Conditions: Anxiety
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 390
Healthy volunteers: no

Brief summary:
The purposes of this study are:

* To further examine the efficacy and safety of Tenoten® in the treatment of anxiety in patients with somatoform, stress-related and other neurotic disorders.
* To compare the efficacy of two dosing regimens of Tenoten® (4 tablets daily vs.8 tablets daily, both for 12 weeks) in the treatment of anxiety in patients with somatoform, stress-related and other neurotic disorders.

Detailed description:
Design: an international, a multicenter, double-blind, randomized, parallel group placebo-controlled trial to evaluate efficacy and safety of study treatment.

The study will enroll outpatient subjects of both genders aged 18-45 years with verified diagnoses of somatoform, stress-related and other neurotic disorders (F43, F45, F48) and signs of clinically relevant anxiety according to The Hospital Anxiety and Depression scale (HADS).

After signing the informed consent form to participate in the clinical study the subject will be interviewed (complaints, medical history, concomitant therapy) and objective examination will be performed; the subject will fill HADS scale. The severity of anxiety at screening should be ≥ 11 according to HADS. If the subject meets inclusion criteria and has no exclusion criteria he/she will be enrolled into the study. The investigator will determine the severity of anxiety using НАМ-А scale; the subject will fill EQ-5D-3L questionnaire. At Visit 1 (Day 1) the subject will be randomized into one of the treatment groups:

* Group 1: Tenoten® at 2 tablets twice daily (4 tablets/day);
* Group 2: Placebo at 2 tablets twice daily (4 tablets/day);
* Group 3: Tenoten® at 2 tablets 4 daily (8 tablets/day).
* Group 4: Placebo at 2 tablets 4 daily (8 tablets/day). The first dose should be administered at Visit 1 after the visit procedures are completed. Further administration of the study product will be made according to the dosing scheme. The subject will administer the study product and will be followed for 12 weeks during which additional three visits will be made. At Visit 2 (Week 4), Visit 3 (Week 8) and Visit 4 (Week 12) the physician will record patients' complaints and physical examination data, fill HAM-A scale, check the study and concomitant therapy, assess treatment safety and patient compliance with the study treatment. At the final Visit 4 the subject will fill EQ-5D-3L questionnaire and the investigator will fill the Clinical Global Impression Scale Efficacy Index (CGI-EI).

Subjects will be allowed to take symptomatic therapy and medications for their co-morbidities during the study, except for the medicines listed in "Prohibited therapy".

Arms:
arm 1: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets twice daily (4 tablets/day). The tablets should be held in the mouth until dissolution, without meal. arm 2: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets twice daily (4 tablets/day). The tablets should be held in the mouth until dissolution, without meal. arm 3: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 4 times daily (8 tablets/days). The tablets should be held in the mouth until dissolution, without meal. arm 4: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 4 times daily (8 tablets/days). The tablets should be held in the mouth until dissolution, without meal.

Interventions: intervention 1: Tenoten intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet for oral use. intervention 2: Tablet for oral use.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
An international multicenter, randomised, double-blind,  
placebo-controlled parallel-group clinical study of efficacy 
and safety of various schemes of Tenoten® in the treatment 
of anxiety in subjects with somatoform, stress-related 
disorders and other neurotic disorders 
 
 
 
 
Phase IV 
 
 
 
 
 
 
 
 
 
 
Sponsor 
OOO «NPF «MATERIA MEDICA HOLDING» 
Protocol number 
MMH-TN-001 
Version date: 
April 19, 2016 
ClinicalTrials.gov Id: 
NCT03036293 


Protocol No. MMH-TN-001 
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Page 2 of 15 
 
Protocol Summary 
 
This document represents the protocol summary for the study on human subjects. The study will 
be carried out in accordance with ICH GCP, National Standard of the Russian Federation GOST 
52379-2005 "Good Clinical Practice", Helsinki Declaration of World Medical Association, 
relevant requirements of the regulatory authorities as well as the study procedures. 
Title of Study 
An international multicenter randomized double-blind placebo-controlled parallel-group clinical 
study of efficacy and safety of various schemes of Tenoten in the treatment of anxiety in subjects 
with somatoform, stress-related disorders and other neurotic disorders 
Phase: IV 
Sponsor: OOO "NPF "Materia Medica Holding", Moscow, Russia 
Protocol No. MMH-TN-001 
 
Objective of the study 
 To obtain additional efficacy and safety data for various schemes of Tenoten® dosing in the 
treatment of anxiety in subjects with somatoform, stress-related or other neurotic disorders. 
 To compare efficacy of the two schemes of Tenoten® dosing (daily dose of 4 and 8 tablets for 
12 weeks) in the treatment of anxiety in subjects with somatoform, stress-related or other 
neurotic disorders.   
Endpoints  
Primary endpoint 
1. 
Change from baseline in mean HAM-A score after 12 weeks of treatment. 
1. group 1 (Tenoten® 4 tablets a day) 
2. group 3 (Tenoten® 8 tablets a day). 
Secondary endpoints 
1. Change from baseline in mean HAM-A score after 4 weeks of treatment: 
1.1. group 1 (Tenoten® 4 tablets a day) 
1.2. group 3 (Tenoten® 8 tablets a day). 
2. Change from baseline in mean HAM-A score after 8 weeks of treatment. 
2.1. group 1 (Tenoten® 4 tablets a day) 
2.2. group 3 (Tenoten® 8 tablets a day). 


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3. Proportion of the subjects with reduced anxiety by ≥ 50% according to HAM-A scale vs. 
baseline: 
3.1. group 1 (Tenoten® 4 tablets a day)  
3.1.1. after 4 weeks of therapy 
3.1.2. after 8 weeks of therapy 
3.1.3. after 12 weeks of therapy 
3.2. group 3 (Tenoten® 8 tablets a day) 
3.2.1. after 4 weeks of therapy 
3.2.2. after 8 weeks of therapy 
3.2.3. after 12 weeks of therapy.  
4. Proportion of subjects with lack of anxiety (<14 points according to HAM-A scale): 
4.1. group 1 (Tenoten® 4 tablets a day)  
4.1.1. after 4 weeks of therapy 
4.1.2. after 8 weeks of therapy 
4.1.3. after 12 weeks of therapy 
4.2. group 3 (Tenoten® 8 tablets a day)  
4.2.1. after 4 weeks of therapy 
4.2.2. after 8 weeks of therapy 
4.2.3. after 12 weeks of therapy. 
5. Change from baseline in total EQ-5D-3L score after 12 weeks of treatment. 
5.1. group 1 (Tenoten® 4 tablets a day) 
5.2. group 3 (Tenoten® 8 tablets a day). 
6. Total CGI score: 
6.1. group 1 (Tenoten® 4 tablets a day) 
6.2. group 3 (Tenoten® 8 tablets a day). 
Safety assessment  
 Occurrence and nature of adverse events, their intensity (severity), causal relationship to the 
study drug, and outcome. 
 Changes in vital signs during the treatment. 
Study design  
Design – an international multicenter, randomized, double-blind, placebo-controlled parallel- 
group clinical trial to evaluate efficacy and safety of various schemes of Tenoten® in the 
treatment of anxiety. 


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The study will enroll outpatient subjects of both genders aged 18-45 years with verified 
diagnoses of somatoform, stress-related and other neurotic disorders (F43, F45, F48) and signs 
of clinically relevant anxiety according to The Hospital Anxiety and Depression scale (HADS). 
After signing information sheet (informed consent form) to participate in the clinical study the 
subject will be interviewed (complaints, medical history, concomitant therapy) and physical 
examination will be performed; the subject will fill HADS scale. Degree of anxiety at screening 
should be ≥ 11 according to HADS. Where the subject meets inclusion criteria and has no 
exclusion criteria he/she will be enrolled into the study. The investigator will determine degree 
of anxiety using НАМ-А scale; the subject will fill EQ-5D-3L questionnaire. At Visit 1 (Day 1) 
the subject will be randomized into one of the follow treatment groups: 
 Group 1: Tenoten® at 2 tablets twice daily (4 tablets/day); 
 Group 2: Placebo at 2 tablets twice daily (4 tablets/day); 
 Group 3: Tenoten® at 2 tablets 4 daily (8 tablets/day). 
 Group 4: Placebo at 2 tablets 4 daily (8 tablets/day). 
The first dose of the study drug should be administered at Visit 1 after the visit procedures are 
completed. Further administration of the study product will be made according to the dosing 
scheme. The subject will administer the study drug and will be followed for 12 weeks during 
which additional three visits will be made. At Visit 2 (Week 4), Visit 3 (Week 8) and Visit 4 
(Week 12) the physician will record patients’ complaints and physical examination data, fill 
HAM-A scale, check the study and concomitant therapy, assess treatment safety and patient 
compliance with the study treatment. At the final Visit 4 the subject will fill EQ-5D-3L 
questionnaire and the investigator will determine Clinical Global Impression Scale Efficacy 
Index (CGI-EI) score. 
The patients will be allowed to take symptomatic therapy and medications for their co-
morbidities during the study, except for the medicines listed in “Forbidden concomitant 
therapy”. 
Inclusion and exclusion criteria 
Inclusion criteria 
1. Age between 18 and 45 years old inclusively. 
2. Diagnosis of somatoform, stress-related and other neurotic disorders (F43, F45, F48)1 
established according to ICD-10 study diagnostic criteria.  
3. Clinically relevant anxiety at screening (≥11 points according to HADS scale).  
                                                 
1 Diagnosis of diseases and diagnostic procedures to verify somatoform, stress-related and other neurotic disorders 
in the subjects will not be the study objective; the diagnostics algorithm will be defined by the investigator.  


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4. Availability of signed patient information sheet (Informed Consent form) for participation in 
the clinical trial. 
5. Usage of contraceptive methods2 by both gender patients of reproductive age during the trial 
and within 30 days of ending the participation in the trial. 
Exclusion criteria 
1. Expressed depression symptoms at screening (≥ 11 points according to HADS scale). 
2. Organic including symptomatic, mental disorders (F00-09). 
3. Mental disorders or behavioural disorders associated with psychoactive substances (F10-19). 
4. Schizophrenia, schizotic conditions and delusional disorders (F20-29). 
5. Mood disorders [affective disorders] (F30-39). 
6. Phobic (F40) and other anxiety disorders (F41), obsessive-compulsive disorder (F42), 
dissociative [conversion] disorders (F44), depersonalization syndrome (F48.1). 
7. Behavioural syndromes associated with physiological disorders and physical factors  
(F50-59). 
8. Personality and behavioural disorders at mature age (F60-69). 
9. Mental deficiency (F70-79). 
10. Inflammatory and traumatic injuries of brain with persistent neurological deficit.  
11. Prior diagnosis of heart failure defined by the New York Heart Association classification 
(1964) as III or IV FC. 
12. Malignant neoplasm/suspected malignant neoplasm 
13. Patients allergic to/intolerant of any constituent of the medications used in the treatment.  
14. Malabsorption syndrome, including congenital or acquired lactase deficiency (or any other 
disaccharidase deficiency) and galactosemia. 
15. Any conditions which, according to the investigator, may interfere with the subject’s 
participation in the study. 
16. Scheduled hospiralizations, surgeries during the study. 
17. Patients who, from the investigator’s point of view, will not comply with the observation 
requirements of the study or adhere to study drug dosing regimens. 
18. Use of any medicine listed in the section "Prohibited concomitant treatment" within 30 days 
preceding the inclusion in this study. 
19. Drug addiction, alcohol usage in the amount exceeding 2 units of alcohol per day3. 
20. Pregnancy, breast-feeding. 
                                                 
2 Acceptable contraception includes intrauterine device; barrier method (condom, contraceptive cap, cervical cap or 
spermicide), previous surgical sterilization or vasectomy (for male subjects or partners). Throughout the study 
systemic hormonal contraceptives including oral contraceptives will not be allowed. 
3 1 unit of alcohol is equivalent to 0.33 L of lager/150 mL of unfortified wine, or 40 mL of a spirit 


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21. Participation in other clinical trials in the previous 3 months. 
22. Patients who are related to any of the on-site research personnel directly involved in the 
conduct of the trial or are an immediate relative of the study investigator. ‘Immediate 
relative’ means husband, wife, parent, son, daughter, brother, or sister (regardless of whether 
they are natural or adopted). 
23. Patients who work for OOO “NPF “Materia Medica Holding” (i.e. the company's 
employees, temporary contract workers, appointed officials responsible for carrying out the 
research or immediate relatives of the aforementioned). 
Criteria for Withdrawal or Termination 
1. Participant's failure or decline to comply with the protocol requirements.  
2. Necessity for prescribing medications not permitted during the study. 
3. An adverse event requiring discontinuation of the study product; 
4. Pregnancy. 
5. Patient’s decision to withdraw early for lack of efficacy or other reasons. 
6. Eligibility error. 
7. Cases not stipulated in the protocol where the investigator decides that further participation 
may harm the patient.   
Number of subjects 
It is planned to include 390 subjects, which is expected to yield at least 310 patients completing 
all protocol procedures. 
Interim analysis 
An interim statistical analysis is not scheduled within the study.  
Treatment 
 
Group 1 
Name of the medicinal product: Tenoten 
Active ingredient: Affinity purified antibodies to brain-specific S-100 protein - 0.003 g* 
* applied onto lactose as a water-alcohol mixture containing no more than 10-15 ng/g active form of the API.   
Excipients: Lactose monohydrate (lactose) - 0.267g (Eur. Ph.4, USP5 NF, BP6) 
 Microcrystalline cellulose - 0.03 g (Eur. Ph., USP NF, BP) 
                    Magnesium stearate - 0.003 g (Eur. Ph., USP NF, BP) 
                                                 
4 Eur. Ph. European Pharmacopoeia (current edition) 
5 USP – current US Pharmacopeia 
6 EP – current European Pharmacopoeia 


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Method of administration: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 
twice daily (4 tablets/day). The tablets should be held in the mouth until dissolution, without 
meal.    
Dosage form: Tablets. 
Description: White to off-white, round, flat, scored on one side and beveled tablets. 
Storage conditions: Store in a place protected from light at a temperature below 25 С. Keep out 
of the reach of children. 
Group 2 
Name of the medicinal product: Placebo 
Active ingredient: NA 
Excipients: Lactose monohydrate (lactose) - 0.267 g (Eur. Ph4., USP5 NF, BP6) 
                    Microcrystalline cellulose - 0.03 g (Eur. Ph., USP NF, BP) 
                    Magnesium stearate - 0.003 g (Eur. Ph., USP NF, BP) 
Method of administration: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 
twice daily (4 tablets/day). The tablets should be held in the mouth until dissolution, without 
meal.    
Dosage form: Tablets. 
Description: White to off-white, round, flat, scored on one side and beveled tablets. 
Storage conditions: Store in a place protected from light at a temperature below 25 С. Keep out 
of the reach of children. 
Group 3 
Active ingredient: Affinity purified antibodies to brain-specific S-100 protein - 0.003 g* 
* applied onto lactose as a water-alcohol mixture containing no more than 10-15 ng/g active form of the API.   
Excipients: Lactose monohydrate (lactose) - 0.267g (Eur. Ph.7, USP8 NF, BP9) 
 Microcrystalline cellulose - 0.03 g (Eur. Ph., USP NF, BP) 
                    Magnesium stearate - 0.003 g (Eur. Ph., USP NF, BP) 
Method of administration: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 4 
times daily (8 tablets/days). The tablets should be held in the mouth until dissolution, without 
meal.    
Dosage form: Tablets. 
Description: White to off-white, round, flat, scored on one side and beveled tablets. 
                                                 
7 Eur. Ph. European Pharmacopoeia (current edition) 
8 USP – current US Pharmacopeia 
9 EP – current European Pharmacopoeia 


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Storage conditions: Store in a place protected from light at a temperature below 25 С. Keep out 
of the reach of children. 
Group 4 
Name of the medicinal product: Placebo 
Active ingredient: NA 
Excipients: Lactose monohydrate (lactose) - 0.267 g (Eur. Ph4., USP5 NF, BP6) 
                    Microcrystalline cellulose - 0.03 g (Eur. Ph., USP NF, BP) 
                    Magnesium stearate - 0.003 g (Eur. Ph., USP NF, BP) 
Method of administration: Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 4 
times daily (8 tablets/days). The tablets should be held in the mouth until dissolution, without 
meal.    
Dosage form: Tablets. 
Description: White to off-white, round, flat, scored on one side and beveled tablets. 
Storage conditions: Store in a place protected from light at a temperature below 25 С. Keep out 
of the reach of children. 
Treatment duration 
Tenoten/Placebo treatment duration is 12 weeks.  
Observation period 
In total the patients will be monitored for 12 weeks.  
Symptomatic (Standard) treatment  
Subjects are allowed to receive medications used to treat coexisting diseases other than those 
representing exclusion criteria, except drugs listed in section "Forbidden concomitant therapy".  
Prohibited concomitant therapy 
Within 4 weeks prior to enrollment and during the study (beginning from signing informed 
consent form and initiation of screening) subjects are not allowed to receive any medications that 
may affect mental and emotional status (parenthesized is the ATC group): 
1. Psycholeptics (ATC group - N05), including antipsychotics, anxiolytics (tranquilizers), 
hypnotics and sedatives. 
2. Psychoanaleptics (ATC group – N06) including antidepressants, psychostimulants, 
nootropic drugs and their combinations. 
3. Antiepileptic drugs (ATC group – N03A). 
4. Anticholinergic drugs (ATC group − N04A). 
5. Dopaminergic drugs (ATC group − N04B). 


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6. Antiaddictive drugs (ATC group − N07В). 
7. Antihypoxic and antioxidant drugs (ethylmethylhydroxypyridine succinate, citicoline, etc.). 
8. Agents improving metabolism and energy supply to tissues, reducing tissue hypoxia 
(cytoflavin, corylip, eltacin, inosie, etc.). 
9. Sex hormones and reproductive function modulators (ATC group - G03). 
10. Vitamins B including combinations with other products (ATC group – А11Е). 
11. Materia Medica Holding products except for the ones assigned in this study. 
12. Homeopathic remedies. 
13. Herbal psychotropic agents (medicinal products and biologically active additives). 
14. Drugs known to have caused allergic reactions. 
15. Psychotherapeutic methods. 
16.  Physiotherapeutic treatments for psychoemotional state. 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING 
12 weeks 
Visit 1 
(Day 1) 
Visit 2 
(Week 4±3 days) 
Visit 4 
(Week 12±3 days) 
RANDOMIZATION 
Group 1: Tenoten 2 tablet 2 times a day for 12 weeks 
Group 2: Placebo 2 tablet 2 times a day for 12 weeks 
Group 3: Tenoten 2 tablet 4 times a day for 12 weeks 
Group 4: Placebo 2 tablet 4 times a day for 12 weeks 
Visit 3  
(Week 8±3 days) 
STUDY 
TERMINATION 


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6.
Antiaddictive drugs (ATC group − N07В). 
7. Antihypoxic and antioxidant drugs (ethylmethylhydroxypyridine succinate, citicoline, etc.). 
8. Agents improving metabolism and energy supply to tissues, reducing tissue hypoxia 
(cytoflavin, corylip, eltacin, inosie, etc.). 
9. Sex hormones and reproductive function modulators (ATC group - G03). 
10. Vitamins B including combinations with other products (ATC group – А11Е). 
11. Materia Medica Holding products except for the ones assigned in this study. 
12. Homeopathic remedies. 
13. Herbal psychotropic agents (medicinal products and biologically active additives). 
14. Drugs known to have caused allergic reactions. 
15. Psychotherapeutic methods. 
16.  Physiotherapeutic treatments for psychoemotional state. 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING 
12 weeks 
Visit 1 
(Day 1) 
Visit 2 
(Week 4±3 days) 
Visit 4 
(Week 12±3 days) 
RANDOMIZATION 
Group 1: Tenoten 2 tablet 2 times a day for 12 weeks 
Group 2: Placebo 2 tablet 2 times a day for 12 weeks 
Group 3: Tenoten 2 tablet 4 times a day for 12 weeks 
Group 4: Placebo 2 tablet 4 times a day for 12 weeks 
Visit 3  
(Week 8±3 days) 
STUDY 
TERMINATION 


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6.
Antiaddictive drugs (ATC group − N07В). 
7. Antihypoxic and antioxidant drugs (ethylmethylhydroxypyridine succinate, citicoline, etc.). 
8. Agents improving metabolism and energy supply to tissues, reducing tissue hypoxia 
(cytoflavin, corylip, eltacin, inosie, etc.). 
9. Sex hormones and reproductive function modulators (ATC group - G03). 
10. Vitamins B including combinations with other products (ATC group – А11Е). 
11. Materia Medica Holding products except for the ones assigned in this study. 
12. Homeopathic remedies. 
13. Herbal psychotropic agents (medicinal products and biologically active additives). 
14. Drugs known to have caused allergic reactions. 
15. Psychotherapeutic methods. 
16.  Physiotherapeutic treatments for psychoemotional state. 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING 
12 weeks 
Visit 1 
(Day 1) 
Visit 2 
(Week 4±3 days) 
Visit 4 
(Week 12±3 days) 
RANDOMIZATION 
Group 1: Tenoten 2 tablet 2 times a day for 12 weeks 
Group 2: Placebo 2 tablet 2 times a day for 12 weeks 
Group 3: Tenoten 2 tablet 4 times a day for 12 weeks 
Group 4: Placebo 2 tablet 4 times a day for 12 weeks 
Visit 3  
(Week 8±3 days) 
STUDY 
TERMINATION 


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Schedule of study procedures  
Procedure/visit 
Visit 1 
(Day 1) 
Visit 2 
(Week 4±3 
days) 
Visit 3 
(Week 8±3 
days) 
Visit 4 
(Week 12±3 
days) 
Informed consent  
+ 
 
 
 
Collection of complaints 
+ 
+ 
+ 
+ 
Medical history  
+ 
 
 
 
Physical examination 
+ 
+ 
+ 
+ 
HADS scale filling 
+ 
 
 
 
HAM-A scale filling 
+ 
+ 
+ 
+ 
EQ-5D-3L questionnaire filling 
+ 
 
 
+ 
Pregnancy test 
+ 
 
 
 
Concomitant therapy  
+ 
+ 
+ 
+ 
Inclusion/exclusion criteria 
+ 
 
 
 
Randomization and prescription of study therapy 
+ 
 
 
 
Study drug supply 
+ 
+ 
+ 
 
Study drug accountability, compliance assessment  
 
+ 
+ 
+ 
CGI scale filling 
 
 
 
+ 
Evaluation of treatment safety 
 
+ 
+ 
+ 
 
Statistical Analyses 
Samples  
Total set includes all the subjects who have signed ICF. This sample will consider all adverse 
events throughout the study, including those occurred prior to the study therapy.  
The sample including all subjects who received at least one dose of the study product to be used 
for analysis of the study treatment safety and tolerability (Safety population), as all adverse 
events identified after the study product administration will be recorded.  
Full Analysis Set This sample will consist of all enrolled subjects, except for those who met at 
least one of the following criteria:  
1) failure to meet inclusion/non-inclusion criteria;  
2) subject failing to take any dose of the study drug; 
3) absence of any data on the subject after the study drug administration.  
This was the best set for the Intention-to-treat method, so it will be used in the Intention-to-treat 
efficacy analysis of the test therapy. 
Per Protocol set. This sample includes all subjects who completed the therapy as per the study 
protocol, without any missing visits or major protocol deviations. This set will be used in the Per 
Protocol efficacy analysis of the test therapy. 
Mean value of the total set for the relevant day will be used to fill lacking/missing data.  


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Data treatment and all statistical calculations under the protocol will be made using SAS-9.4 
statistical software.10 
Evaluation of sample size 
The sample size was assessed in accordance with the following rules and assumptions: 
1. Statistical assumptions 
1.1 the power of statistical tests 'P = (1 − β)' is 80% (the probability of correct rejection of 
the null hypothesis is 0.8) 
1.2 the probability of type 1 error 'a' is less that 5% (the probability of false acceptance of 
the alternative hypothesis is less than 0.05); 
1.3 statistical criteria of intergroup comparisons will be two-sided, equivalence criterion - 
one-sided;  
1.4 calculation of sample size will be based on the assumptions on the expected effect 
declared in the primary efficacy criterion of the protocol; 
1.5 ratio between sample sizes of Tenoten and Placebo groups receiving similar dosing 
schemes will be 2:1 (1 Placebo patient - 2 Tenoten patients); 
1.6 statistical analysis will utilize pooled Placebo group including Placebo with dosing 
scheme 2 tablets 2 times and Placebo group with dosing scheme 4 tablets 2 times a day, 
as the differences between Placebo groups with different dosing schemes are not 
suggested; 
1.7 the study is supposed to use three groups of statistical hypotheses; for this purpose 
probability of type I error α will be corrected by introducing the relevant correction for 
three hypotheses (α=0.05/3); 
1.8 statistical hypotheses will be as follows:  
1.8.1. null and alternative hypotheses on superiority of the study product with dosing 
scheme 2 tablets 2 times a day: 
H0: Δµт1=Δµп 
Ha: Δµт1≠Δµп, 
where Δµт1 – mean reduction (initial – final score) of HAM-A total score in 
Tenoten group with dosing scheme 2 tablets 2 times a day, Δµп – mean 
reduction (initial – final score) of HAM-A total score in Placebo group; 
1.8.2. null and alternative hypotheses on superiority of the study product with dosing 
scheme 4 tablets 2 times a day: 
H0: Δµт2=Δµп 
                                                 
10 Holder of license: ООО "NPF "Materia Medica Holding", No. 70100045. 


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Ha: Δµт2≠Δµп, 
where Δµт2 – mean reduction (initial – final score) of HAM-A total score in 
Tenoten group with dosing scheme 4 tablets 2 times a day, Δµп – mean 
reduction (initial – final score) of HAM-A total score in Placebo group; 
1.8.3. null and alternative hypotheses on equivalence of the study product with dosing 
scheme 2 tablets 2 times a day with the study product with dosing scheme 4 
tablets 2 times a day: 
H0: |Δµт1 - Δµт2| ≥ δ 
Ha: |Δµт1 - Δµт2| < δ, 
where µт1 – mean reduction (initial – final score) of HAM-A total score in 
Tenoten group with dosing scheme 2 tablets 2 times a day, µт2 – mean reduction 
(initial – final score) of HAM-A total score in Tenoten group with dosing 
scheme 4 tablets 2 times a day, δ – equivalence margin accepted as 0.15*M 
where M – mean total population score at baseline; 
1.9 calculation of sample size for statistical criteria will be made using the group of 
formulas:  
1.9.1. calculation of sample size to evaluate superiority of the study product over 
placebo: 
, 
where n1, n2 is sample size for the study product group; ε – expected difference 
in mean reduction of the total score between Placebo and Tenoten groups; ϭ – 
standard deviation of mean reduction of the total score (calculated as standard 
deviation of difference between two uncorrelated random variables); zα/2 – 
tabular value of two-sided z-test for α value; zβ – tabular value of one-sided z-
test for β value; 
1.9.2. calculation of sample size for equivalence evaluation: 
, 
where n1, n2 is sample size for the study product group; ε – expected difference 
in mean reduction of the total score between Tenoten with dosing scheme 2 
tablets 2 times a day and Tenoten with dosing scheme 4 tablets 2 times a day; ϭ 
– standard deviation of mean reduction of the total score (calculated as standard 


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deviation of the difference between two uncorrelated random variables); zα – 
tabular value of z-test for α value; zβ – tabular value of z-test for β value, δ – 
equivalence margin accepted as 0.15*M where M – mean total population score 
at baseline;  
1.10 sample size will be determined using the formula:  
NPP=max{ ni, all pairs of interest (i)},  
where NPP – Per Protocol sample size; ni – result of calculation in cl. 1.6, i.e. the result 
for each of the three study hypotheses; 
1.11 final sample size will be determined using the formula:  
NT=NPP/(1-Cw),  
where NT – final sample size; NPP – result of calculation in cl. 1.7, i.e. the scheduled 
number of the subjects completing the study per protocol; Cw – withdrawal coefficient. 
2. Assumptions on expected clinical study effects: 
Mean HAM-A total score at 12 weeks of therapy in Tenoten groups with both dosing 
schemes is expected to reduced by at least 10 units, in Placebo - by no more than 6 units 
(difference – at least 4 points). Population variance for total score change was ϭ2=44 (based 
on preliminary analysis). 
HAM-A mean score changes after 12 weeks in Tenoten groups for both dosing schemes are 
expected to differ by less than 3 points. Population variance was accepted as ϭ2=44 (based on 
preliminary analysis). 
According to the statistical criteria and the assumptions above, for evaluation of differences in 
various dosing schemes, group size will be 103 subjects for Tenoten group (each dosing scheme) 
and 52 subjects for Placebo group (each dosing scheme). To evaluate superiority of the study 
product over placebo at different dosing schemes the group size will be 58 subjects for Tenoten 
group (each dosing scheme) and 26 subjects for Placebo group (each dosing scheme). The final 
sample size will be 103 subjects for Tenoten groups (each dosing scheme) and 52 subjects for 
Placebo group (each dosing scheme). 
Given potential withdrawal of at least 20% subjects during the study for various reasons, at least 
390 subjects will be required to sign informed consent.  
Statistical criteria  
All statistical calculations will be made using two groups of statistical criteria:  
 
parametric - to evaluate continuous and interval random values;  
 
nonparametric – to obtain: 
 evaluations of equality/inequality of proportions of the subjects upon their comparison 
for various visits,  


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 analysis of frequencies of the features compared, 
and 
 evaluation of continuous and interval random values in case of non-compliance with 
normal random distribution. 
Parametric criteria 
Prior to analysis using parametric statistics, data samples under comparison will be tested for 
normality (the Kolmogorov-Smirnov test). Data normalizing transformations (e.g. Box-Cox, 
Yeo-Johnson etc.) would be applied if necessary. 
The following parameters and approaches are to be used: 
1. To evaluate the differences in continuous variables obtained in one group at two different 
visits – Student’s test for matched samples. 
2. To evaluate time changes in parameters compared - analysis of variance (ANOVA) or 
modified repeated measures covariance (ANCOVA).  
3. In case of multiple comparisons of the groups various corrections for multiplicity will be 
used, e.g. Dunnett, Tukey, Scheffe, Holm adapted test, etc.  
4. Generalized Linear Models and/or Mixed Linear Models will be used in case of abnormal 
data distribution.  
5. Selection of the type of distribution, specification of factor and covariance structures of the 
model will be made using fit-statistics such as AIC (Akaike information criterion). 
The following SAS software programs are supposed to be applied to the above listed tests and 
techniques:  
 UNIVARIATE: normality verification of the distributions under comparison; 
 CORR, MEANS - calculation of descriptive statistics 
 TTEST – Student’s test with all modifications;  
 GLM – generalized linear models for analysis of time changes (ANOVA, ANCOVA); 
 GENMOD – generalized linear models. 
 MIXED – mixed linear models. 
Non-parametric criteria 
Below are potential types of comparisons with relevant criteria: 
1. To evaluate time changes in the parameters compared – Friedman test, nonparametric 
analogue of repeated measures analysis of variance. 
2. For frequency analysis of contingency tables 2×2 – χ2 (if the frequency under comparison > 
5) or exact Fisher’s test (if one of the frequencies under comparison < 5).  
3. Cochran-Mantel-Haenszel test (modified χ2 test for multiple comparisons) – to perform 
frequency analysis based on independent strata.  


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4. For frequency analysis of data on presence/absence of an event or outcome during repeated 
measurements (contingency tables with dependent strata) – survival analysis.  
To perform the above-mentioned nonparametric statistical analysis the following SAS 
procedures are to be used:  
 FREQ – Friedman test, χ2 test and/or exact Fisher’s test; Cochran-Mantel-Haenszel test. 
 LIFETEST – survival analysis.  
 NPAR1WAY - Mann-Whitney test. 
Safety parameters  
Adverse events recorded during the study will be grouped into frequency tables by severity, 
seriousness and relationship with the study drug. 
Data presentation 
Descriptive statistics will be provided for each study continuous / interval variable. Numerical 
data will be presented by mean, standard deviation, min and max values. Comparisons 
suggesting statistical conclusion will have the relevant confidence intervals. Outliers will be 
analyzed individually. The data will be grouped by visits. The categorical variables will be 
presented as frequency tables by visits.