) 
= Two 
 
Effect size g 
= 0.1 
 
α err prob 
= 0.05 
 
Power (1-β err prob) 
= 0.8 
 
Constant proportion 
= 0.8 
Output: 
Lower critical N 
= 76 
 
Upper critical N 
= 94 
 
Total sample size 
= 107 
 
Actual power 
= 0.819 
 
Actual α 
= 0.040 
 
Table 2. Protocol of sample size estimation at frequency comparison for two independent groups, 
Fisher’s exact test, two-sided critical zone (G*Power 3.1.5). 
 
Exact - Proportions: Inequality, two independent groups (Fisher's exact test)  
Options: 
Exact distribution 
Analysis: 
A priori: Compute required sample size  
Input: 
Tail(s) 
= Two 
 
Proportion p1 
= 0.6 
 
Proportion p2 
= 0.9 
 
α err prob 
= 0.05 
 
Power (1-β err prob) 
= 0.8 
 
Allocation ratio N2/N1 
= 5 
Output: 
Sample size group 1 
= 18 
 
Sample size group 2 
= 90 
 
Total sample size 
= 108 
 
Actual power 
= 0.812 
 
Actual α 
= 0.024