Conditions: Attention Deficit Hyperactivity Disorder (ADHD) Anxiety Disorders and Symptoms
Keywords: Mexidol hyperactivity ADHD oppositional defiant disorder inattention Neurodevelopmental disorders Hyperactive behavior Impulsive behavior anxiety
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 333
Healthy volunteers: no

Brief summary:
The primary objective of this study was to evaluate the efficacy and safety of Mexidol® film-coated tablets (125 mg) compared to a placebo in children aged 6 to 12 years with Attention Deficit Hyperactivity Disorder (ADHD). This multicenter, prospective, double-blind, randomized trial included 333 children who met the diagnostic criteria established by the International Classification of Diseases (ICD-10) and the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Participants received either Mexidol or placebo for 42 days, and various efficacy and safety parameters were assessed.

Detailed description:

Arms:
arm 1: Participants received Mexidol 125 mg 1 tablet orally once a day and Mexidol Placebo matching Mexidol 125 mg 1 tablet orally once a day for 42 days. arm 2: Participants received Mexidol 125 mg 1 tablet orally twice a day for 42 days. arm 3: Participants received Mexidol Placebo matching Mexidol 125 mg 1 tablet orally twice a day for 42 days.

Interventions: intervention 1: Mexidol intervention 2: Placebo intervention 3: Mexidol + Placebo
Intervention descriptions: intervention 1: 125 mg tablets intervention 2: Placebo tablets intervention 3: Combination of Mexidol and Placebo

Protocol document:
Prot_000.pdf: 
 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 
 
A multicentre, double-blind, randomised, placebo-controlled 
clinical trial in three parallel groups to evaluate the safety and 
efficacy of Mexidol® film-coated tablets, 125 mg (RPC Pharmasoft 
LLC, Russia) in the treatment of attention deficit hyperactivity 
disorder (ADHD) in children aged 6-12 years under different 
dosing regimens (MEGA). 
 
 
 
 
 
NCT Number: NCT06854601 
 
 
Pharmasoft 
October 15, 2019 
 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
2 
Protocol version 4.0 dated 15.10.2019. 
 
 
CLINICAL TRIAL PROTOCOL 
A multicentre, double-blind, randomised, placebo-controlled clinical trial in three parallel 
groups to evaluate the safety and efficacy of Mexidol® film-coated tablets, 125 mg (RPC 
Pharmasoft LLC, Russia) in the treatment of attention deficit hyperactivity disorder (ADHD) 
in children aged 6-12 years under different dosing regimens (MEGA). 
Protocol No. 
PHS-ADHD-002-MEX-TAB 
Version: 
4.0 dated 15.10.2019. 
Development Phase: 
II-III 
Sponsor: 
Limited Liability Company "Research and Production 
Company "PHARMASOFT" / RPC PHARMASOFT 
LLC Legal address: Russian Federation, 115407, 
Moscow, 41, Sudostroitelnaya St., floor 1, room 12 
Postal address: Russian Federation, 109544, Moscow, 
Enthusiastov Boulevard, 2 
Tel./fax: +7 (495) 626 47 55 
CONFIDENTIAL INFORMATION 
The information in this document is strictly confidential and can only be disclosed by 
investigators, potential investigators and Local Ethical Committees. The information contained 
in this document cannot be disclosed except to the extent necessary to obtain informed consent 
from potential trial subjects 
 
 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
3 
Protocol version 4.0 dated 15.10.2019. 
 
 
TRIAL SPONSOR PROTOCOL APPROVAL PAGE 
Trial Title 
A multicentre, double-blind, randomised, placebo-
controlled clinical trial in three parallel groups to evaluate 
the safety and efficacy of Mexidol® film-coated tablets, 
125 mg (Pharmasoft, Russia) in the treatment of attention 
deficit hyperactivity disorder (ADHD) in children aged 6-
12 years under different dosing regimens (MEGA). 
Protocol 
PHS-ADHD-002-MEX-TAB 
version 
4.0 
dated 
15.10.2019. 
Agreed by 
Tatyana Anatolievna Mityushkina 
 
Medical Director 
 
RPC PHARMASOFT LLC  
 
Tel: +7 (495) 626 47 55 ext. 140 
 
e-mail: mityushkina_t@pharmasoft.ru 
 
 
Date   
Signature 
 
 
 
 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
4 
Protocol version 4.0 dated 15.10.2019. 
 
 
CRO PROTOCOL APPROVAL PAGE 
Trial Title 
A multicentre, double-blind, randomised, placebo-
controlled clinical trial in three parallel groups to evaluate 
the safety and efficacy of Mexidol® film-coated tablets, 
125 mg (Pharmasoft, Russia) in the treatment of attention 
deficit hyperactivity disorder (ADHD) in children aged 6-
12 years under different dosing regimens (MEGA). 
Protocol 
PHS-ADHD-002-MEX-TAB 
version 
4.0 
dated 
15.10.2019. 
Agreed by 
Nikolay Olegovich Pozdnyakov 
 
Director 
 
ClinPharmDevelopment LLC 
 
Russia, 150031, Yaroslavl, Uglichskaya str. 68, office. 1. 
 
Tel: +7 (4852) 59-47-79, http://www.cphd.ru 
 
 
Date  
Signature_  
 
 
 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
5 
Protocol version 4.0 dated 15.10.2019. 
 
 
Approval and signature of the Principal Investigator 
 
(Name of principal investigator) 
A multicentre, double-blind, randomised, placebo-controlled clinical trial in three parallel 
groups to evaluate the safety and efficacy of Mexidol® film-coated tablets, 125 mg (Pharmasoft, 
Russia) in the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-
12 years under different dosing regimens (MEGA). 
Protocol version 4.0 dated 15.10.2019. 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical trial in accordance with this protocol, current principles of Good Clinical Practice, local 
laws and requirements. 
I will ensure that all trial assistants and members of the trial team read and understand all aspects 
of the protocol. 
I have received and read all the information provided to me relevant to the trial. 
The objectives and contents of this protocol and the results obtained will be considered 
confidential and will not be made available to third parties without the prior consent of the 
Sponsor. 
Site Name: 
 
 
Principal Investigator: 
 
 
FULL NAME 
 
 
 
 
 
 
Signature 
 
date 
 
 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
Table of contents 
TRIAL SPONSOR PROTOCOL APPROVAL PAGE ........................................................ 3 
TRIAL INITIATOR PROTOCOL APPROVAL PAGE ..................................................... 4 
LIST OF ABBREVIATIONS ................................................................................................ 10 
1. 
GENERAL INFORMATION ................................................................................... 12 
1.1. Protocol summary .................................................................................................... 12 
1.2. Schedule of trial visits and procedures .................................................................. 19 
1.3. Trial Sponsor ............................................................................................................ 22 
1.4. Organizer of the trial ............................................................................................... 22 
1.5. Clinical Research Associate (CRA) .................. Ошибка! Закладка не определена. 
1.6. Person authorised by the Sponsor to sign the protocol and amendments thereto
 
22 
1.7. Clinical laboratories and other organizations relevant to the trial ..................... 23 
1.8. Investigators and investigational sites .................................................................... 23 
2. 
TRIAL RATIONALE ................................................................................................ 23 
2.1. Name and description of the investigational products ......................................... 25 
2.1.1. 
Investigational product: ................................................................................ 25 
2.1.2. 
Placebo ......................................................................................................... 29 
2.2. Summary of results of preclinical and clinical studies ......................................... 29 
2.3. Summary of known and potential risks and benefits to patients ........................ 32 
2.4. Description and justification of the method of administration, dosage, regimen 
and course of treatment .................................................................................................... 32 
2.5. Conditions of the trial .............................................................................................. 35 
2.6. Description of the trial population ......................................................................... 35 
3. 
TRIAL AIMS AND OBJECTIVES .......................................................................... 36 
3.1. Trial aimes ................................................................................................................ 36 
3.2. Trial objectives ......................................................................................................... 36 
4. 
TRIAL DESIGN ......................................................................................................... 36 
4.1. Efficacy criteria ........................................................................................................ 36 
4.2. Trial design ............................................................................................................... 37 
4.3. Description of measures aimed at minimising/eliminating subjectivity ............. 38 
4.3.1. 
Randomisation .............................................................................................. 38 
4.3.2. 
Blinding ........................................................................................................ 39 
4.4. Investigational products, dosages, routes of administration, packaging, labelling
 
39 
4.4.1. 
Information on Investigational products ...................................................... 39 
4.4.2. 
Production, packaging and labelling ............................................................ 40 
4.4.3. 
Dosing in patients ......................................................................................... 41 
4.5. Expected duration of patient participation in the trial, description of Trial 
periods and procedures ..................................................................................................... 42 
4.5.1. 
Trial duration ................................................................................................ 42 
4.5.2. 
Beginning of the Trial. Visit 1 (Day -14 -1) Screening. .............................. 42 
4.5.3. 
Visit 2 (Day 1). Randomization. Initiation of therapy. ................................ 43 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
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Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
4.5.4. 
Visit 3 (Day 14±2), telephone contact ......................................................... 44 
4.5.5. 
Visit 4 (Day 28±2), telephone contact ......................................................... 44 
4.5.6. 
Visit 5 (Day 43+1). End of therapy. ............................................................. 44 
4.5.7. 
Visit 6 (Day 50+3). Follow-up ..................................................................... 45 
4.5.8. 
Unscheduled visits ........................................................................................ 45 
4.5.9. 
Examination in case of early termination ..................................................... 45 
4.5.10. 
Completion of the trial ................................................................................. 45 
4.6. Description of the trial procedures ......................................................................... 45 
4.6.1. 
Collection of demographic data and anamnesis, anthropometry ................. 45 
4.6.2. 
Physical examination .................................................................................... 46 
4.6.3. 
Vital signs ..................................................................................................... 46 
4.6.4. 
Neurological status ....................................................................................... 46 
4.6.5. 
Anthropometry ............................................................................................. 47 
4.6.6. 
Patient diary .................................................................................................. 47 
4.6.7. 
Completion of questionnaires ....................................................................... 47 
4.6.8. 
Laboratory tests ............................................................................................ 47 
4.7. Termination of the trial ........................................................................................... 48 
4.8. Accounting for investigational products ................................................................ 49 
4.9. Storage of randomization codes and procedure for their disclosure .................. 50 
4.10. Data recorded directly in the eCRF ....................................................................... 51 
5. 
PATIENT SELECTION AND EXCLUSION ......................................................... 51 
5.1. Inclusion criteria ...................................................................................................... 51 
5.2. Inclusion criteria ...................................................................................................... 52 
5.3. Patient exclusion criteria ......................................................................................... 52 
5.4. Rules for participation in the trial .......................................................................... 53 
5.5. Collection of data from trial subjects who has early discontinued their 
participation in the trial .................................................................................................... 53 
5.6. Substitution procedure ............................................................................................ 54 
5.7. Follow-up of patients who early terminated their participation in the trial ...... 54 
5.8. Documentation of data from patients who failed screened .................................. 54 
6. 
TREATMENT ............................................................................................................ 54 
6.1. Use of Investigational products ............................................................................... 54 
6.2. Allowed and prohibited concomitant therapies .................................................... 54 
6.2.1. 
Psycho-correctional therapy ......................................................................... 54 
6.2.2. 
Allowed concomitant therapy ...................................................................... 55 
6.2.3. 
Prohibited concomitant therapy ................................................................... 55 
6.3. Methods for monitoring compliance with stuudy procedures ............................. 56 
7. 
EFFICACY EVALUATION ..................................................................................... 56 
7.1. Efficacy criteria ........................................................................................................ 56 
7.2. Methods and timing for estimating efficacy parameters ...................................... 56 
8. 
SAFETY ASSESSMENT ........................................................................................... 57 
8.1. Safety parameters .................................................................................................... 57 
8.2. Adverse events .......................................................................................................... 57 
8.2.1. 
Definition of adverse events ......................................................................... 57 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
8.2.2. 
Reporting adverse events ............................................................................. 57 
8.2.3. 
Determination of adverse event parameters ................................................. 58 
8.3. Continued follow-up period for the AE ................................................................. 61 
8.4. SAE reporting ........................................................................................................... 62 
9. 
STATISTICS .............................................................................................................. 63 
9.1. Description of statistical methods ........................................................................... 63 
9.2. Planned number of patients .................................................................................... 64 
9.3. Applied significance level ........................................................................................ 66 
9.4. Criteria for trial termination .................................................................................. 66 
9.5. Procedures for recording missing, unanalysable and questionable data ............ 66 
9.6. Procedures for reporting any deviations from the original statistical plan ........ 66 
9.7. Selection of data for statistical analysis .................................................................. 66 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ........................... 67 
10.1. Protocol compliance ................................................................................................. 67 
10.2. Deviations from protocol ......................................................................................... 67 
10.3. Confidentiality of patient data ................................................................................ 67 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................... 68 
11.1. Selection of investigational sites .............................................................................. 68 
11.2. Trial conduction ....................................................................................................... 68 
11.3. Monitoring ................................................................................................................ 68 
11.4. Data identification .................................................................................................... 68 
11.5. Audit and inspection ................................................................................................ 69 
12. 
ETHICAL AND LEGAL REQUIREMENTS ......................................................... 69 
12.1. General requirements .............................................................................................. 69 
12.2. Ethical review ........................................................................................................... 69 
12.3. Regulatory permission ............................................................................................. 70 
12.4. Informed consent ...................................................................................................... 70 
13. 
DATA MANAGEMENT AND RECORD KEEPING ............................................ 71 
13.1. Data processing ........................................................................................................ 71 
13.2. Data storage .............................................................................................................. 71 
14. 
FINANCING AND INSURANCE ............................................................................ 71 
15. 
USE OF INFORMATION AND PUBLICATIONS ................................................ 72 
16. 
FINAL REPORT ........................................................................................................ 72 
17. 
APPENDICES ............................................................................................................ 72 
17.1. SNAP-IV scale .......................................................................................................... 72 
17.2. Child Anxiety Scale (SCAS) - parental assessment ............................................... 76 
17.3. ADHD Rating Scale-IV ............................................................................................ 78 
17.4. Clinical Global Impressions-ADHD-Severity - CGI-ADHD-S ............................ 78 
17.5. Clinical Global Impressions Scale - Improvement (CGI-I) ................................. 79 
17.6. Patient diary ............................................................................................................. 80 
17.7. Assessment card for a child/adolescent with headache. ....................................... 85 
17.8. PedMIDAS questionnaire (to be completed only if the child has a headache) ... 86 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
18. 
REFERENCE LIST ................................................................................................... 90 
 
 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
LIST OF ABBREVIATIONS 
BD 
blood pressure 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ULN 
upper limit of normal 
HIV 
human immunodeficiency virus 
GABA 
gamma-aminobutyric acid 
CI 
Confidence Interval 
BMI 
Body Mass Index 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organisation 
LEC 
Local Ethics Committee 
mg 
milligram 
ICD-10 
International Classification of Diseases, 10th revision 
INN 
international non-proprietary name 
AE 
Adverse Event 
ADHD 
Attention Deficit Hyperactivity Disorder 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SEM 
standard error of the mean 
RR 
respiratory rate 
HR 
heart rate 
QPPV 
Qualified Person Responsible for Pharmacovigilance 
ADHD Rating 
Scale-IV 
Attention Deficit Hyperactivity Disorder rating scale 
CGI-ADHD-S ADHD severity rating scale for overall clinical impression of ADHD severity 
CGI-I 
Clinical Global Impression-Improvement 
CV 
coefficient of variation 
DSM-IV-TR 
Diagnostic and Statistical Manual of Mental Disorders IV text revision 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders 5 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IWRS 
Interactive Web Response System 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
M 
mean 
mITT 
modified intent-to-treat 
PP 
per protocol 
SNAP-IV 
Swanson, Nolan and Pelham Teacher and Parent Rating Scale 
SCAS 
Spence Children's Anxiety Scale 
TRR1/2 
drug elimination half-life 
 
 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
1. GENERAL INFORMATION 
1.1. Protocol summary 
Trial Title: 
A multicentre, double-blind, randomised, placebo-controlled 
clinical trial in three parallel groups to evaluate the safety and 
efficacy of Mexidol® film-coated tablets, 125 mg (RPC Pharmasoft 
LLC, Russia) in the treatment of attention deficit hyperactivity 
disorder (ADHD) in children aged 6-12 years under different dosing 
regimens (MEGA). 
Estimated trial period estimated trial start date: February 2019. 
estimated trial completion date: June 2020. 
Trial purpose: 
To evaluate the safety and efficacy of Mexidol® film-coated tablets, 
125 mg (PRC Pharmasoft LLC, Russia) vs. placebo in children aged 
6 to 12 years inclusive with attention deficit hyperactivity disorder 
(ADHD). 
Trial objectives: 
Primary objective: 
1. To evaluate the efficacy of Mexidol® film-coated tablets, 125 
mg (PRC PHARMASOFT LLC, Russia) vs. placebo after 6 
weeks from the beginning of therapy in relation to the average 
change in the total score on the "inattention" and 
"hyperactivity/impulsivity" subscales of the SNAP-IV scale 
when administered at a dose of 125 mg OD. 
2. To evaluate the efficacy of Mexidol® film-coated tablets, 125 
mg (PRC PHARMASOFT LLC, Russia) vs. placebo after 6 
weeks from the beginning of therapy in relation to the mean 
change 
in 
the 
total 
score 
on 
the 
"inattention", 
"hyperactivity/impulsivity" subscales of the SNAP-IV scale 
when administered at a dose of 125 mg BID. 
Secondary objectives: 
1. 
To evaluate the efficacy of Mexidol® film-coated tablets 125 
mg (PRC PHARMASOFT LLC, Russia) vs. placebo after 6 
weeks from the beginning of therapy when administered at a 
dose of 125 mg OD and 125 mg BID on the basis of the 
following parameters: 
a. 
mean change on the SNAP-IV subscale - inattention; 
b. mean 
change 
on 
SNAP-IV 
subscale 
- 
hyperactivity/impulsivity; 
c. 
mean change on the SNAP-IV subscale - 
oppositional defiant disorder; 
d. mean change on the SNAP-IV subscale - Conners' 
clinical index; 
e. 
mean change on the Spence Children's Anxiety Scale 
(SCAS); 
f. 
mean change on ADHD Rating Scale-IV;  


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
g. mean change on the Clinical Global Impressions-
ADHD-Severity (CGI-ADHD-S) scale; 
h. assessment of the dynamics of PedMIDAS 
questionnaire scores (number of days with restriction 
of daily activity due to headache, number of days 
with headache, average headache severity and 
maximum headache severity in scores); 
i. 
The 
Clinical 
Global 
Impressions 
Scale 
- 
Improvement (CGI-I) score. 
2. 
To evaluate the safety of Mexidol® film-coated tablets, 125 
mg (RPC PHARMASOFT LLC, Russia) vs. placebo based 
on the assessment of frequency, severity and nature of 
adverse events. 
Trial design: 
A multicentre, prospective, double-blind, randomised in three 
parallel groups with a 1:1:1 ratio trial to evaluate the efficacy and 
safety of Mexidol® film-coated tablets, 125 mg using placebo 
controls. 
Randomisation 
method 
Patient randomisation will be performed at Visit 2 with a 1:1:1:1 
patient allocation using the online IWRS (Interactive Web Response 
System). A patient randomisation number will be assigned to the 
trial subject in the order in which they access the IWRS system. 
Planned number of 
patients: 
The trial is planned to enrol 417 patients, from which 333 patients 
will be randomised, in order to obtain 300 completed cases (100 in 
each of the three groups). 
Patient population: 
Outpatients, boys and girls, aged 6 to 12 years (inclusive) with a 
diagnosis of attention deficit hyperactivity disorder, established 
according to the criteria of the 10th revision of the International 
Classification of Diseases (ICD-10) (F90.0) and the Diagnostic and 
Statistical Manual of Mental Disorders 5th edition (DSM-5) by a 
psychiatrist or neurologist. 
Trial duration: 
The duration of treatment - 42 days and the duration of the follow-
up period - 7 days. 
Screening and randomisation can be carried out on the same day 
provided all screening procedures are performed and results are 
available. 
The total minimum duration of patient participation in the trial will 
be 49 full days: a screening and therapy period of 42 days plus a 
follow-up period of 7 days. 
The total maximum duration of patient participation in the trial will 
be 67 days: a screening period of 14 days plus a therapy period of 
42 days plus a follow-up period of 7 days, plus a window for the 
end-of-therapy visit (Visit 5) of 1 day and the follow-up visit (Visit 
6) of 3 days. 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
Diagnosis and basic 
selection criteria: 
Inclusion criteria: 
1. 
Signed written informed consent for participation in the trial 
from the patient's parents. 
2. 
Patients are boys and girls, aged 6 to 12 years inclusive at the 
time of signing the informed consent. 
3. 
Child is being raised by the father and/or mother. 
4. 
Child's attendance at a mainstream pre-school or school. 
5. 
Diagnosis of attention deficit hyperactivity disorder 
established according to ICD-10 and DSM-5 criteria by a 
psychiatrist or neurologist, namely: 
According to the DSM-5 
a. 
6 or more symptoms of inattention persisting for at least 
6 months and/or; 
b. 6 or more symptoms of hyperactivity and impulsivity 
persisting for at least 6 months; 
c. 
symptoms are present in at least two areas of activity 
(preschool or school and home). 
and/or 
According to the ICD-10 
d. at least 6 symptoms of attention deficit disorder; 
e. 
at least 3 symptoms of hyperactivity; 
f. 
at least 1 symptom of impulsivity; 
g. stable for at least 6 months. 
6. 
Moderate severity of illness according to the General 
Clinical Impression of ADHD Severity Scale (CGI-ADHD-
S), not requiring hospitalisation for treatment. 
7. 
Presence of no more than two comorbid disorders that do not, 
in the opinion of the investigator, require additional 
pharmacotherapy at the time of the trial. 
Non-inclusion criteria: 
1. 
Hypersensitivity 
to 
the 
active 
substance 
of 
the 
investigational 
product 
(ethylmethylhydroxypyridine 
succinate) and/or other components of the product. 
2. 
Liver dysfunction: ALT and/or AST ≥2.5 upper limit of 
normal (ULN) by screening tests. 
3. 
Renal function disorders: blood creatinine ≥1.5 ULN by 
screening tests. 
4. 
Intracranial pathology (including but not limited to: 
intracranial haemorrhage, tumour, infection, history of head 
injury, excluding concussion). 
5. 
Associated autism spectrum disorders, Asperger's syndrome. 
6. 
Mental retardation of any degree. 
7. 
Other mental illnesses, except behavioural disorders (ICD-
10 code F91). 
8. 
Failure to withdraw psychotropic medications used to treat 


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Protocol version 4.0 dated 15.10.2019. 
 
 
ADHD. 
9. 
Other somatic and/or neurological diseases, the treatment of 
which requires the use of drugs that may affect the efficacy 
of the Investigational product (including but not limited to: 
epilepsy, depression). 
10. 
Administration 
of 
nootropics, 
vasoactive 
drugs, 
neuroprotectants, antioxidants, metabolic drugs for 7 days or 
5 half-lives (whichever is longer) before randomisation. 
11. 
Presence of any history of cancer within 5 years prior to the 
screening visit. 
12. 
Participation in any other clinical trial of mrdicinal products 
and/or medical devices within 3 months prior to the 
screening visit and/or 5 half-lives, whichever is longer. 
13. 
Inability or impossibility to follow the requirements of the 
protocol, including for physical, mental or social reasons, in 
the opinion of the investigator. 
14. 
Lactose intolerance, lactase deficiency, glucose-galactose 
malabsorption. 
Early termination criteria: 
1. 
Withdrawal of informed consent by parents 
of the patient. 
2. 
Adverse events requiring cancellation of the investigational 
product. 
3. 
Need for drugs that are prohibited under the terms of the 
protocol. 
4. 
Continued participation in the trial is contrary to the patient's 
best interests. 
5. 
Discontinuation of the trial by the Sponsor. 
6. 
Discontinuation of the trial by regulatory authorities. 
7. 
Loss of communication with the patient. 
Trial 
procedures/frequency: 
See the Schedule of Trial Visits and Procedures 
Investigational 
product, dose and 
method of 
administration: 
Investigational product + Placebo (group 1) 
Mexidol® (ethylmethylhydroxypyridine succinate) film-coated 
tablets, 125 mg (RPC PHARMASOFT LLC, Russia). 
Method of administration: the drug will be administered orally 1 
tablet OD. 
Group 1 patients will additionally take 1 placebo tablet. The interval 
between doses of Mexidol and placebo - 12±1 hours. Thus, a single 
dosing regimen for all three groups - 1 tablet BID to maintain 
double-blinding of the prescribed therapy - will be followed. 
Duration of therapy: 42 days. 


RPC PHARMASOFT LLC  
Clinical Trial Protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
Investigational product (group 2) 
Mexidol® (ethylmethylhydroxypyridine succinate) film-coated 
tablets, 125 mg (RPC PHARMASOFT LLC, Russia). 
Method of administration: the drug will be administered orally 1 
tablet BID. 
Duration of therapy: 42 days. 
Placebo, dose and 
method of 
administration: 
Placebo (group 3) (RPC PHARMASOFT LLC, Russia). 
Method of administration: placebo will be administered orally 1 
tablet BID. 
Duration of therapy: 42 days. 
Prohibited therapy 
1) neuroprotectants, antioxidants, metabolic drugs, vasoactive and 
nootropic agents, including but not limited to: actovegin, aminalon, 
biotredine, vasobral, gliatilin, glycine, dimefosfon, instenon, 
cohitum, cortexin, kudesan, minisem, noben, pantogam, picamilon, 
piracetam, tenoten for children, phenibut, cerebrolysin, cinnarizine, 
encephabol. 
2) other agents affecting the central nervous system: ginkgo biloba 
leaf extract, atomoxetine, tranquillisers and antidepressants. 
Efficacy evaluation: 
Evaluation of the efficacy of therapy will be based on primary and 
secondary efficacy criteria. 
Primary efficacy criterion: 
1. 
Mean change in the total score on the inattention and 
hyperactivity/impulsivity subscales of the SNAP-IV scale 
after 6 weeks of therapy vs. baseline. 
Secondary efficacy criteria: 
1. 
mean change on the SNAP-IV inattention subscale after 6 
weeks of therapy vs. baseline 
2. 
mean 
change 
on 
SNAP-IV 
subscale 
hyperactivity/impulsivity after 6 weeks of therapy vs. 
baseline 
3. 
mean change on the SNAP-IV subscale, oppositional defiant 
disorder, after 6 weeks of therapy vs. baseline; 
4. 
mean change on the SNAP-IV subscale - Conners' clinical 
index; 
5. 
mean change on the Spence children's anxiety scale (SCAS) 
after 6 weeks of therapy vs. baseline; 
6. 
mean change on ADHD Rating Scale-IV scores after 6 weeks 


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of therapy vs. baseline; 
7. 
clinical Global Impressions-ADHD-Severity (CGI-ADHD-
S) scale score after 6 weeks of therapy vs. baseline; 
8. 
assessment of the dynamics of PedMIDAS questionnaire 
scores (number of days with restriction of daily activity due 
to headache, number of days with headache, average 
headache severity and maximum headache severity in 
scores); 
9. 
Clinical Global Impressions Scale - Improvement (CGI-I) 
score after 6 weeks of therapy vs. baseline. 
Safety evaluation: 
The safety of investigational product administration will be 
evaluated using the following criteria: 
1. Number of adverse events (AEs) and serious AEs (SAEs). 
2. Frequency and severity of AE/SAE associated with 
investigational product/placebo. 
Safety assessment will be based on patient and/or patient's parents 
interview, physical examination findings (including assessment of 
vital signs: BP, HR, RR), data from the Patient Diary and results of 
laboratory and instrumental examination (clinical and biochemical 
blood tests). 
Statistical methods: 
Statistical analysis 
Statistical analysis populations: 
1) the safety population will include all randomised patients 
who have taken at least one dose of Investigational product; 
2) the full analysis set (FAS) population will include all 
randomised patients who have taken at least one dose of 
Investigational product and who have an assessment of 
response to therapy after 6 weeks of therapy. This will be the 
main population for efficacy analyses; 
3) PP (per protocol population) is a subgroup of the FAS 
population that will include patients in the absence of 
significant 
protocol 
deviations 
with 
respect 
to 
inclusion/exclusion criteria, adherence to therapy, and use of 
concomitant therapy. This will be an additional population 
used for efficacy analyses. 
Descriptive statistics for data whose distribution follows the law of 
normal distribution will be presented using the arithmetic mean and 
standard deviation. For otherwise distributed data, descriptive 
statistics will be presented using non-parametric measures 
(median/mode, quartiles). 
Two-sided confidence intervals will be used to assess treatment 
efficacy (primary and secondary efficacy criteria). A conclusion on 


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superiority can be made if the upper bound of the two-sided 95% 
confidence interval for the difference in mean changes in SNAP 
scores of Mexidol® vs. placebo is negative. 
For primary and secondary efficacy criteria, differences will be 
considered statistically significant at the p-value level of <0.05. 
The χ-square test or Fisher's exact test will be used to assess 
differences in event rates. 
The χ-square test or Fisher's exact test will also be used to assess 
differences in patient adherence. 
Safety parameters will be tabulated for all patients who received 
investigational medicinal product. Comparisons of safety profiles 
between trial groups will be made using the χ-square test (for 
qualitative data) and the t-test for data whose distribution follows 
the law of normal distribution, or its non-parametric analogue (for 
data whose distribution does not follow the law of normal 
distribution). 
AEs will be coded per MedDRA and categorised using Organ 
System Classes and preferred term. The protocol provides for the 
recording of all AEs that occur to the patient after the first 
administration of the trial therapy and until the end of the patient's 
participation in the trial. 
During screening, information about medical adverse events will be 
attributed to the patient's medical history (pre-existing/concomitant 
conditions). 
The planned trial will record all deviations in the health status of 
patients (based on the results of physical examination, laboratory 
and instrumental methods of investigation) from the data obtained 
at the Screening and from the accepted reference values. 
After obtaining the necessary information, the investigating 
physician will categorise the patient's condition as 'normal', 
'clinically insignificant abnormalities' or 'clinically significant 
abnormalities'. In case the abnormalities detected during the trial 
have not been previously reported, or there is an aggravation of the 
patient's condition vs. the data staffobtained at Screening, the 
detected abnormalities will be classified as AEs. 
 


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1.2.  Schedule of trial visits and procedures 
 
Procedures 
 
Visits 
 
 
Therapy 
Follow-up 
 
Screening 
Initiation of 
therapy 
Telephone contact1 
Telephone contact2 
End of therapy 
 
Day 
-14-1 
1 
14±2 
28±2 
43+1 
50+3 
Visit number 
1 
2 
3 
4 
5 
6 
Informed consent 
Х 
 
 
 
 
 
Demographic data and history 
Х 
 
 
 
 
 
Measurement of height, body 
weight, BMI calculation 
Х 
 
 
 
 
 
Registration of previous therapy 
Х 
 
 
 
 
 
Registration of previous pathology 
Х 
 
 
 
 
 
Registration of comorbidities 
Х 
 
 
 
 
 
Registration of concomitant therapy 
Х 
Х 
Х 
Х 
Х 
Х 
Inclusion / non-inclusion criteria 
Х 
Х 
 
 
 
 
Exclusion criteria 
 
Х 
 
 
Х 
 
Physical examination with 
measurement of BP, HR, and RR 
Х 
 
 
 
Х 
Х 
Complete Blood Count3 
Х 
 
 
 
Х 
 
Biochemical blood test4 
Х 
 
 
 
Х 
 
__________________ 
1 During telephone contact, the investigator should obtain information about the general tolerability of treatment, the occurrence of AEs, prescribed concomitant medications, and remind about 
compliance with the therapy regimen 
2 During the telephone contact, the investigator should obtain information about general tolerability of treatment, occurrence of NSAIDs, prescribed concomitant medications, ADHD Rating Scale IV 
score, and remind about adherence to the therapy regimen 
3 Haemoglobin; haematocrit; red blood cell count; platelet count; white blood cell count and complete white blood cell count; ESR 
4 Total protein; albumin; glucose; ALT; AST; total bilirubin, alkaline phosphatase (ALP), amylase, creatinine 


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Procedures 
 
Visits 
 
 
Therapy 
Follow-up 
 
Screening 
Initiation of 
therapy 
Telephone contact1 
Telephone contact2 
End of therapy 
 
Day 
-14-1 
1 
14±2 
28±2 
43+1 
50+3 
Visit number 
1 
2 
3 
4 
5 
6 
Clinical urinalysis5 
Х 
 
 
 
Х 
 
AE registration 
 
Х 
Х 
Х 
Х 
Х 
Neurological status 
Х 
 
 
 
Х 
Х 
SNAP-IV score 
Х 
Х 
 
 
Х 
 
Randomization 
 
Х 
 
 
 
 
SCAS score 
 
Х 
 
 
Х 
 
ADHD Rating Scale IV score 
 
Х 
 
Х 
Х 
 
CGI-ADHD-S score 
Х 
Х 
 
 
Х 
 
CGI-I score 
 
 
 
 
Х 
 
PedMIDAS questionnaire score6 
 
Х 
 
 
Х 
 
Completion of an assessment card 
for a child/adolescent with 
headache7 
 
Х 
 
 
Х 
 
Dispensing and/or record keeping 
of medications 
 
Х 
 
 
Х 
 
Assessment of adherence to therapy 
 
 
 
 
Х 
 
__________________ 
5 Colour, transparency, pH, specific gravity, protein, glucose, leucocytes, red blood cells, bacteria, cylinders, salts 
6,7 If the patient has headache complaints, at Visit 2, to be completed for the previous 3 months; if the patient has headache complaints identified at Visit 2, to be completed at Visit 5, to be completed for 
the last 1.5 months (6 weeks) 
 
 
 
 


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Protocol version 4.0 dated 15.10.2019. 
 
 
Procedures 
 
Visits 
 
 
Therapy 
Follow-up 
 
Screening 
Initiation of 
therapy 
Telephone contact1 
Telephone contact2 
End of therapy 
 
Day 
-14-1 
1 
14±2 
28±2 
43+1 
50+3 
Visit number 
1 
2 
3 
4 
5 
6 
Issuance of the Patient Diary and 
instructions on how to complete it 
 
Х 
 
 
 
 
Collecting the Patient Diary and 
monitoring its completion 
 
 
 
 
Х 
 
 


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1.3. Trial Sponsor 
Sponsor: 
RPC PHARMASOFT LTD 
Legal address: Russian Federation, 115407, Moscow, 41, 
Sudostroitelnaya St., floor 1, room. 12 
Postal 
address: 
Russian 
Federation, 
109544, 
Moscow, 
Enthusiastov Boulevard, 2 
Tel./fax: +7 (495) 626 47 55 
Sponsor's 
Responsible 
Representative: 
Tatyana Anatolievna Mityushkina 
Medical Director 
RPC PHARMASOFT LLC  
Tel: +7 (495) 626 47 55 ext. 140 
e-mail: mityushkina_t@pharmasoft.ru 
In case of serious adverse 
events, notify: 
Qualified 
Person Responsible for Pharmacovigilance 
(QPPV): Irina Vladimirovna Medvedeva 
RPC PHARMASOFT LLC  
tel.: +7 (495) 626 47 55 ext. 162 
e-mail: pv@pharmasoft.ru 
1.4. Organizer of the trial 
Organizer: 
ClinPharmDevelopment LLC 
Russia, 150031, Yaroslavl, Uglichskaya str. 68, office. 1. 
Tel: +7 (4852) 59-47-79, http://www.cphd.ru 
Organizer’s 
Responsible 
Representative: 
Nikolay Olegovich Pozdnyakov 
Director 
Address: Russia, 150031, Yaroslavl, Uglichskaya str. 68, office. 
1. 
Tel: +7 (4852) 59-47-79 
E-mail: no_pozdnyakov@cphd.ru 
1.5.  Clinical Research Associate (CRA) 
ClinPharmDevelopment LLC 
Russia, 150031, Yaroslavl, Uglichskaya str. 68, office. 1. 
Tel: +7 (4852) 59-47-79, http://www.cphd.ru 
1.6. Person authorised by the Sponsor to sign the protocol and amendments 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
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thereto 
Tatyana Anatolievna Mityushkina 
Medical Director 
RPC PHARMASOFT LLC  
tel.: +7 (495) 626 47 55 ext. 140 
e-mail: mityushkina_t@pharmasoft.ru 
1.7. Clinical laboratories and other organizations relevant to the trial 
The Clinical Central Laboratory will not be involved in this trial. 
1.8. Investigators and Investigational sites 
The list of investigators and Investigational sites will be provided in a separate document.  
2. TRIAL RATIONALE 
Attention deficit hyperactivity disorder (ADHD) is characterised by a triad of symptoms: 
attention deficit disorder, hyperactivity and impulsivity (coded as F90.0 in the International 
Classification of Diseases 10th revision)1. ADHD is the most common behavioural disorder in 
children: according to various authors, the prevalence in the paediatric population ranges from 
2 to 12% (average 3-7%). The high prevalence and social maladaptation resulting from ADHD 
represent a major social problem1-7. 
The etiology of ADHD remains controversial to date. Several concepts of the origin of this 
syndrome have been proposed, one of which is genetic, according to which ADHD is a 
polygenic disorder and its development is determined by multiple genes. Neurobiological and 
neurophysiological concepts link the emergence of ADHD with a decrease in local cerebral 
blood flow in the frontal cortex and subcortical nodes, deficit of inhibition in the sensorimotor 
system both at the level of cortical structures (frontal lobe) and at the level of subcortical 
formations (caudate nucleus) causing activation of sensorimotor cortex1,6. The existing 
hypotheses do not exclude each other, but describe disturbances in different systems6. The 
results of biochemical studies have shown that the major neurotransmitter systems of the brain 
- dopaminergic, noradrenergic and serotoninergic - play an important role in pathogenesis. It 
was found that there are fundamental differences in monoamine metabolism in this pathology6. 
Several studies have shown reduced blood flow and low neuronal activity in striatal and 
prefrontal orbital areas, whereas increased blood flow has been reported in primary sensory and 
sensorimotor areas6. 
Currently, the diagnosis of ADHD is based on clinical criteria7. Uniform criteria for the 
diagnosis of ADHD are represented by two major international classifications: DSM-5 (until 
2013 the DSM- IV-TR version was used) and ICD-10. There are no fundamental differences in 
the approach to diagnosis between these classifications. Diagnosis is made on the basis of 
qualitative criteria that are descriptive or based on the presence of a number of standard 
behavioural patterns that occur at a certain age and lead to impaired social adaptation8. In 
general, both classifications use the same set of symptoms, but there are some fairly important 
differences. The DSM-5 identifies the following subtypes of ADHD: 


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a) 
with predominant symptoms of inattention; 
b) 
with predominant symptoms of hyperactivity and impulsivity; 
c) 
mixed type. 
Symptoms of inattention: inability to focus on details and making mistakes due to inattention 
in school, work or other activities; difficulty maintaining attention on tasks or in play activities; 
lack of attention to spoken language; difficulty following instructions and inability to complete 
lessons, homework or workplace duties (not due to oppositional behaviour or inability to 
understand instructions); impaired organization of tasks and activities; avoidance or 
dissatisfaction, resistance to involvement in tasks that require prolonged mental effort; loss of 
things necessary for the performance of any work; increased distractibility by external stimuli, 
forgetfulness in everyday situations7. 
Symptoms of hyperactivity and impulsivity: restless inappropriate movements of hands and 
feet; inability to sit still; inadequate noisy activity in games, difficulty in quiet leisure time; 
constant movement; talkativeness; impatience; difficulty waiting in queues; interrupting 
conversations, games, other people's work7. 
ICD-10 does not distinguish forms and subtypes of ADHD, but hyperkinetic behaviour disorder 
(F90.1) is distinguished along with ADHD (F90.0), which are grouped under the general 
heading of hyperkinetic disorders (F90)7,8. 
A DSM-5 diagnosis of ADHD requires the presence of 6 (or more) of the listed symptoms of 
inattention and 6 (or more) of the listed symptoms of hyperactivity and impulsivity that are 
persistent for at least 6 months or more7; with several symptoms of inattention and 
hyperactivity-impulsivity present before age 12 years, occurring in two or more types of 
settings, clear evidence that the symptoms are having a significant impact by reducing the 
quality of performance, symptoms are not associated with anincrease in the quality of activity, 
and symptoms are not associated with a decrease in the quality of activity. To diagnose attention 
deficit hyperactivity disorder, the ICD-10 research criteria require at least 6 symptoms of 
inattention out of 9, three symptoms of hyperactivity out of 5, and at least 1 symptom of 
impulsivity out of 48. 
Compared to DSM-IV and ICD-10, DSM-5 includes the same 18 leading symptoms of ADHD, 
but the new version contains the following major changes: age of onset is defined up to 12 years 
(under ICD-10 and DSM-IV - up to 7 years); the requirement for the cross-situational nature of 
symptoms is strengthened - the patient must have more than one symptom confirmed in each 
type of setting; the description of symptoms is supplemented with typical examples illustrating 
their manifestations at different age periods; autistic disorders are not mentioned as an exclusion 
criterion; a threshold number of ADHD symptoms for adult patients (older than 17 years) is 
given for the first time: at least 5 (rather than 6 as in children) symptoms of one or two sections 
of the diagnostic criteria must be confirmed7. 
Since clinical psychopathological criteria in both the DSM and the ICD are standardised but 
not ranked in terms of severity, specially developed assessment scales are used for scoring 
symptoms, which allow to evaluate the quantitative manifestations of symptoms, the degree of 
their severity, as well as the dynamics of the patient's condition in the process of therapeutic 
measures and social rehabilitation6,8. 
Treatment of ADHD should be comprehensive and include methods of behavioural correction, 


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psychotherapy, and neuropsychological correction7. Psychological and pedagogical correction 
is considered as one of the main methods of therapy1. Pharmacotherapy is prescribed on an 
individual basis when cognitive and behavioural disorders cannot be overcome by behavioural 
therapy, psycho-educational correction and psychotherapy6. Drug therapy requires sufficient 
duration, as the improvement should not only extend to the main symptoms but also to the 
socio-psychological side of patients' lives7. The programme of medication treatment of ADHD 
consists in the sequential prescription of complexes of drugs of different pharmacological 
groups. Approaches to drug therapy for ADHD vary around the world7. Most ADHD drugs 
used in the West are either not registered in Russia (amphetamine, dextroamphetamine, 
methylphenidate) or are not approved for use in ADHD and are not used in paediatric practice 
(clonidine, guanfacine, bupropion, imipramine)1. In Russia, ADHD therapy traditionally 
includes gamma-aminobutyric acid, nootropic and neurometabolic drugs, as well as some 
tranquilisers, atypical neuroleptics, antidepressants and amoxetine. At the same time, the issue 
of the efficacy of medication methods for ADHD correction is still debatable1. It should be 
noted that in children without pronounced attention disorders, the use of nootropic drugs, which 
are most often used in the treatment of ADHD in Russia7, is not always justified due to the 
possibility of such side effects as agitation and sleep disturbances. 
Mexidol® is an inhibitor of free-radical processes, a membrane-protector with antihypoxic, 
stress-protective, nootropic, anticonvulsant and anxiolytic action. Anti-stressor effect is 
manifested in normalisation of post-stress behaviour, somatovegetative disorders, restoration 
of sleep-wake cycles, disturbed learning and memory processes, reduction of dystrophic and 
morphological changes in various brain structures. Thus, Mexidol® may potentially act 
favourably on the neurobiological and neurophysiological mechanisms of ADHD development, 
allowing to reduce the severity of symptoms9. 
There are no studies of safety and efficacy of Mexidol® in adults for the proposed indication, 
which is due to the fact that this pathology is characteristic of childhood and practically does 
not occur in the adult population. While the present trial is planned to include the age group of 
children from 6 to 12 years inclusive. 
In this regard, the Sponsor has planned a multi-centre prospective, double-blind, placebo-
controlled, randomised clinical trial in three parallel groups to study the safety and efficacy of 
Mexidol® in the treatment of attention deficit hyperactivity disorder in children 6-12 years of 
age. 
2.1. Name and description of the trial products 
2.1.1. 
Investigational product: 
Name: Mexidol® 
Group name: Ethylmethylhydroxypyridine succinate 
Dosage form: film-coated tablets 
Composition: 
Active substance: ethylmethylhydroxypyridine succinate (2-ethyl-6methyl-3-hydroxypyridine 
succinate) - 125 mg. 
Excipients: lactose monohydrate - 97.5 mg, povidone 25.0 mg, magnesium stearate - 2.50 mg. 


RPC PHARMASOFT LLC  
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Protocol PHS-ADHD-002-MEX-TAB 
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Protocol version 4.0 dated 15.10.2019. 
 
 
Film coating: opadray II white 33G28435 - 7.5 mg (hypromellose -3.0 mg, titanium dioxide - 
1.875 mg, lactose monohydrate - 1.575 mg, polyethylene glycol (macrogol) - 0.6 mg, triacetin 
- 0.45 mg). 
Description: round, biconvex, film-coated tablets, from white to white with a creamy tinge 
colour. 
Pharmacotherapeutic group: antioxidant agent. 
ATC code: N07XX 
Pharmacodynamics: 
Mexidol® is an inhibitor of free-radical processes, a membrane-protector with antihypoxic, 
stress-protective, nootropic, anticonvulsant and anxiolytic action. The drug increases the body's 
resistance to various damaging factors (shock, hypoxia and ischaemia, cerebral circulatory 
disorders, intoxication with alcohol and antipsychotic drugs (neuroleptics)). 
Mechanism of action of Mexidol® is due to its antioxidant, antihypoxant and membrane-
protective action. It inhibits lipid peroxidation, increases superoxide dismutase activity, 
increases the lipid-protein ratio, decreases membrane viscosity, and increases membrane 
fluidity. Mexilol® modulates the activity of membrane-bound enzymes (calcium independent 
phosphodiesterase, 
adenylate 
cyclase, 
acetylcholinesterase), 
receptor 
complexes 
(benzodiazepine, GABA, acetylcholine), which enhances their ability to bind to ligands, 
contributes to the preservation of structural and functional organisation of biomembranes, 
transport of neurotransmitters and improvement of synaptic transmission. Mexidol® increases 
the content of dopamine in the brain. It causes enhancement of compensatory activation of 
aerobic glycolysis and reduction of the degree of inhibition of oxidative processes in the Krebs 
cycle under hypoxia with an increase in the content of ATP and creatine phosphate, activation 
of energy-synthesising functions of mitochondria, stabilisation of cell membranes. 
The drug improves metabolism and blood supply to the brain, improves microcirculation and 
rheological properties of blood, reduces platelet aggregation. Stabilises membrane structures of 
blood cells (erythrocytes and platelets) during haemolysis. It has hypolipidemic action, reduces 
the content of total cholesterol and low-density lipoproteins. 
Anti-stressor effect is manifested in normalisation of post-stress behaviour, somatovegetative 
disorders, restoration of sleep-wake cycles, disturbed learning and memory processes, reduction 
of dystrophic and morphological changes in various brain structures. 
Mexidol® has a pronounced antitoxic effect in withdrawal syndrome. It eliminates neurological 
and neurotoxic manifestations of acute alcohol intoxication, restores behavioural disorders, 
autonomic functions, and is also able to relieve cognitive impairment caused by long-term 
ethanol intake and its withdrawal. Under the influence of Mexidol® enhances the effect of 
tranquilising, neuroleptic, antidepressant, antidepressant, sleeping and anticonvulsant drugs, 
which allows to reduce their doses and side effects. Mexidol® improves the functional state of 
ischaemic myocardium. In conditions of coronary insufficiency increases collateral blood 
supply of ischaemic myocardium, promotes preservation of integrity 
of cardiomyocytes and maintenance of their functional activity. It effectively restores 
myocardial contractility in reversible cardiac dysfunction. 


RPC PHARMASOFT LLC  
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Pharmacokinetics 
It is rapidly absorbed when taken orally. The maximum concentration at doses of 400500 mg 
is 3.5-4.0 µg/ml. It is rapidly distributed in organs and tissues. The average retention time of 
the drug in the body when administered orally is 4.9-5.2 h. It is metabolised in the liver by 
glucuronidation. Five metabolites have been identified: 3-oxypyridine phosphate - formed in 
the liver and broken down into phosphoric acid and 3-oxypyridine with the participation of 
alkaline phosphatase; the 2nd metabolite - pharmacologically active, formed in large quantities 
and detected in the urine 1-2 days after administration; the 3rd - excreted in large quantities 
with urine; the 4th and 5th - glucuronconjugates. T1/2 at ingestion is 2.0-2.6 h. It is rapidly 
excreted with urine mainly in the form of metabolites and in an insignificant amount - in 
unchanged form. It is most intensively excreted during the first 4 hours after taking the drug. 
Urinary excretion rates of unchanged drug and metabolites have individual variability. 
Indications for use: 
 
Consequences of acute cerebral circulatory disorders, including after transient 
ischaemic attacks, in the phase of subcompensation as prophylactic courses; 
 
Mild head injury, consequences of head injuries; 
 
Encephalopathies of various genesis (dyscirculatory, dysmetabolic, post-traumatic, 
mixed); 
 
Autonomic dystonia syndrome; 
 
Mild cognitive disorders of atherosclerotic genesis; 
 
Anxiety disorders in neurotic and neurosis-like states; 
 
Ischaemic heart disease as part of complex therapy; 
 
Coping with withdrawal syndrome in alcoholism with predominance of neurosis-like 
and vegetative-vascular disorders, post-abstinence disorders; 
 
Condition after acute intoxication with antipsychotic drugs; 
 
Asthenic conditions, as well as for the prevention of somatic diseases under the 
influence of extreme factors and loads; 
 
Exposure to extreme (stressor) factors. 
Contraindications 
 
acute liver and/or renal dysfunction; 
 
hypersensitivity to the drug and its components; 
 
infancy (due to insufficiently studied effect of the drug); 
 
pregnancy, breastfeeding (due to insufficient study of the drug action); 
 
lactose intolerance, lactase deficiency, glucose-galactose malabsorption. 
Use in pregnancy and during breastfeeding: 
Mexidol® is contraindicated in pregnancy and during breastfeeding. 


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Method of administration and doses 
For adults: orally, 125-250 mg TID; maximum daily dose - 800 mg (6 tablets). Duration of 
treatment 2-6 weeks; for alcohol withdrawal - 5-7 days. Treatment is discontinued gradually, 
reducing the dose over 2-3 days. 
The initial dose is 125-250 mg (1-2 tablets) 1-2 times a day with gradual increase until 
therapeutic effect is obtained; maximum daily dose - 800 mg (6 tablets)1. 
Duration of the course of therapy in patients with ischaemic heart disease is not less than 1.5-2 
months. Repeated courses (on the doctor's recommendation) should preferably be carried out 
in the spring and autumn periods. 
Side effects 
The frequency of side effects was determined according to the World Health Organisation 
(WHO) classification: very frequent (≥10%); common (≥1%, but <10%); uncommon (≥0.1%, 
but <1%); rare (≥0.01%, but <0.1%); very rare (<0.01%); frequency unknown (frequency 
cannot be determined from available data). 
Immune system disorders: very rare - angioedema, urticaria. 
Mental disorders: very rare - somnolence. 
Nervous system disorders: very rare - headache. 
Gastrointestinal disorders: very rare - dry mouth, nausea, pain, burning and discomfort in the 
epigastric region, heartburn, flatulence, diarrhoea. 
Skin and subcutaneous tissue disorders: very rare - rash, pruritus, hyperaemia. 
Interaction with other drugs: 
Mexidol® is combined with all drugs used for the treatment of somatic diseases. It enhances the 
effect 
of benzodiazepine drugs, 
antidepressants, 
anxiolytics, anticonvulsants 
and 
antiparkinsonian drugs. It reduces the toxic effects of ethyl alcohol. 
Overdose 
Symptoms: drowsiness, insomnia. 
Treatment: due to low toxicity, overdose is unlikely. Treatment is usually not required - 
symptoms disappear on their own within 24 hours. In severe manifestations, supportive and 
symptomatic treatment is carried out. 
Effect of the drug on the ability to drive vehicles or operate mechanisms: 
1 When administered intravenously, the maximum daily dose of Mexidol® is 2000 mg. 
During the period of drug administration, caution should be exercised in work requiring quick 
psychophysical reactions (driving vehicles, mechanisms, etc.). 
Pharmaceutical form: Film-coated tablets, 125 mg. 10 tablets each in a PVC/Alu blister. 1, 2, 
3, 4, 5 blisters together with instructions for use in a carton pack. 
Storage conditions 


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Protocol version 4.0 dated 15.10.2019. 
 
 
Store in a dry place, protected from light, at a temperature not exceeding 25°C. Keep out of 
reach of children. 
Shelf life 
3 years. Do not use after the expiry date indicated on the pack. 
Manufacturer: 
ZiO-Zdorovye CJSC, Russia, 142103, Moscow region, Podolsk, Zheleznodorozhnaya St., 2 
Tel: +7(495)642-05-42 
Fax: +7(495)642-05-43 
Marketing Authorization Holder/ Claims Receiving Organisation: 
RPC PHARMASOFT LLC, Russia, 115407, Moscow, 41, Sudostroitelnaya St., floor 1, room. 
12 
Tel./fax: +7(495)626-47-55 
2.1.2. 
 Placebo 
Name: placebo 
INN or group name: not applicable 
Dosage form: film-coated tablets 
Composition: lactose monohydrate - 222.50 mg, povidone 25.0 mg, magnesium stearate - 2.50 
mg. 
Film coating: opadray II white 33G28435 - 7.5 mg (hypromellose - 3.0 mg, titanium dioxide - 
1.875 mg, lactose monohydrate - 1.575 mg, polyethylene glycol (macrogol) - 0.6 mg, triacetin 
- 0.45 mg). 
Description: round, biconvex, film-coated tablets, from white to white with a creamy tinge 
colour. 
Pharmacotherapeutic group: not applicable 
ATC code: not applicable 
Manufacturer: 
ZiO-Zdorovye CJSC, Russia, 142103, Moscow region, Podolsk, Zheleznodorozhnaya St., 2 
Tel: +7(495)642-05-42 
Fax: +7(495)642-05-43 
2.2. Summary of results of preclinical and clinical studies 
2-ethyl-6-methyl-3-oxypyridine succinate (under the code SOP-1) was synthesised in the 1980s 
by L.D. Smirnov and V.I. Kuzmin. Smirnov and V.I. Kuzmin. In the same years, under the 
direction of Professor T.A. Voronina, Doctor of Medical Sciences, it was first shown that for 
SOP-1 (Mexidol), which combines the properties of a tranquiliser and nootropic, anxiolytic and 
anti-stressor effects are dominant in the spectrum of psychotropic action, and SOP-1 is superior 
to piracetam and piritinol in its anti-amnesic action. From this point onwards, numerous studies 


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have revealed other pharmacological effects peculiar to this substance, in particular antioxidant, 
membranotropic, antihypoxic, radioprotective, geroprotective, antitoxic, etc. 
Mexidol® is the first preparation of ethylmethylhydroxypyridine succinate included in the Order 
of the Ministry of Health of the Russian Federation dated 31 December 1996 No. 432 "On 
Approval of Medical Use" (in the dosage form of solution for intramuscular and intravenous 
administration). Mexidol® in the pharmaceutical form of film-coated tablets, 125 mg is 
approved for medical use in accordance with the Order of the Ministry of Health of the Russian 
Federation No. 21 dated 26 January 1998. In accordance with Federal Law No. 61-FZ "On 
Circulation of Medicines" dated 12.04.2010, Mexidol® (film-coated tablets, solution for 
intravenous and intramuscular administration) is recognised by FSBI NCESMP of the Ministry 
of Health of Russia as a reference (original) drug (letter of the Ministry of Health of Russia No. 
20-3/1262 dated 19.09.2016, letter of FSBI NCESMP of the Ministry of Health of Russia dated 
09.09.2016). 
According to the data of numerous preclinical studies it was shown antihypoxic, anti-ischaemic 
(including myocardial infarction) action, antioxidant and membranoprotective effects, 
anxiolytic and anti-stressor effects, positive effects in experimental alcoholism and drug 
addiction, the presence of antiarrhythmic activity, positive effect in dyslipoproteidaemia, anti-
atherogenic effect, hypolipidemic, anti-allergic action. 
The potential efficacy of Mexidol® against ADHD has been demonstrated in animal 
experiments. In a model of hyperactivity in rats with spontaneous hypertension of the SHR line, 
behavioural functions were studied in an open-field test (study of vertical and horizontal 
activity). Efficacy was evaluated against the paediatric ADHD drug, Strattera (INN: 
atomoxetine), at two dose levels equivalent to a daily dose of 125 and 250 mg for humans. 
Administration of Mexidol® in SHR rats at a dose of 75 mg/kg (equivalent to 250 mg/day for 
humans) statistically significantly reduced hyperactivity and this effect was comparable to 
Strattera® and was maintained over the following two weeks. 
Another experiment in Wistar rats examined one of the cognitive functions (attention) and 
general impulsivity, which is an integral component of ADHD, in the 5-CSRTT (reaction time 
when choosing among 5 possibilities) test. Wistar rats are initially highly impulsive, as 
manifested in the 5-CSRTT test as a "premature response," i.e., the number of times the nose 
was inserted into one of the five holes between attempts or during a timeout (no illumination 
for 5 seconds). The attention index was quantified as the number of correct attempts. Putting 
the nose through the illuminated hole within 18 seconds of the start of the attempt was taken as 
a correct attempt, which was reinforced by providing the rat with a pellet of food. It was 
demonstrated that administration of Mexidol® in rats at a dose of 75 mg/kg (equivalent to 250 
mg/day for humans) statistically significantly leads to an improvement in attention performance 
(increase in the proportion of correct attempts) and reduces the impulsivity index (decrease in 
the proportion of premature attempts) and this effect was comparable to Strattera®. 
As part of the development of the drug for a new indication for use in paediatric practice, 
preclinical toxicological studies were conducted on two species of immature animals in the 
whole age range of development. 
According to the results of the study of acute toxicity and determination of maximum tolerated 
dose of Mexidol® at a single injection into the stomach by probe to male and female SD rats at 


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the age of 2 weeks it was found that the maximum tolerated dose for males was 1700 mg/kg, 
for females - 1500 mg/kg, the LD50 value for male rats was 2010±101 mg/kg, for females - 
1957±104 mg/kg. 
As a result of acute toxicity study and determination of the maximum tolerated dose of 
Mexidol® when administered once in the stomach to male and female Sprague-Dawley (SD) 
rats at the age of 4 weeks, it was found that the maximum tolerated dose for males and females 
was 5000 mg/kg, the LD50 value for male rats was 6328±207 mg/kg, for females - 6098±192 
mg/kg. 
According to the results of the study of acute toxicity and determination of maximum tolerated 
dose of the medicinal product Mexidol® at a single injection into the stomach by probe to male 
and female SD rats at the age of 7.5 weeks it was found that the maximum tolerated dose for 
male and female rats is 5000 mg/kg, the LD50 value for male rats was 6328±207 mg/kg, for 
females - 6098±192 mg/kg. 
To assess subchronic toxicity, a study of Mexidol® film-coated tablets 125 mg was conducted 
during multiple intragastric administration to immature rats and rabbits with assessment of 
possible delayed action. Within the framework of the conducted study on immature animals it 
was shown that the investigated Mexidol® film-coated tablets, 125 mg (RPC Pharmasoft LLC., 
Russia) is a low-toxic substance. At doses of 50 mg/kg for rats and 25 mg/kg for rabbits, which 
approximate the maximum therapeutic doses for adult humans, the drug did not cause toxic 
disorders. At doses of 600 mg/kg in rats and 200 mg/kg in rabbits (greater than the maximum 
therapeutic doses by a factor of 12 and 8, respectively, per animal), the drug also did not cause 
toxic changes. The doses of Mexidol® coated tablets that do not cause adverse effects in 
immature rats and in immature rabbits are in the dose range of 600 - 1200 mg/kg and 200 - 400 
mg/kg, respectively. 
These studies concluded that it was feasible to conduct clinical studies involving children. 
Indications for prescribing Mexidol® in adults are the following conditions and diseases: 
 
Consequences of acute cerebral circulatory disorders, including after transient 
ischaemic attacks, in the phase of subcompensation as prophylactic courses; 
 
Mild head injury, consequences of head injuries; 
 
Encephalopathies of various genesis (dyscirculatory, dysmetabolic, post-traumatic, 
mixed); 
 
Autonomic dystonia syndrome; 
 
Mild cognitive disorders of atherosclerotic genesis; 
 
Anxiety disorders in neurotic and neurosis-like states; 
 
Ischaemic heart disease as part of complex therapy; 
 
Coping with withdrawal syndrome in alcoholism with predominance of neurosis-like 
and vegetative-vascular disorders, post-abstinence disorders; 
 
Condition after acute intoxication with antipsychotic drugs; 
 
Asthenic conditions, as well as for the prevention of somatic diseases under the 


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influence of extreme factors and loads; 
 
Exposure to extreme (stressor) factors. 
Previously, clinical studies to register the drug for use in children have not been conducted. 
However, there are a number of publications investigating the effects of the drug in neurology 
in a paediatric population. According to the results of these studies, the efficacy of Mexidol® 
film-coated tablets 125 mg for school adaptation in children with attention deficit hyperactivity 
disorder, posthypoxic encephalopathy, correction of autonomic dysregulation syndrome and 
autonomic status, posttraumatic epilepsy was shown. However, the authors did not note any 
safety concerns with the use of the drug in children. Individual adverse reactions may occur 
when using the drug. The safety profile of the drug in children is not expected to be significantly 
different from the safety profile in the adult population. 
For more details, all information on the results of the preclinical studies, please refer to the 
Investigator Brochure. 
2.3. Summary of known and potential risks and benefits to patients 
The Trial Sponsor, RPC PHARMASOFT LLC, Russia, is planning to conduct a multicentre 
prospective, double-blind, placebo-controlled randomised clinical trial in three parallel groups 
to evaluate the safety and efficacy of Mexidol® film-coated tablets 125 mg in the treatment of 
attention deficit hyperactivity disorder in children 6-12 years old with different dosing regimen. 
Mexidol® is registered in the Russian Federation for use in adults for various indications and 
currently the positive benefit/risk ratio of its use is beyond doubt. 
Currently, psychological and pedagogical correction is considered as the main method of 
ADHD therapy, the question of the effectiveness of medication methods remains debatable1, so 
the use of placebo against the background of psychological and pedagogical correction in one 
of the therapy groups will not bring additional risks for patients. 
There are virtually no risks associated with the tests and examinations required under the terms 
of this protocol for patients. Blood sampling is required for the examinations required by this 
protocol and there is an unlikely risk of hematoma formation at the puncture site and infection, 
which can be eliminated by skilled performance of the procedure by professional staff at the 
participating clinical sites. Mild painful sensations may occur during the blood sampling 
procedure, which pass on their own and do not require additional therapeutic interventions. 
Dizziness and/or weakness may occur during or shortly after the blood sampling procedure. 
The investigator will closely monitor the patients' condition throughout the clinical trial. 
Patients will receive reliable information about their health status as a result of the examination 
and follow-up conducted as part of their examinations. 
A detailed description of possible side effects of the investigational product as well as special 
instructions for its use are given in section 2.1. of this protocol. 
2.4. Description and justification of the method of administration, dosage, 
regimen and course of treatment 
Investigational product: 


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Mexidol® (ethylmethylhydroxypyridine succinate) film-coated tablets, 125 mg (RPC 
PHARMASOFT LLC, Russia). 
Method of administration: 
In Group 1, the drug will be administered orally 1 tablet OD. To maintain double-blinding and 
a uniform dosing regimen of the prescribed therapy, patients will take 1 placebo tablet. The 
interval between doses should be 12±1 hours. 
In Group 2, the drug will be administered orally 1 tablet BID, morning and evening with an 
interval between doses of 12±1 hours. 
Duration of therapy: 42 days. 
Placebo 
Placebo film-coated tablets (RPC PHARMASOFT LLC, Russia). 
Method of administration: placebo will be administered orally 1 tablet BID, morning and 
evening with an interval between doses of 12±1 hours. 
Duration of therapy: 42 days. 
According to the results of the study of general toxic properties in acute and subchronic 
experiments on immature animals, the doses that do not cause adverse effects were determined: 
in immature rats the dose interval was 600 - 1200 mg/kg, in immature rabbits - 200 - 400 mg/kg, 
respectively. 
To assess the safety of the selected dosage, the maximum recommended initial dose (MRID) 
was calculated according to the preclinical study guidelines1. 
In accordance with the guidelines, the highest dose levels that did not cause a significant 
increase in adverse effects compared to the control group were selected as the dose with no 
observed adverse effect (NOEL) in animals. In a subchronic toxicity study, the NOEL in rats 
was 1200 mg/kg and in rabbits 400 mg/kg. The human equivalent dose (HED) calculated using 
the formula provided in the guidance is then: 
HED = NOEL for rats 1200 mg/kg / 6.0 = 200 mg/kg; 
HED = NOEL for rabbits 400 mg/kg / 3.2 = 125 mg/kg. 
For further calculations, the minimum resulting HED was used. 
MRID = HED / safety factor (SF). 
Standard SF = 10. 
Then, MRID = 125 mg/kg / 10 = 12.5 mg/kg, which, taking into account the body weight of an 
"average" child of age 6 years, equal to 20 kg, will be 250 mg per day. 
Thus, the suggested daily dosage of 250 mg in the present clinical trial in a dosing regimen of 
one 125 mg tablet BID appears to be reasonable and safe for use in children. 
The safety profile of the drug in children is not expected to be significantly different from the 
__________________ 
1 Guidelines for conducting preclinical studies of medicinal products. Part One, ed. by A.N. Mironov. 2012, 
Moscow: Griff & Co. 944 


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safety profile in the adult population. 
However, since Mexidol® in children has not been previously studied in controlled trials, 2 
dosing regimens will be used to assess efficacy: 1 tablet 125 mg OD and 1 tablet 125 mg BID. 
Group 1 patients receiving Mexidol® 1 tablet of 125 mg OD will additionally take 1 tablet of 
placebo. The interval between doses should be 12±1 hours. Thus, a single dosing regimen for 
all three groups - 1 tablet BID to maintain double-blinding of the prescribed therapy - will be 
followed. 
In the approved instruction for medical use of Mexidol® for adults the maximum daily dose is 
set at 800 mg1 (6 tablets), the recommended dose is 125-250 mg TID. The duration of treatment 
is 2-6 weeks. 
Thus, the maximum investigational daily dose (250 mg) proposed in this protocol is 3.2 times 
less than the approved maximum adult dosage. 
At the moment, there are no Russian regulatory guidelines for conducting clinical trials of 
medicines for ADHD, so the recommendations of the European Medicines Agency (EMA) have 
been used, in which the minimum recommended duration of use of an investigational medicine 
in a stable dose is 6 weeks14. This duration also corresponds to the maximum recommended 
duration of use of Mexidol® in adults. With this in mind, a duration of 6 weeks of drug 
administration was chosen for the initial demonstration of efficacy. 
In addition, the safety of the drug use in the proposed doses in children is confirmed by the 
standards of medical care for various diseases in children approved by the Ministry of Health 
of Russia, starting from the period of newborn, in which the average daily dose is 200 mg, while 
the minimum weight of boys in the period of newborn averages 3.3 kg, girls - 3.2 kg. Thus, the 
daily dosage for a boy is 60.6 mg/kg and for a girl 62.5 mg/kg. The daily dosage proposed in 
this trial is lower than the approved standards and from this point of view seems safe [Order of 
the Ministry of Health of the Russian Federation from 24 December 2012 №1425n "On 
approval of the standard of specialised medical care for children with tick-borne viral 
encephalitis of severe severity"; Order of the Ministry of Health of the Russian Federation from 
09.11.2012 №804n "On approval of the standard of specialised medical care for children with 
generalised meningococcal infection of severe severity"]. 
In a similar daily dosage, Mexidol® is included for use in children in the clinical 
recommendations (treatment protocol) "Provision of medical care to children with 
meningococcal infection" (FSBI NIIDI FMBA of Russia, Public Organisation "Euroasian 
Society for Infectious Diseases", 2015) and clinical recommendations for the management of 
children with the consequences of perinatal damage to the central nervous system with diffuse 
muscular hypotonia (2013). Additionally, the safety of Mexidol® in children, including 
newborns (at least 763 children), in various nosologies is confirmed by extensive experience in 
the use of the drug in clinical practice in Russia. In the trial of Askerova J.M.10 Mexidol® was 
used in newborn children (both premature and premature) with the syndrome of intrauterine 
developmental delay in the correction of hypoxic-ischaemic lesions of the central nervous 
system in a daily dose of 0.1-0.2 ml/kg for 7-10 days, and no side effects were observed. In the 
trial by Zvonareva E.V.11 Mexidol® was used in children aged 1-6 months with posthypoxic 
__________________ 
1 When administered intravenously, the maximum daily dose of Mexidol® is 1200 mg 


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encephalopathy at a daily dose of 5 mg/kg per day for 30 days (tablet form of the drug was 
used), and good tolerability of the drug and absence of side effects both during its administration 
and after completion of the course were noted. 
In the trial by Tsypina L.G.12 Mexidol® was used in children aged 2 months to 15 years in the 
complex therapy of acute neuroinfections. Depending on the degree of aggressiveness and 
severity of the infection, Mexidol® was administered in the acute stage of the disease by 100-
200 mg 1-2 times a day intravenous drip for 5-7 days, then 50100 mg (depending on the age 
and weight of the child) intramuscularly in a total dose up to 15 days, followed by oral intake 
for 4-6 weeks. Dosage of the drug when taken orally in children of the first year of life was 1/4 
tablet 2-3 times OD, from 1 to 3 years - 1/2 tablet BID, from 3 to 7 years - 1/2 tablet TID and 
in 7-10 years - 1 tablet 2-3 times a day. No side effects were reported by the authors. 
In the trial by Potapova I.S. et al.9 Mexidol® was used in children aged 7-9 years in the 
correction of school adaptation of children with attention deficit hyperactivity disorder in a 
daily dose of 1/2 tablet 2 times a day (daily dose 125 mg) for 30 days. No side effects were 
reported by the authors. In a trial by OkunevaM.A.13 Mexidol® was used in adolescents aged 
16-20 years for correction of autonomic dysregulation syndrome as a consequence of perinatal 
CNS lesions in a daily dose of 375 mg for 28 days, the authors did not report any side effects. 
Thus, it is suggested that the use of the drug in a daily dose of up to 250 mg is reasonable in 
terms of safety. 
2.5. Conditions of the trial 
This clinical trial will be conducted in accordance with this protocol, the principles of the World 
Medical Association Declaration of Helsinki, the ICH Good Clinical Practice (ICH GCP) 
standard, and Russian law: 
1. 
Federal Law dated 12 April 2010 N 61-FZ "On Circulation of Medicines" (in the 
current version); 
2. 
National Standard of the Russian Federation GOST R 52379-2005 "Good Clinical 
Practice"; 
3. 
Order of the Ministry of Health of the Russian Federation No. 200n dated 01 April 
2016 "On Approval of the Rules of Good Clinical Practice"; 
4. 
Resolution of the Government of the Russian Federation dated 13 September 2010 N 
714 "On Approval of Model Rules for Compulsory Life and Health Insurance of a 
Patient Participating in Clinical Trials of a Medicinal Product" (current version); 
5. 
Order of the Ministry of Health of the Russian Federation No. 986n of 29 November 
2012 "On Approval of the Regulations on the Ethics Council"; 
6. 
Decision of the Council of the Eurasian Economic Commission of 03.11.2016 No. 79 
"On Approval of the Rules of Good Clinical Practice of the Eurasian Economic 
Union". 
2.6. Description of the trial population 
Outpatients - boys and girls, aged 6 to 12 years (inclusive) with a diagnosis of attention deficit 
hyperactivity disorder, established in accordance with the criteria of the 10th revision of the 
International Classification of Diseases (ICD-10) (F90.0) and the Diagnostic and Statistical 
Manual of Mental Disorders 5th edition (DSM-5) by a psychiatrist or neurologist. 


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3. TRIAL AIMS AND OBJECTIVES 
3.1. Trial aimes 
To evaluate the efficacy and safety of two dosing regimes of Mexidol® film-coated tablets, 125 
mg (PRC Pharmasoft LLC, Russia) vs. placebo in children aged 6 to 12 years inclusive with 
attention deficit hyperactivity disorder (ADHD). 
3.2. Trial objectives 
Primary objective: 
1. To evaluate the efficacy of Mexidol® film-coated tablets, 125 mg (PRC 
PHARMASOFT LLC, Russia) vs. placebo after 6 weeks from the beginning of therapy 
in relation to the average change in the total score on the "inattention" and 
"hyperactivity/impulsivity" subscales of the SNAP-IV scale when administered at a 
dose of 125 mg OD. 
2. To evaluate the efficacy of Mexidol® film-coated tablets, 125 mg (PRC 
PHARMASOFT LLC, Russia) vs. placebo after 6 weeks from the beginning of therapy 
in relation to the mean change in the total score on the "inattention", 
"hyperactivity/impulsivity" subscales of the SNAP-IV scale when administered at a 
dose of 125 mg BID. 
Secondary objectives: 
1. To evaluate the efficacy of Mexidol® film-coated tablets 125 mg (PRC 
PHARMASOFT LLC, Russia) vs. placebo after 6 weeks from the beginning of therapy 
when administered at a dose of 125 mg OD and 125 mg BID on the basis of the 
following parameters: 
a. 
mean change on the SNAP-IV subscale - inattention; 
b. mean change on SNAP-IV subscale - hyperactivity/impulsivity 
c. 
mean change on the SNAP-IV subscale - oppositional defiant disorder; 
d. mean change on the SNAP-IV subscale - Conners' clinical index; 
e. 
mean change on the Spence Children's Anxiety Scale (SCAS); 
f. 
mean change on ADHD Rating Scale-IV value; 
g. Clinical Global Impressions-ADHD-Severity scale (CGI-ADHD-S); 
h. assessment of the dynamics of PedMIDAS questionnaire scores (number of 
days with restriction of daily activity due to headache, number of days with 
headache, average headache severity and maximum headache severity in 
scores); 
i. 
Clinical Global Impressions Scale - Improvement (CGI-I). 
2. To evaluate the safety of Mexidol® film-coated tablets, 125 mg (RPC PHARMASOFT 
LLC, Russia) vs. placebo based on the assessment of frequency, severity and nature of 
adverse events. 
4. TRIAL DESIGN 
4.1. Efficacy criteria 
Evaluation of the efficacy of therapy will be based on primary and secondary efficacy criteria. 


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Primary efficacy criterion: 
1. Mean change in the total score on the inattention and hyperactivity/impulsivity 
subscales of the SNAP-IV scale after 6 weeks of therapy vs. baseline. 
Secondary efficacy criteria: 
1. mean change on the SNAP-IV inattention subscale after 6 weeks of therapy vs. baseline; 
2. mean change on SNAP-IV subscale hyperactivity/impulsivity after 6 weeks of therapy 
vs. baseline 
3. mean change on the SNAP-IV subscale, oppositional defiant disorder, after 6 weeks of 
therapy vs. baseline; 
4. mean change in SNAP-IV subscale - Conners index after 6 weeks of therapy vs. 
baseline; 
5. mean change on the Spence children's anxiety scale (SCAS) after 6 weeks of therapy 
vs. baseline; 
6. mean change on ADHD Rating Scale-IV scores after 6 weeks of therapy vs. baseline; 
7. clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scale score after 6 weeks 
of therapy vs. baseline; 
8. assessment of the dynamics of PedMIDAS questionnaire scores (number of days with 
restriction of daily activity due to headache, number of days with headache, average 
headache severity and maximum headache severity in scores); 
9. Clinical Global Impressions Scale - Improvement (CGI-I) score after 6 weeks of therapy 
vs. baseline. 
4.2. Trial design 
This trial is a multicentre, prospective, double-blind, randomised 1:1:1 clinical trial of the safety 
and efficacy of Mexidol® film-coated tablets 125 mg in three parallel groups using placebo 
control (Figure 1). 
Figure 1. Graphical design of the trial 


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4.3. Description of measures aimed at minimising/eliminating subjectivity 
4.3.1. 
Randomisation 
Patient randomisation will be performed at Visit 2 with a 1:1:1:1 patient allocation using the 
online IWRS (Interactive Web Response System). A patient randomisation number will be 
assigned to the trial subject in the order in which they access the IWRS system. 
The corresponding randomisation list will be generated in the statistical software using a 
random number generator by the responsible biostatistician of the Sponsor/Sponsor's 
representative company. The randomisation list is not intended to be shared with research 
centres and will be held by the Sponsor. Due to the use of a centralised randomisation system, 
envelopes or other means of conducting randomisation will not be provided to centres. 
Investigators will be given online training on how to use the IWRS system. 
The randomisation list will be included in the Trial Master File and the final clinical trial report. 
A register of screened and randomised patients will be maintained for all sites. The register 
form is contained in the Investigator Site File. The form should be completed by the investigator 
on a regular basis with all necessary data entered. 
The randomisation number is the unique code of the patient in the clinical trial. The investigator 
records the patient's randomisation number in the source documentation and electronic Case 
Report Form (eCRF) and enters the randomised patient's information in the list of included 
patients. The randomisation number cannot be changed during the course of the trial. 
The prescribed therapy cannot be changed during the trial. 
Patients who early terminate the trial will not be replaced. 
Each patient will be assigned an individual identification number of the following form of three 
digits: _ _ _ - __ __ __ __ - _ _ _ _ _, where the first two digits of the number correspond to the 
centre number, the next two digits denote the screening number within each clinical centre, the 


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last three digits of the number correspond to the randomisation number generated by the IWRS 
randomisation system. 
4.3.2. 
Blinding 
The trial is double-blind, so neither the patient nor the investigator will be aware of the therapy 
group to which the patient will be randomised. To ensure a double-blind trial design, 
randomisation using the online IWRS system and appropriate labelling of the investigational 
products is provided. 
As the trial will investigate 2 dosing regimens - taking 1 tablet OD (group 1) and 1 tablet BID 
(group 2), to maintain double-blinding of the prescribed therapy, patients in group 1 will take 
1 tablet of placebo, 12±1 hours after taking the investigational product. Thus, for all groups, a 
2-fold dosing regimen will be followed. 
4.4. Investigational products, dosages, routes of administration, packaging, 
labelling 
4.4.1. 
Information on Investigational Products 
Investigational Product 
Name  
Mexidol® 
Group name: 
Ethylmethylhydroxypyridine succinate 
Dosage form 
film-coated tablets 
Composition: 
Composition: 
Active substance: ethylmethylhydroxypyridine succinate (2-
ethyl-6-methyl-3-hydroxypyridine succinate) - 125.0 mg 
Excipients: lactose monohydrate - 97.5 mg, povidone 25.0 mg, 
magnesium stearate - 2.50 mg. 
Film coating: opadray II white 33G28435 - 7.5 mg 
(hypromellose - 3.0 mg, titanium dioxide - 1.875 mg, lactose 
monohydrate - 1.575 mg, polyethylene glycol (macrogol) - 0.6 
mg, triacetin - 0.45 mg) 
Description: 
round, biconvex, film-coated tablets, from white to white 
with 
creamy colour 
Pharmacotherapeutic group 
antioxidant agent 
ATC Code: 
N07XX 
Placebo 
Name of the drug 
not applicable 
INN: 
not applicable 
Dosage form 
film-coated tablets 
Composition: 
Composition: 
lactose monohydrate - 222.5 mg, povidone 25.0 mg, 
magnesium stearate - 2.50 mg 
Film coating: opadray II white 33G28435 - 7.5 mg 
(hypromellose - 3.0 mg, titanium dioxide - 1.875 mg, lactose 


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monohydrate - 1.575 mg, polyethylene glycol (macrogol) - 
0.6 mg, triacetin - 0.45 mg) 
Description: 
round, biconvex, film-coated tablets, from white to white 
with a creamy tinge colour 
Pharmacotherapeutic group 
not applicable 
ATC Code: 
not applicable 
4.4.2. 
Production, packaging and labelling 
In accordance with the requirements of the Good Manufacturing Practice Rules (approved by 
Order of the Ministry of Industry and Trade of the Russian Federation No. 916 dated 14 June 
2013; current version), the following information will be applied to the primary packaging of 
medicinal products for clinical trials: 
 
name of the medicinal product Mexidol® / placebo; 
 
Sponsor; 
 
pharmaceutical form, dosage and number of tablets in the package; 
 
number (code) of the trial; 
 
"For clinical trials”; 
 
batch number; 
 
expiry date 
 
"Morning" or "Evening." 
The following information will be labelled on the secondary packaging of the medicinal product 
for the clinical trial: 
 
sponsor's name and contact information; 
 
name and contact details of the manufacturer; 
 
name of the medicinal product Mexidol® / placebo; 
 
pharmaceutical form, dosage and number of tablets in the package; 
 
"If you experience any side effects, consult a doctor!"; 
 
protocol number (code); 
 
directions for use; 
 
method of application; 
 
storage conditions; 
 
"Keep out of reach of children." 
 
"For clinical trials”; 
 
"Morning" or "Evening”; 
 
date of prescription; 
 
return date; 
 
patient identification information; 
 
patient's randomisation code; 
 
visit number; 
 
Full name of the investigator; 
 
batch number; 
 
date of manufacture; 
 
shelf life. 
The following information will be labelled on the tertiary packaging of the medicinal product 


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Protocol PHS-ADHD-002-MEX-TAB 
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for the clinical trial: 
 
sponsor's name and contact information; 
 
name and contact details of the manufacturer; 
 
name of the medicinal product Mexidol® / placebo; 
 
dosage form, dosage, number of packs and tablets in the pack; 
 
patient identification information; 
 
Full name of the investigator; 
 
protocol number (code); 
 
Full name of the investigator; 
 
patient's randomisation code; 
 
method of application; 
 
batch number; 
 
date of manufacture; 
 
shelf life; 
 
"If you experience any side effects, consult a doctor!"; 
 
directions for use; 
 
storage conditions; 
 
"Keep out of reach of children." 
 
"For clinical trials”. 
The primary package will be a blister with 10 tablets. Five blisters will be enclosed in secondary 
packaging - 2 carton packs, each labelled "Morning" or "Evening" for the morning or evening 
dose respectively. Patients in all groups will therefore be given a set of two secondary packs 
contained in a single tertiary pack (carton pack). 
4.4.3. 
Dosing in patients 
Investigational product 
Mexidol® (ethylmethylhydroxypyridine succinate) film-coated tablets, 125 mg (RPC 
PHARMASOFT LLC, Russia). 
Method of administration: 
In Group 1 , the drug will be administered orally 1 tablet OD. Patients additionally take 1 
placebo tablet. The interval between drug and placebo administration was 12±1 hours. 
Duration of therapy: 42 days. 
In Group 2 , the drug will be administered orally 1 tablet BID. The interval between doses is 
12±1 hours. 
Duration of therapy: 42 days. 
Placebo film-coated tablets (RPC PHARMASOFT LLC, Russia). 
Method of administration: 
In group 3, placebo will be administered orally 1 tablet BID. The interval between doses is 
12±1 hours. 
Duration of therapy: 42 days. 


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4.5.  Expected duration of patient participation in the trial, description of trial 
periods and procedures 
4.5.1. 
Trial duration 
The duration of treatment is 42 days. The duration of the follow-up period is 7 days. 
Screening and randomisation can be carried out on the same day provided all screening 
procedures are performed, and results are available. 
The total minimum duration of patient participation in the trial will be 49 full days: a screening 
and therapy period of 42 days plus a follow-up period of 7 days. 
The total maximum duration of patient participation in the trial will be 67 days: a screening 
period of 14 days plus a therapy period of 42 days plus a follow-up period of 7 days, plus a 
window for the end-of-therapy visit (Visit 5) of 1 day and the follow-up visit (Visit 6) of 3 days. 
4.5.2. 
Beginning of the Trial. Visit 1 (Day -14 -1) Screening. 
The start of the trial will be the inclusion (screening) of the first patient in the trial. In the 
Russian Federation, in accordance with the Federal Law "On Circulation of Medicines", the 
head of a medical organisation (research centre) shall, within a period not exceeding three 
working days from the date of commencement of a clinical trial of a medicinal product for 
human use, notify the authorised federal executive body that issued the permit to conduct such 
a trial, in the form established by it. 
Each potential research participant should be adequately informed about the aims, methods, 
expected benefits of the research and the risks and inconveniences associated with participation 
in the research. 
Patients must be provided with comprehensive and accurate information regarding all aspects 
of the trial prior to any procedures and activities related to the trial. Prior to any procedures, the 
Patient Information Sheet with the Informed Consent Form (hereinafter referred to as Informed 
Consent) must be personally signed and dated by one of the patient's parents in 2 copies, thus 
confirming consent to the patient's participation in the trial, one of which is handed over to the 
patient's parent. Immediately after signing the Informed Consent, the patient/patient's parent 
will be issued an Insurance Policy for the patient participating in the clinical trial. 
Next, an electronic Case Report Form (eCRF) is created for each patient, where all the necessary 
data is entered. 
The patient's parents are cautioned about restrictions on the use of concomitant therapy during 
the trial. A list of prohibited medications is listed in the Patient Information Sheet. 
In addition, parents will be given a handout with information on how to comply with the rules 
of patient participation in the trial, restrictions and how to complete the Patient Diary. 
Once the Informed Consent is signed by one of the patient's parents, screening procedures are 
performed. 
Screening confirms that the patient fulfils the trial eligibility criteria: fulfilment of all inclusion 
criteria and absence of all non-inclusion criteria. 
The duration of screening can be up to 14 days before randomisation. 


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At the visit, the investigator records the diagnosis and the following procedures are performed: 
 collection of demographic data and history; 
 measurement of height, body weight, calculation of body mass index (BMI); 
 assessment of inclusion/non-inclusion criteria; 
 registration of concomitant and pre-existing pathology; 
 registration of concomitant and prior therapy; 
 physical examination with recording of BP, HR, and RR; 
 Complete Blood Count; 
 blood chemistry; 
 urinalysis; 
 neurological status; 
 completion of the SNAP-IV scale by the investigator from the parents' words; 
 CGI-ADHD-S scale score by the investigator. 
The sum of the total score on the inattention, hyperactivity/impulsivity subscales of the SNAP-
IV scale obtained at screening will be considered as the baseline against which the efficacy 
assessment planned in this protocol will be performed. 
A date is set for the next visit (if necessary) or a randomisation visit (Visit 2) is conducted, 
provided all screening procedures have been completed and results of all tests have been 
obtained. 
4.5.3. 
Visit 2 (Day 1). Randomization. Initiation of therapy. 
The following procedures are performed on Visit 2: 
 registration of concomitant therapy; 
 assessment of inclusion/non-inclusion criteria; 
 evaluation of exclusion criteria; 
 AEs registration; 
 sNAP-IV and CGI-ADHD-S score if the interval between Visit 1 and Visit 2 is 7 or 
more days. 
In this case, the value obtained at Visit 2 is taken as the initial value of the sum of scores on the 
"inattention" and "hyperactivity/impulsivity" subscales of the SNAP-IV scale, and this value is 
used in further calculations of performance indicators. 
If the patient continues to meet all the criteria for trial participation, the randomization 
procedure and the following procedures are performed: 
 SCAS score: to be completed by the investigator from the patient's parents 
 ADHD Rating Scale IV: to be completed by the investigator from the patient's parents; 
 completion of an examination card for a child/adolescent with headache (if the patient 
has complaints of headache, at Visit 2 it is completed for the previous 3 months); 
 completion of the PedMIDAS questionnaire (if the patient has complaints of headache, 
at Visit 2 it is completed for the previous 3 months). 
The drug is dispensed in a quantity sufficient to provide therapy until the date of the next visit. 
The scheme of administration of the drug is explained. A handout for parents, the Patient Diary 
and instructions on how to complete it are given. A date is set for the next visit. The patient is 


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warned to bring all unused medication in its original packaging and a completed Patient Diary 
to the next visit. 
4.5.4. 
Visit 3 (Day 14±2), telephone contact 
Visit 3 takes the form of a telephone contact by the investigator 14 days from the start of 
treatment with the patient's parents. It is necessary to obtain information from parents about the 
general tolerability of therapy, adverse events that have occurred since the last assessment, 
prescribed drugs of concomitant therapy, remind about compliance with the therapy regime. If 
necessary, an unscheduled visit to the clinical centre by the patient may be scheduled based on 
the information received, or a follow-up telephone contact may be scheduled at the discretion 
of the investigator to monitor adherence to recommendations. 
4.5.5. 
Visit 4 (Day 28±2), telephone contact 
Visit 4 takes the form of a telephone contact by the investigator 28 days from the start of 
treatment with the patient's parents. It is necessary to obtain information from parents about the 
general tolerability of therapy, adverse events that have occurred since the last evaluation, 
symptom scores according to the ADHD Rating Scale IV, concomitant medications prescribed, 
and remind them of compliance with therapy. If necessary, an unscheduled visit to the clinical 
site by the patient may be scheduled based on the information received, or a follow-up telephone 
contact may be scheduled at the discretion of the investigator to monitor adherence to 
recommendations. 
4.5.6. 
Visit 5 (Day 43+1). End of therapy. 
Visit 5 is conducted after a full 42 days (on day 43+1) from the start of therapy to monitor the 
patient's condition, assess the efficacy and safety of treatment. Therefore, this visit should be 
scheduled for the day after the last evening dose of Investigational product/placebo, with a 
maximum of one follow-up visit allowed. Deviations to the lesser side (i.e. 41st, 40th, etc.) are 
unacceptable. The following procedures are performed on Visit 5: 
 
registration of concomitant therapy; 
 
evaluation of exclusion criteria; 
 
physical examination with measurement of BP, HR, and RR; 
 
Complete Blood Count; 
 
blood chemistry; 
 
urinalysis; 
 
AEs registration; 
 
neurological status; 
 
SNAP-IV score; 
 
SCAS score; 
 
ADHD Rating Scale IV score; 
 
CGI-ADHD-S score; 
 
CGI-I score; 
 
completion of a child/adolescent headache assessment card (if the patient has headache 
complaints identified at Visit 2, completed at Visit 5 for the past 1.5 months (6 weeks)); 
 
completion of the PedMIDAS questionnaire (if the patient has headache complaints 
identified at Visit 2, to be completed at Visit 5 for the past 1.5 months (6 weeks). 


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All scales are completed by the investigator: directly for the CGI-ADHD-S and CGI-I 
scales, and by the parents for the SNAP-IV, SCAS, ADHD Rating Scale IV, 
Child/Adolescent Headache Assessment Card and PedMIDAS questionnaire at Visit 5 
when visiting the clinical site. 
 
accounting for the Investigational product; 
 
assessment of adherence to therapy; 
 
collecting and supervising the completion of the Patient Diary. 
A date is set for the next visit. 
4.5.7. 
Visit 6 (Day 50+3). Follow-up 
 
registration of concomitant therapy; 
 
physical examination with measurement of BP, HR, and RR; 
 
AEs registration; 
 
neurological status. 
Once the procedures of visit 6 have been completed, the trial will be considered complete for 
the patient. 
After completion of all the procedures of the follow-up visit, if necessary, the investigator will 
prescribe treatment to the patient according to his/her judgement in accordance with current 
clinical practice. 
4.5.8. 
Unscheduled visits 
Additional unscheduled visits may be made if necessary (e.g., in the case of AEs/SAEs). In this 
case, detailed information about the visit (reason for visit, examination results) is entered on 
the relevant pages of the eCRF "Unscheduled visit". 
4.5.9. 
Examination in case of early termination 
If a patient is early withdrawn from the trial or parents withdraw consent for the patient to 
participate in the trial after the start of investigational product administration, the patient will 
be asked to return to the site for a final safety assessment to ensure the patient's well-being. The 
procedure for this examination is identical to the procedures at Visit 5. 
4.5.10. Completion of the trial 
The investigational site must fully complete the trial and complete all required documentation 
in full compliance with the protocol. The trial may be suspended by either the Sponsor or the 
investigational site until completion of the trial if objective reasons arise. Notices of suspension 
should be sent to all parties involved in the trial as soon as possible. Any increase in the trial 
timeline must be agreed between the Sponsor and the investigational site and documented. 
Notification of the completion of the trial must be sent to the authorised federal authorities 
within 5 working days. 
4.6. Description of the trial procedures 
4.6.1. 
Collection of demographic data and anamnesis, anthropometry 
At the Screening Visit, after signing the informed consent form, the following data will be 


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collected from all patients: 
 Gender, age (date of birth). 
 Detailed medical history (anamnesis vitae et anamnesis morbi), including: o previous 
injuries and surgeries (dates, indications, extent of surgical intervention); 
o past illnesses; 
o allergological history; 
o medicines used in the previous 30 days or 5 half-lives (whichever is longer) prior 
to the screening visit and currently used medicines, as well as herbal medicines 
and nutritional supplements. 
4.6.2. 
Physical examination 
Physical examination will be performed at the screening visit (Visit 1), Visits 5 and 6 to 
ascertain normal and altered patient physical findings prior to administration of investigational 
products and to identify possible changes after administration. Acceptable examination 
turnaround times are shown in Table 1.2. 
The physical examination includes assessment of: 
 general condition; 
 skin conditions; 
 musculoskeletal system; 
 lymph nodes; 
 thyroid gland; 
 upper respiratory tract and lungs; 
 heart, the blood vessels; 
 abdominal organs, kidneys; 
 neuropsychiatric status. 
4.6.3. 
Vital signs 
Measurement of vital signs of body activity will be performed at each visit (except for the 
randomization visit). Allowable time periods are shown in Table 1.2. 
The assessment includes: 
 systolic and diastolic blood pressure (BP); 
 pulse rate per 1 minute; 
 respiratory movements per 1 minute 
BP and pulse rate measurements are taken on the same arm in a seated or semi-recumbent 
position, after 5 minutes of rest and, if possible, by the same investigational site team member 
during a particular patient's participation in the trial. 
4.6.4. 
Neurological status 
Neurological status will be assessed at the screening visit to see if there are changes in 


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neuropsychiatric status prior to administration of Investigational products, and at visits 5 and 6 
to see if there are possible changes after administration. Acceptable examination turnaround 
times are shown in Table 1.2. Neurological status includes assessment of general 
symptomatology and history, general cerebral and focal symptoms, assessment of motor 
functions, assessment of sensory sphere, reflexes, assessment of other systems and organs 
(including memory functions, intellectual level, emotional state). 
4.6.5. 
Anthropometry 
Anthropometry involves measuring: 
 
height (without shoes), the value obtained is recorded by rounding to the nearest 
integer value in centimetres. 
 
body weight (without street clothes and shoes), the value obtained is recorded by 
rounding to the nearest tenth of a kilogram. 
Body mass index is calculated using the formula weight / (height, m)2 (kg/m2). 
4.6.6. 
Patient diary 
The patient diary is issued at Visit 2 after randomization. In the Diary, the patient/patient's 
parents should record the dates and times of drug administration, any adverse events that 
occurred during treatment, if any, and all concomitant medications (both those first prescribed 
during the trial and dosage changes to previously prescribed medications, including 
withdrawals). The patient diary is returned at Visit 5. The investigator should check the quality 
and completeness of the completion of the Patient Diary. 
4.6.7. 
Completion of questionnaires 
The SNAP-IV, SCAS, ADHD Rating Scale IV questionnaires, child/adolescent headache 
examination charts, and PedMIDAS questionnaires are completed by the investigator from the 
patient's parents at the trial visits (Table 1.2). The questionnaires should be assessed by the 
same parent throughout the trial. The Child/Adolescent Headache Assessment Card and 
PedMIDAS questionnaire are completed only if the patient has headache complaints identified 
at Visit 2; scale data are completed at Visit 2 for the past 3 months, at Visit 5 for the past 1.5 
months (6 weeks). 
The CGI-ADHD-S, CGI-I scales are assessed by the investiator. These scales are scored and 
completed by the same researcher who made the original measurements. 
4.6.8. 
Laboratory tests 
Clinical laboratory tests (including collection of biological samples) will be performed by the 
local laboratory of the research centre according to the standards of the respective centre. The 
physician researcher will receive the results of the tests, review, assess the clinical significance 
of each parameter deviating from normal values (used in the local laboratory), date and sign 
and store as source documentation. Blood samples for laboratory tests are taken on an empty 
stomach, i.e. the patient should not eat or drink anything other than water for 10 hours before 
the sample is taken. 
Complete blood count 
The examination of blood samples will be carried out in the laboratory of the Investigational 


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site, according to the methodology adopted by the laboratory of the site. Blood tests should be 
taken in fasting condition. The following parameters are investigated: 
 
haemoglobin; 
 
haematocrit; 
 
red blood cell count; 
 
platelet count; 
 
white blood cell count and complete white blood cell count; 
 
ESR. 
Biochemical blood test 
 
total protein; 
 
albumin; 
 
glucose; 
 
ALT; 
 
AST; 
 
total bilirubin; 
 
alkaline phosphatase (ALP); 
 
amylase; 
 
creatinine. 
Clinical urinalysis with sediment microscopy: 
 
colour; 
 
transparency; 
 
pH; 
 
specific gravity; 
 
protein; 
 
glucose; 
 
white blood cells; 
 
red blood cells; 
 
bacteria; 
 
cylinders; 
 
salt. 
4.7. Termination of the trial 
Exclusion criteria for individual patients are described in section 5.3. 


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If a patient is excluded from the trial, or the parents decide to terminate the patient's 
participation in the trial, or if the trial is early terminated, patients must participate in a final 
physical examination in accordance with Visit 5 procedures. The final examination is 
performed to ensure patient safety: this examination may reveal any patient health conditions 
that require treatment and are related to the patient's participation in the trial. 
In accordance with the rules of good clinical practice, a clinical trial may be suspended or 
terminated if a danger to the life, health of patients is detected in the process of conducting the 
trial. In case of danger to the life, health of a patient participating in a clinical trial, the 
investigators are obliged to inform the head of the medical organisation and the organisation 
that has received permission from the authorized federal executive body to organise a clinical 
trial of a medicinal product. The decision to suspend a clinical trial of a medicinal product is 
made by the head of the medical organisation and (or) the Sponsor of the trial, the decision to 
terminate such a trial is made by the authorized federal executive authority based on a written 
report from the head of the medical organisation or the Sponsor of the trial. 
Within a period not exceeding five working days from the date of completion, suspension or 
termination of a clinical trial of a medicinal product, a notification thereof shall be sent to the 
authorised federal executive body in the form established by it. 
The investigator is obliged to immediately inform the trial subjects about the suspension or 
termination of the trial, provide them with appropriate medical care and supervision. In 
terminating the trial, the investigator must ensure that the interests of the trial subjects are 
adequately protected. 
The investigator and/or medical organisation must promptly inform the Sponsor of the 
termination or suspension of the trial with a detailed explanation of the reasons in writing. 
If the Sponsor terminates or suspends the trial, the investigator must immediately notify the 
health care provider administration. 
The investigator and/or health care institution must immediately inform the Ethics Council of 
the termination or suspension of the trial with a detailed explanation of the reasons in writing. 
If the Ethics Council definitively or temporarily withdraws the decision to conduct the trial, the 
investigator must inform the administration of the medical institution. 
The investigator and/or health care institution must immediately inform the development 
organisation of the final or temporary withdrawal of the decision to conduct a clinical trial, with 
a detailed written explanation of the reasons. 
A clinical trial may be suspended or terminated upon submission by the relevant authorized 
federal executive body of a conclusion on the conduct of a clinical trial with violations of the 
rules of Good Clinical Practice, based on the results of an audit of the activities of one or more 
medical organisations that conduct clinical studies of a medicinal product. 
An individual centre-based trial may be discontinued if the Sponsor or its representatives, the 
investigator, regulatory authorities or the clinical centre's local ethics committee (LEC) deems 
it necessary for any reason. 
4.8. Accounting for Investigational products 


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The Investigational product and placebo for the trial will be handed over by the Sponsor to the 
trial organizer with an acceptance certificate and quality assurance document. Supplies of the 
investigational products from the Sponsor must be received and administered by a responsible 
person (investigator or his/her authorized person). The investigational products will be stored 
in a specially equipped room suitable for storage of medicinal products, in conditions of limited 
access with regular monitoring of the temperature regime, at a temperature not exceeding 25°C 
(for the Investigational product and placebo) in a place protected from exposure to intense light. 
The trial organizer sends the investigational product and placebo to the investigational site in 
sufficient quantities for the trial. 
The control, record keeping and storage of the medicinal products at the investigational site is 
carried out by a responsible person authorized by the Principal Investigator in accordance with 
the internal regulations of the investigational site and instructions provided by the Sponsor. 
Investigational products must be stored in accordance with the instructions provided by the 
Sponsor (instructions for the medical use of the drug) and applicable regulatory requirements. 
Records of the investigational product and placebo are kept by the investigator in a logbook for 
recording, storing and dispensing the investigational products. Dispensing of the investigational 
products to patients will be documented in the Investigator Site File. The investigator is 
responsible for using the investigational product and placebo in strict accordance with the 
approved protocol. Any discrepancies should be explained and documented. 
The record of dispensed investigational products is kept for each patient, and the number and 
initials of the patient to whom the investigational product was dispensed, the date of dispensing 
the investigational product to the patient, the quantity of the investigational product dispensed, 
the date of return of the unused investigational product, and the quantity of the returned unused 
investigational product are recorded. The person responsible for recording and storing the 
investigational product and the Principal Investigator shall prepare and sign the report. 
Upon completion of the trial, all unused or partially used investigational product must be 
returned to the Sponsor with the appropriate report. 
4.9. Storage of randomization codes and procedure for their disclosure 
The patient's randomisation code is provided in documents for use outside the Investigational 
site (eCRFs, SAEs reports, etc.). The assigned patient code is entered into the eCRF and 
associated forms. The patient code does not change during the course of the trial. 
The randomization plan is kept on file with the Sponsor or its representative. Members of the 
trial staff are responsible for following the centralized randomization procedure. 
In the event of unintentional unblinding of a patient or members of the trial staff, the Sponsor 
must be notified as soon as possible. 
In cases where unblinding of the treatment group and the investigational product used is 
necessary to ensure the safety of the trial participant (e.g., if a SAEs develops), unblinding must 
be done after approval and with the knowledge of the Sponsor's medical expert. The fact of 
disclosure of the randomization code should be reflected in the source documentation and the 
eCRF. 
Disclosure of the randomization code as a whole will be made after the trial is completed and 


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the database is closed. 
4.10. Data recorded directly in the eCRF 
In this trial, the eCRF will not act as source documentation, all data entered into the eCRF will 
be corroborated by other source documents. 
Source data are all information contained in the original medical records and certified copies 
thereof, describing the results of clinical observations, examinations, and other activities that 
allow for the reconstruction and evaluation of the clinical trial. Source data are contained in 
source documentation (originals or certified copies). 
The investigator authorises trial monitoring, audit(s), LEC review and regulatory inspection, 
and the submission of direct access to source data/records. 
Source records should be retained for 25 years. For each included patient, the investigator will 
indicate in the soutce records the fact that the patient is participating in this trial and complete 
trial information. 
The Investigator Site File should contain complete information about the trial, with all the 
events and the times in which they occurred.  
5. PATIENT SELECTION AND EXCLUSION 
The patient is considered to be enrolled in the trial from the moment the informed consent is 
signed. 
5.1. Inclusion criteria 
To participate in the trial, the patient must meet all of the following criteria: 
1. Signed written informed consent for participation in the trial from the patient's parents1. 
2. Patients are boys and girls, aged 6 to 12 years, inclusive, at the time of signing the 
informed consent. 
3. Child is being raised by the father and/or mother. 
4. Child's attendance at a mainstream pre-school or school. 
5. Diagnosis of attention deficit hyperactivity disorder established according to ICD-10 
and DSM-5 criteria by a psychiatrist or neurologist, namely: 
According to the DSM-5 
a. 6 or more symptoms of inattention persisting for at least 6 months and/or 
b. 6 or more symptoms of hyperactivity and impulsivity persisting for at least 6 
months 
c. symptoms are present in at least two areas of activity (preschool or school and 
home). 
and/or 
According to the ICD-10 
d. at least 6 symptoms of attention deficit disorder 
e. at least 3 symptoms of hyperactivity 
f. at least 1 symptom of impulsivity 
__________________ 
1 Hereinafter in the protocol: the term "parents" refers to both, either the mother or the father or one of them 


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g. stable for at least 6 months. 
6. Moderate severity of ADHD according to the General Clinical Impression of ADHD 
Severity Scale (CGI-ADHD- S), not requiring hospitalization for treatment. 
7. Not more than two comorbid disorders not requiring, in the opinion of the investigator, 
additional pharmacotherapy at the time of the trial 
5.2. Non-Inclusion criteria 
Patients with at least one of the following criteria should not be included in the trial: 
1. 
Hypersensitivity to the active substance of the investigational 
product 
(ethylmethylhydroxypyridine succinate) and/or other components of the product. 
2. 
Liver dysfunction: ALT and/or AST ≥2.5 upper limit of normal (ULN) by screening 
tests. 
3. 
Renal function disorders: blood creatinine ≥1.5 ULN by screening tests. 
4. 
Intracranial pathology (including but not limited to: intracranial haemorrhage, tumour, 
infection, history of head injury, excluding concussion). 
5. 
Associated autism spectrum disorders, Asperger's syndrome 
6. 
Mental retardation of any degree 
7. 
Other mental illnesses, except behavioural disorders (ICD-10 code F91). 
8. 
Failure to withdraw psychotropic medications used to treat ADHD. 
9. 
Other somatic and/or neurological diseases, the treatment of which requires the use of 
drugs that may affect the efficacy of the Investigational product (including but not 
limited to: epilepsy, depression). 
10. Administration of nootropics, vasoactive drugs, neuroprotectants, antioxidants, 
metabolic drugs for 7 days or 5 half-lives (whichever is longer) before randomization 
11. Presence of any history of cancer within 5 years prior to the screening visit. 
12. Participation in any other clinical trial of drugs and/or medical devices within 3 months 
prior to the screening visit and/or 5 half-lives, whichever is longer. 
13. Inability or impossibility to follow the requirements of the protocol, including for 
physical, mental or social reasons, in the opinion of the investigator. 
14. Lactose intolerance, lactase deficiency, glucose-galactose malabsorption. 
5.3. Patient exclusion criteria 
The investigator must inform patients that their participation in the clinical trial is purely 
voluntary and they have the right to terminate their participation in the trial at any time without 
giving reasons. Information about the voluntary participation in the trial will be included in the 
text of the Patient Information Sheet with the Informed Consent Form. 
A patient's parent may withdraw consent to participate in the trial at any time without giving a 
reason. In this case, the patient's parent should immediately contact the investigator and inform 
them of the decision to withdraw the patient from the trial. 
Possible reasons for early termination of participation in the clinical trial include: 
1. 
Withdrawal of informed consent by the patient's parent. 
2. 
Adverse events requiring cancellation of the investigational product 
3. 
Need for drugs that are prohibited under the terms of the protocol. 
4. 
Continued participation in the trial is contrary to the patient's best interests. 


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5. 
Discontinuation of the trial by the Sponsor. 
6. 
Discontinuation of the trial by regulatory authorities. 
7. 
Loss of communication with the patient. 
If a patient early terminates the trial, all procedures of the follow-up visit should be performed, 
if possible (see procedure schedule - Visit 5), within 24 hours of the decision to exclude the 
patient from the trial. 
The investigator must indicate the reason for early termination in the source documentation and 
eCRF. If the patient/patient's parents wish to terminate (the patient's) participation in the trial 
of their own decision, the investigator should try to find out the reason. If the early withdrawal 
is due to an adverse event, the investigator should make every effort to collect information about 
the outcome and record it in the eCRF in the adverse event section. If the withdrawal from the 
trial was due to a SAE, the procedure for immediately notifying the Sponsor on the SAE must 
be followed. 
To establish loss of contact with the patient, the investigator must make three attempts to contact 
the patient's parents on the telephone numbers provided by the patient at 2-day intervals. If the 
patient's parents remain unavailable for contact for the specified period of time, the investigator 
records this data in the eCRF and the patient is excluded from the trial. 
Follow-up of early withdrawn patients is not specifically planned. If a patient drops out of the 
trial due to AE/SAE, the patient will be followed until the AE/SAE resolves or becomes chronic. 
5.4. Rules for participation in the trial 
The patient/patient's parents must agree with the following restrictions and requirements, which 
are described in the Patient Information Sheet: 
 
adherence to the trial visit schedule; 
 
consent not to use any prohibited concomitant therapy and, if it is necessary, to inform 
the investigator immediately. 
5.5. Collection of data from trial subjects who has early discontinued their 
participation in the trial 
All participant withdrawals from the trial will be documented. The investigator must indicate 
the date and reason for early trial discontinuation in the source documentation and eCRF in the 
section on trial completion. 
If a patient wishes to stop participating in a trial, the investigator should try to find out the 
reason. If early patient discontinuation is due to an AE or serious adverse event (SAE), the 
investigator should make every effort to collect information about the patient's outcome and 
record it in the eCRF in the section on AEs/SAEs. If exclusion/withdrawal from the trial was 
due to a SAE, the procedure for notifying the Sponsor of the SAE must be followed (see section 
8.4). 
All AEs that occurred during the trial in patients who dropped out of the trial, including AEs at 
the time of discontinuation of the patient's participation in the trial, will be analysed and 
included in the final clinical trial report. 
If dropout/exclusion from the trial occurs after the investigational product has been 


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administered, patient data collected up to the time of dropout/exclusion from the trial will be 
considered in the safety analysis and, if possible, in the efficacy analysis. 
5.6. Substitution procedure 
Patients who drop out before randomisation will not be replaced by new patients but will be 
treated as not screened. Patients who drop out of the trial after randomisation and administration 
of the investigational product will not be replaced by new patients and their data will be 
included in the final analysis. 
5.7. Follow-up of patients who early terminated their participation in the trial 
Follow-up of early withdrawn patients is not specifically planned. 
If a patient dropped out of the trial due to an AE/SAE, the patient will be followed until the 
AE/SAE resolves or is deemed "chronic" or "stable" by the investigator. Follow-up of patients 
who early terminated their participation in the trial and still experience AE is also described in 
section 8.3. 
5.8. Documentation of data from patients who failed screened 
The investigator is responsible for all patients whose parent has signed informed consent. 
Patients whose parent has signed informed consent and yet do not fulfil the inclusion/non-
inclusion criteria as a result of the screening performed are considered as screening failure. 
The reason why a patient cannot be randomised into the trial should be stated in the source 
documentation. 
Identification numbers assigned to patients who failed screening cannot be reused. 
For patients who have failed screening, the investigator will need to complete the source 
documentation and screening visit in the eCRF. 
6. TREATMENT 
6.1. Use of Investigational products 
Patients who meet the trial eligibility criteria will be randomised to one of the three therapy 
groups in a 1:1:1:1 ratio: 
1. therapy group 1 - Investigational product Mexidol® film-coated tablets, 125 mg, 1 tablet 
OD + 1 placebo tablet; 
2. therapy group 2 - Investigational product Mexidol® film-coated tablets, 125 mg, 1 tablet 
BID, morning and evening; 
3. therapy group 3 - placebo 1 tablet BID, morning and evening. 
Method of administration: the Investigational product or placebo will be administered orally, 
with an interval between doses of 12±1 hours. 
Duration of therapy: 42 days. 
6.2. Allowed and prohibited concomitant therapies 
6.2.1. 
Psycho-correctional therapy 


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Since psychocorrectional therapies are multimodal and individualized for each patient, it is not 
possible within the scope of this protocol to standardize these approaches and generalize them 
to the whole patient sample. 
Nevertheless, in order to maintain uniformity in the nature of psychotherapeutic care applied to 
all patients, this protocol provides for consultations by a psychologist or psychotherapist for 
children with ADHD and their parents (one of the parents) during treatment with 
Mexidol®/placebo, i.e. family and parental therapy with parental competence skills. The 
purpose of these consultations is to inform parents about general principles of parenting 
children with ADHD and to teach techniques to modify the child's behaviour and to plan and 
structure time in daily interactions with the child. 
6.2.2. 
Allowed concomitant therapy 
At the screening visit the investigator shall record all medications (including herbal medicines) 
being taken at the time of the initial assessment in the source documentation and eCRF. 
Information on prior therapy should be evaluated to determine if it is consistent with the list of 
prohibited drugs. If such drugs are strictly indicated and their withdrawal is not safe, the patient 
cannot participate in the trial. 
Concomitant therapy and all changes (cancellations, changes in dosage and dosing regimen, 
new prescriptions) should be recorded in the source documentation and eCRF by the 
investigator at each visit. 
If concomitant somatic or psychiatric pathology is not a criterion for non-inclusion or does not 
prevent the patient's participation in the trial, its treatment during the trial should be carried out 
in accordance with the approved standards of medical care and clinical recommendations. 
However, concomitant preparations must not be in the group prohibited by this Protocol (see 
Section 6.2.2.). 
Taking into account the proposed restrictions on the selection criteria and on the medicinal 
products that are prohibited to be taken concomitantly with the Investigational product 
Mexidol® / placebo, the randomized nature of the trial will maintain the equality of the groups 
on this factor and will not lead to systematic error or distortion of the results of the trial. 
Information on concomitant medications (INN, dosage, indication, frequency of administration, 
route of administration, start date, discontinuation date) that the patient was taking before and 
during the trial should be recorded in the appropriate section of the eCRF, including the 
screening visit. All subsequent changes in concomitant therapy during the trial should also be 
reflected in the eCRF. 
6.2.3. 
Prohibited concomitant therapy 
The following medications are prohibited in this trial for the duration of the trial: 
1. neuroprotectants, antioxidants, metabolic drugs, vasoactive and nootropic agents, 
including but not limited to: actovegin, Aminalon, Biotredine, Vasobral, Gliatilin, 
Glycine, Dimefosfon, Instenon, Cogitum, Cortexin, Cudesan, Minisem, Noben, 
Pantogam, Picamilon, Piracetam, Tenoten Children's, Phenibut, Cerebrolysin, 
Cinnarizine, Encephabol; 
2. other agents affecting the central nervous system: ginkgo biloba leaf extract, 


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atomoxetine, tranquillisers and antidepressants. 
6.3. Methods for monitoring compliance with trial procedures 
It is the responsibility of the investigator to ensure that the trial procedures are followed. 
Adherence to therapy will be monitored at visit 5 by counting the Investigational product given 
and returned. 
The investigator is responsible for monitoring compliance with the visit schedule. To ensure 
that the patient's visit schedule is adhered to, the investigator should remind the patient of the 
date and time of the visit well in advance of the scheduled outpatient visit (phone call, fax, 
email, etc.). Attempts to contact the patient and reschedule the visit are recorded three times. If 
the patient cannot perform the next visit at the scheduled time, the possibility of rescheduling 
the visit is discussed, taking into account tolerances. 
7. EFFICACY EVALUATION 
7.1. Efficacy criteria 
Evaluation of the efficacy of therapy will be based on primary and secondary efficacy criteria. 
Primary efficacy criterion: 
1. Mean change in the total score on the inattention and hyperactivity/impulsivity subscales of 
the SNAP-IV scale after 6 weeks of therapy vs. baseline. 
Secondary efficacy criteria: 
1. Mean change on the SNAP-IV inattention subscale after 6 weeks of therapy vs. baseline; 
2. Mean change on SNAP-IV subscale hyperactivity/impulsivity after 6 weeks of therapy vs. 
baseline. 
3. Mean change on the SNAP-IV subscale, oppositional defiant disorder, after 6 weeks of 
therapy vs. baseline. 
4. Mean change in SNAP-IV subscale - Conners index after 6 weeks of therapy vs. baseline. 
5. Mean change on the Spence children's anxiety scale (SCAS) after 6 weeks of therapy vs. 
baseline. 
6. Mean change on ADHD Rating Scale-IV scores after 6 weeks of therapy vs. baseline. 
7. Clinical Global Impressions-ADHD-Severity scale (CGI-ADHD-S). 
8. assessment of the dynamics of PedMIDAS questionnaire scores (number of days with 
restriction of daily activity due to headache, number of days with headache, average 
headache severity and maximum headache severity in scores). 
9. The Clinical Global Impressions Scale - Improvement (CGI-I) score. 
At the moment there are no Russian regulatory recommendations for conducting clinical studies 
of medicinal products for ADHD, so the recommendations of the European Medicines Agency 
(EMA)14 are used as the main ones, according to which it is recommended to use rating scales 
as the main criterion for assessing efficacy. 
7.2. Methods and timing for estimating efficacy parameters 
Primary and secondary efficacy criteria will be assessed using appropriate scales (scales are 
provided in Section 17). 


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8. SAFETY ASSESSMENT 
Safety analyses will be based on an assessment of adverse events based on patient complaints 
and interview, physical examination (including assessment of vital signs) and laboratory results. 
All laboratory analyses will be carried out in the sites' local laboratories. Reference ranges of 
local laboratory normal values will be applied. Prior to the start of therapy (at visit 2), medical 
events will be recorded to correctly assess the patient's baseline condition. 
During screening, information about medical adverse events will be attributed to the patient's 
medical history 
(pre-existing/concomitant illnesses). Clinically significant abnormalities detected by objective 
examination and laboratory and instrumental examination at screening should not be reported 
as AEs, but should be recorded as associated pathology. A worsening of the original 
disease/condition, if it occurred during the trial, should be recorded as an AE. 
8.1. Safety parameters 
1. Number of adverse events (AEs)/serious AEs (SAEs). 
2. Frequency and severity of AE/SAE associated with Investigational product/placebo. 
Patients/patient's parents will be interviewed for adverse events by members of the trial staff at 
each visit. Spontaneous and identified adverse events will be entered on the Clinical Trial 
Adverse Event Reporting Form, source documentation and reported in the eCRF. In case of 
adverse events, the investigator may decide to repeat the clinical examination and/or laboratory 
tests. 
Measurement of vital signs (systolic and diastolic blood pressure, HR, RR) will be performed 
at all visits (except the randomisation visit). 
Physical examination will be performed at visits 1, 5, and 6. 
Complete blood count will be performed at visits 1 and 5. 
Biochemical blood tests will be performed at visits 1 and 5. 
Clinical urinalysis will be performed at visits 1 and 5. 
8.2. Adverse events 
8.2.1. 
Definition of adverse events 
An adverse event (AE) is any adverse change in the health status of a patient or subject of a 
clinical trial to whom a medicinal (investigational) product has been administered, regardless 
of the causal relationship with its use. An adverse event may be any unfavourable and 
unintended change (including a deviation of a laboratory indicator from the norm), symptom or 
disease, the time of occurrence of which does not exclude a causal relationship with the use of 
the medicinal product, regardless of the presence or absence of a relationship with the use of 
the medicinal product. 
8.2.2. 
Reporting adverse events 
The investigator and members of the trial staff at the Investigational site are responsible for 


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identifying, providing appropriate medical care, documenting and reporting cases that fall 
within the definition of adverse events and serious adverse events. 
The protocol provides for the recording of all AEs that occur to the patient after the first 
administration of the trial therapy and until the end of the patient's participation in the trial. 
During screening, information about medical adverse events will be attributed to the patient's 
medical history 
(pre-existing/concomitant illnesses). 
The planned trial will record all deviations in the health status of patients (based on the results 
of physical examination, laboratory and instrumental methods of investigation) from the data 
obtained at the Screening and from the accepted reference values. 
After obtaining the necessary information, the investigating physician will categorise the 
patient's condition as 'normal', 'clinically insignificant abnormalities' or 'clinically significant 
abnormalities'. In case the abnormalities detected during the trial have not been previously 
reported, or there is an aggravation of the patient's condition vs. the data obtained at Screening, 
the detected abnormalities will be classified as AEs. 
The patient will be informed by the investigator to report all adverse events that occur during 
the trial. 
Investigators should document all adverse events that were observed in the patient during the 
trial in medical histories and Case Report Forms. The patient is warned to report any new 
symptoms they develop to the investigator between visits. 
Each individual AE should be described in detail. Regardless of the presumed causal 
relationship, all adverse events spontaneously reported by the patient, or identified by the 
investigator and/or members of the trial staff, should be reported on the adverse event form of 
the eCRF. For serious AEs (SAEs), a SAE form must also be completed. 
The registration of an AE is completed according to the results of the examination at the 6th 
visit. 
Records of adverse events should include the following: 
 
date of the Investigational product therapy start (if applicable); 
 
date of an AE onset; 
 
patient identification (initials, age, randomization number in the trial; 
 
description of the event (symptoms, diagnosis) and its outcome; 
 
classification (severity, foreseeability, severity, outcome, relationship to drug use); 
 
measures taken (therapeutic or diagnostic measures prescribed, if applicable); 
 
description of the results of therapeutic and diagnostic measures (if applicable); 
 
date the AE resolved. 
An additional procedure must be followed for serious AEs (SAEs) (see section 8.4). 
8.2.3. 
Determination of adverse event parameters 
According to current guidelines, the parameters of AEa in relation to the variables of severity, 
foreseeability, severity, outcome and causality will be assessed as follows: 
Severity: 


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"Serious" adverse event is defined as any adverse medical event that, regardless of the dose of 
the medicinal product: 
 
resulted in death; 
 
was life-threatening; 
 
has caused severe or permanent disability or incapacity for work; 
 
required an inpatient admission (other than a previously planned admission) or causes 
an extension of the current hospitalization; 
 
resulted in a congenital anomaly/developmental defect; 
 
required medical intervention to prevent the above conditions; 
 
there has been transmission of an infectious agent through a medicinal product. 
In addition, a serious adverse event includes any event that does not formally fit the above 
criteria but is a significant medical event from the investigator's point of view. 
"Serious" adverse reaction is a serious adverse event with a causal relationship (possible, 
probable, or credible) to the use of the Investigational product; 
All other AEs that do not meet these criteria will be considered as “non-serious". 
Listedness: Unlisted adverse reaction - an adverse reaction whose nature, severity or outcome 
is not consistent with the information contained in the investigator's brochure. 
Severity: 
The severity of AEs is assessed as follows: 
The investigator assesses the severity of an adverse event according to the Common 
Terminology Criteria for Adverse Events (CTCAE) current version at the time of the trial. If an 
adverse event cannot be classified according to the CTCAE criteria, the Investigator will select 
the closest description of the severity of the adverse event from those given in the classification 
based on personal clinical experience: 
Degree of 
severity 
Category 
Definition/Description 
1 
Mild 
No symptoms or mild symptoms, only clinical or 
diagnostic follow-up is required; no intervention is 
indicated 
2 
Moderate 
Only minimal, localised or non-invasive interventions 
are indicated; limitation of daily living activities 
3 
Severe 
Severe or clinically significant but not immediately 
life-threatening; hospitalization or prolongation of 
hospitalization indicated; disability; limitation of self-
care in activities of daily living 
4 
Life-threatening/ 
Disability to work 
Life-threatening consequences, urgent intervention 
required 
5 
Fatal 
Death associated with an adverse event 
"Severe" adverse event will not necessarily be “serious" in nature, “serious" adverse event will 
not necessarily be "severe" by definition. 
Outcome: 


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The outcome of an AE is assessed as follows: 
Transition to the SAE: 
AE resulted in a condition that meets the 
criteria of seriousness (resulted in death, was 
life-threatening, required hospitalization of the 
patient or its prolongation, resulted in 
permanent or pronounced disability or 
incapacity, 
congenital 
anomalies 
or 
malformations, required medical intervention 
to 
prevent 
the 
development 
of 
these 
conditions. In case of any unexpected 
suspected transmission of an infectious agent 
through a medicinal product has occurred) 
Recovery without consequences 
The AE has completely resolved without 
observed residual events  
Improved condition 
AE in the process of resolution 
No change in condition 
AE has not resolved 
Recovery with consequences 
The resolution of the AE has occurred, but the 
patient still has some residual effects 
Death 
Patient died due to an AE (death is an 
outcome, not an AE) 
Unknown 
The outcome of an AE is unknown because the 
patient did not show up for the follow-up 
examination and attempts to obtain follow-up 
information were unsuccessful (lost for 
follow-up) 
Relationship to the use of the Investigational product: 
Determination of the relationship of an AE with the use of the Investigational product 
The association of an AE with the use of investigational products will be assessed using 
World Health Organisation (WHO) criteria: 
 Definite. Clinical manifestations of an AE, including abnormalities of laboratory 
parameters occurring during the period of drug administration, which cannot be 
explained by the presence of existing diseases and the influence of other factors and 
chemical compounds. Manifestations of adverse reaction regress after drug withdrawal 
and occur with repeated administration. 
 Probable. Clinical manifestations of an AE that include changes in laboratory values 
that are temporally related to the use of the Investigational product, that are unlikely to 
be related to comorbidities or other factors, and that regress with drug withdrawal. The 
response to rechallenge is unknown. 
 Possible. Clinical manifestations of an AE that include changes in laboratory values that 
are temporally related to drug administration but can be explained by the presence of 
comorbidities or the administration of other drugs and chemical compounds. 
Information on response to drug withdrawal is unclear. 


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 Doubtful. Clinical manifestations of an AE that include changes in laboratory values 
that occur in the absence of a clear temporal relationship to drug administration; other 
factors (drugs, diseases, chemicals) are present that may be responsible for their 
occurrence. 
 Conditional. Clinical manifestations of an AE involving abnormalities of laboratory 
indications categorised as 'adverse reactions' that need further data (for accurate 
assessment) or these obtained data are currently being analysed. 
 Unclassifiable. Reports of a suspected adverse reaction cannot be evaluated because 
there is insufficient or conflicting information. 
The occurrence of an adverse event will be related to the Investigational product if the 
relationship is considered by the investigator as definite, probable, possible. 
Physician's actions in relation to the AE: 
1. No action required (continuation of the trial according to the protocol). 
2. Reducing the dose, which could mean: 
o reducing the dose of the Investigational product; 
o maintaining a certain dose despite the protocol's request to increase it; 
o reducing the frequency of administration/intake. 
3. Cancellation of Investigational product followed by resumption. 
4. Complete withdrawal of the Investigational product (complete discontinuation of the 
Investigational product). 
5. Prescribing other treatments, such as: 
o for the treatment of the AE; 
o changing the dosage of the concomitant therapy drug; 
o prescribing non-pharmacological therapy. 
8.3. Continued follow-up period for the AE 
All AEs should be traced to their resolution or until they are deemed by the physician to be 
“recovered with consequences". 
If a serious adverse event occurs, the patient will be monitored until the SAE is resolved by 
telephone calls to discuss complaints and history, as well as during visits that are not part of the 
trial schedule but are necessary for patient safety. 
If, in the opinion of the attending physician, an adverse event that is not serious requires follow-
up of the patient, such follow-up may also be conducted by telephone calls and visits, with 
questioning of complaints and history. 
The Sponsor will report all serious unexpected adverse reactions (hereinafter referred to as 
SUAR) for the Investigational product identified during the clinical trial to the regulatory 
authorities: 
 no later than 7 calendar days from the date of receipt of information on the 
identification of SUARs, if they have resulted in death or were life-threatening; 
 no later than 15 calendar days from the date of receipt of information on the 
identification of SUARs for other serious unexpected adverse reactions. 


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8.4. SAE reporting 
When a SAE occurs, the development of the SAE should be recorded in the source 
documentation and an SAE reporting form should be completed. 
The SAE Reporting Form must be submitted to the CRO/Sponsor representative within 24 
hours of the investigators' receipt of the SAE information. 
Representative of a contract research organisation (CRO): 
Maria Igorevna Shunikova 
Tel./fax: + 7 (4852) 594779 
E-mail: mi_shunikova@cphd.ru 
Sponsor's Representative: 
Qualified Person Responsible for Pharmacovigilance (QPPV) of RPC PHARMASOFT LLC: 
Irina Vladimirovna Medvedeva 
Tel: +7 (495) 626 47 55 ext. 162 
E-mail: pv@pharmasoft.ru 
The SAE Reporting Form should be sent even if the investigator has incomplete information 
on the SAE. Each initial report should contain at least the following information: 
 
Trial number (identifier or protocol number). 
 
Patient number. 
 
Investigator's full name and contact details. 
 
Description of the adverse event (date of onset, outcome as of the date of the report). 
 
The result of the investigator's assessment of the seriousness and severity. 
 
The result of the investigator's assessment of relationship with the Investigational product. 
The investigator must receive confirmation that the information has been delivered. An initial 
report containing incomplete information about a SAE should be immediately followed up with 
a subsequent detailed written report when new information becomes available to the 
investigator. 
If significant new information is received on an identified SAE, this information should be 
provided in the form of a follow-up communication. The investigator must comply with the 
following timelines for sending reports on SAEs to the Qualified Person Responsible for 
Pharmacovigilance: 
 
Within 24 hours of being informed of the SAE onset. 
 
After 30 days, if the SAE is still in progress. 
 
After the end of the SAE. 
Notification to the LEC of all SAE cases at the clinical site is carried out by the investigator 
within the timeframes specified in the LEC's SOPs. 
Where applicable requirements apply, Sponsor will provide appropriate notifications of SAEs 
to authorized health authorities. 


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9. STATISTICS 
9.1. Description of statistical methods 
Demographic and other baseline patient characteristics (age, gender, disease duration, prior and 
concomitant disease, prior and concomitant therapy) will be compared between therapy groups 
to demonstrate comparability between groups at baseline using appropriate statistical tests. 
Descriptive statistics for data whose distribution follows the law of normal distribution will be 
presented using the arithmetic mean and standard deviation. For otherwise distributed data 
descriptive statistics will be presented using non-parametric measures (median/mod, quartiles). 
Two-sided confidence intervals will be used to assess treatment efficacy (primary and 
secondary efficacy criteria). 
For primary and secondary efficacy criteria, differences will be considered statistically 
significant at the p-value level of <0.05. 
In accordance with the purpose of the trial, statistical analysis of the results is planned to 
compare the efficacy of the therapy regimen including Mexidol® in the treatment of attention 
deficit hyperactivity disorder (ADHD) in children 6-12 years old at different dosing regimens 
with the efficacy of the regimen including placebo and a combination of the Investigational 
product and placebo. 
The main efficacy criterion is the mean change in the total score on the inattention and 
hyperactivity/impulsivity subscales of the SNAP-IV scale after 6 weeks of therapy vs. baseline. 
Descriptive statistics for this indicator will be given and the following statistical hypotheses 
will be tested: 
H0 : μp=μT; 
H1: μT <μP 
μT - mean change in SNAP score in the trial group (group 1 Mexidol®, 125 mg OD, or 
group 2 (Mexidol®, 125 mg BID); 
μΡ - mean change in SNAP score in control group 3 (placebo). The sign "<" is associated 
with the fact that the change has a negative value. 
Comparison of the values of the two groups of patients will be performed by calculating the 
two-sided 95% confidence interval for the difference of μ1 (μ2) and μ0 values. A conclusion 
on superiority can be made if the upper bound of the two-sided 95% confidence interval for the 
difference in mean changes in SNAP scores of Mexidol® vs. placebo is negative. 
Testing of the null statistical hypothesis can be done using one-factor analysis of variance with 
Dunnett's posterior criterion and evaluation of contrasts or similar applicable statistical analysis 
method. 
The χ-square test or Fisher's exact test will be used to assess differences in event rates. 
The χ-square test or Fisher's exact test will also be used to assess differences in patient 
adherence. 
Safety parameters will be tabulated for all patients receiving Investigational product/placebo. 
Comparisons of safety outcomes between trial groups will be made using the χ-square or 
Fisher's exact test (for qualitative data) and the t-test for data whose distribution follows the law 


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of normal distribution or its non-parametric analogue (for data whose distribution does not 
follow the law of normal distribution). 
A detailed plan for the statistical analysis of the data will be presented in a separate document 
to be included in the clinical trial report submitted to the regulatory authority. 
Deviations from the statistical analysis plan that occur will be described in the clinical trial 
report. 
9.2. Planned number of patients 
To justify the sample size, a search was conducted for publications on the efficacy of treatments 
for children and adolescents with ADHD that evaluated efficacy using the SNAP scale. 
Among studies conducted on a similar population with similar endpoints, Dell'Agnello G, 
Maschietto D, Bravaccio C, Calamoneri F, Masi G, Curatolo P, Besana D, Mancini F, Rossi A, 
Poole L, Escobar R, Zuddas A was detected; LYCY Trial Group. Atomoxetine hydrochloride 
in the treatment of children and adolescents with attention-deficit/hyperactivity disorder and 
comorbid 
oppositional 
defiant 
disorder: 
A 
placebo-controlled 
Italian 
trial. 
Eur 
Neuropsychopharmacol. 2009 Nov;19(11):822-34, in which the change in the sum of scores on 
the "inattention" + "hyperactivity/impulsivity" domains of the SNAP-IV scale was evaluated as 
the primary endpoint - this trial was used to estimate the magnitude of effect in the placebo 
group. According to the data published in the above trial, the change in score in the placebo 
group was -2.0 (4.7). 
Since no studies of Mexidol® for the indication under study have been conducted previously, 
the data of the above-mentioned trial and the trial by Shang CY et al15 were used for 
approximate estimation of the effect size. 
Based on the data from the two studies cited, a similar SNAP rate would be expected at an 
average level across the two studies: 
 Change -8.1 (9.2), n=105; 95% CI: -9.88 to -6.32 (minimum value -6.32). 
 Change, 3.33 (5.58), n=75; 95% CI: -4.64 to -2.02 (minimum value, 2.02. 
95% confidence intervals were calculated based on the following formulae: 
SEM = SD  
√n  
DI = M ± tα,n-1 × SEM 
where: SEM - standard error of the mean; 
SD - standard deviation; 
n - number of observations; 
CI - confidence interval; 
M - mean. 
Using the minimum values (lower limits of the confidence interval), the weighted average was 
calculated using the following formula: 


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m = 
-6.32 × 105 - 2.02 × 75  = -4.5283 
 
105 + 75 
For further calculations, -4.5 scoresrounded to tenths were used. 
Although this estimate is based on experience with another ADHD medication, it suggests 
minimal clinically significant differences and can be used to justify the sample size for 
Mexidol®. 
To assess the variability of the effect, the coefficient of variation (CV) value was calculated for 
all the above change values in the active treatment group: 
CV = SD  
М  
The following values are obtained: 
• 
114% 
• 
167% 
of which the maximum of 167% was used to estimate the standard deviation, which for the 
selected value of change corresponds to the value of 4.5*1.67 = 7.515. 
For the placebo group, the actual data above were used (-2.0 and -4.7 for mean and standard 
deviation, respectively). 
In order to calculate the sample size, the following assumptions were made: 
1. One-sided hypothesis of superior efficacy of Mexidol® over placebo. 
2. The mean change in SNAP score in the placebo group is -2.0 points, and the standard 
deviation for the change is 4.70 points. 
3. The mean change in SNAP score in the Mexidol® group is -4.5 points, and the standard 
deviation for the change is 7.515 points. 
4. The modulus of the difference in mean SNAP scores between the Mexidol and placebo 
groups is 2.5 points 
5. The pooled variance estimate (pooled variance) is: 
SE = √ 
СО21 + СО22 
=√ 
0.12, 0.46 
= 6.27 
2 
2 
6. The minimum adequate strength is 80% (consequently, the II error is 0.20). 
7. The ratio of group volumes is 1:1:1:1. 
8. The significance level is 95% (respectively, the I error is 0.05). Since the boundaries of 
the 95% confidence interval must be two-sided and testing of the superiority hypothesis 
is one-sided, a one-sided error I of 0.025 will be applied to test the hypothesis, which is 
equivalent to an error of 0.05 for a two-sided test. 
9. 20% drop-out rate during screening. 
10. 10% drop out rate during follow-up (based on the above studies). 
All calculations were based on the formulae from the book16 (page 228), where the 
approximating function for power is given by the following equation 
1 -β = 1 – F(tK,α - 
∆ 
) 


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σ√2/ n 
Where Δ - clinically acceptable minimal difference (difference) from placebo and Fz = ∫z∞ 
Normal(0.1), which can also be written by the following expression for n: 
n = 
2σ2 [tκ.α+zβ ]2  
Δ2 
 
Calculations were performed using the statistical package PASS 11 (NCSS Inc., USA), which 
is a validated package that uses formulae directly from the book by Chow et al. cited above. 
The results of the calculations are as follows: 
 
number of patients to complete the trial according to the protocol = at least 100 in each 
group or a total of at least 300; 
 
number of randomized patients = 111 in each group or a total of 333; 
 
number of patients screened, taking into account expected drop-out rate at screening of 
≈20% = 417. 
9.3. Applied significance level 
The plan is to apply a significance level of 0.05 and calculate a two-sided 95% confidence 
interval. 
9.4. Criteria for trial termination 
The trial does not include interim data analyses and statistical criteria for trial termination. 
9.5. Procedures for recording missing, unanalysable and questionable data 
Missing, unanalysable and questionable data will not be replaced and taken into account in the 
statistical analysis of results. 
9.6. Procedures for reporting any deviations from the original statistical plan 
The details of the statistical analysis will be presented in the statistical analysis plan. The 
statistical analysis plan will be approved before the database cut off. All deviations from the 
approved version of the statistical analysis plan will be justified in the clinical trial report. 
9.7. Selection of data for statistical analysis 
Analyses will be conducted in the following populations: 
1) safety population - will include all randomized patients who have taken at least one dose 
of the Investigational product; 
2) the full analysis set (FAS) population will include all randomised patients who have 
taken at least one dose of Investigational product and who have an assessment of 
response to therapy after 6 weeks of therapy. This will be the main population for 
efficacy analyses; 
3) PP (per protocol population) is a subgroup of the FAS population that will include 
patients in the absence of significant protocol deviations with respect to 
inclusion/exclusion criteria, adherence to therapy, and use of concomitant therapy. This 
will be an additional population used for efficacy analyses. 


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10. DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
It is the responsibility of the investigator to provide direct access to the source 
data/documentation to the employees of RPC PHARMASOFT LLC and its representatives, 
employees of authorized bodies for the purposes of monitoring, audit, expertise, and inspection. 
The Sponsor / Sponsor's representative must ensure that one of the patient's parents has given 
written consent for direct access to the patient's original medical records for the purposes of 
monitoring, auditing, ethical review, and inspection by authorized bodies. 
10.1. Protocol compliance 
The investigator conducts the clinical trial in accordance with a protocol developed by the 
Sponsor and approved by the appropriate regulatory authorities/independent ethical 
committee. Changes to the protocol are not permitted unless there is an immediate threat to 
trial subjects and if the changes relate to organizational and financial matters. The Sponsor 
must submit all protocol changes to the regulatory authorities/independent ethics committee 
as required. Any deviation from the protocol during its execution must be recorded and 
reflected in the trial documentation. 
10.2. Deviations from protocol 
In general, any deviation from the protocol may be accepted only in an urgent case or after 
obtaining written agreement from the Sponsor and subject to approval by the Ethics Committee. 
Any deviation from the protocol should be clearly explained in the source documentation and 
in the eCRF. Classification of protocol deviations will be made before the database cutt off by 
the Sponsor's medical expert. Deviations from the protocol will be considered significant in the 
following cases (the list may be expanded in a subsequent evaluation of protocol deviations): 
 
skip of visit 5; 
 
violation of inclusion / non-inclusion criteria; 
 
violation of the exclusion criteria; 
 
taking the Investigational product/placebo <80% or >120% of the total number of 
tablets prescribed; 
 
administration of prohibited drugs. 
If significant deviations from the protocol are identified, the CRA must immediately inform the 
Sponsor. 
In the absence of data at Visit 5 when data are available at Visit 6, these patients will not be 
included in the FAS and PP populations, but will be analysed in the safety population. 
In the presence of data at Visit 5 and the presence of the other listed significant protocol 
deviations, these patients will be included in the full analysis population, safety population, but 
excluded from the protocol population. 
10.3. Confidentiality of patient data 
The investigator will ensure that the confidentiality of patient data is maintained. In the eCRF 
and any other documents submitted to the Sponsor, patients will be referred to by assigned 
numbers (codes) rather than by their names. Initials will not be used in this process. Documents 
not intended to be sent to the Sponsor, such as a list of personal data and associated patient 
identification numbers, must be kept strictly confidential by the investigator. 


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11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. Selection of Investigational sites 
The selection of investigational sites will be approved by the Sponsor prior to start of the trial 
to ensure that the personnel required in the trial are available and to assess the ability of these 
personnel to perform the trial in accordance with Good Clinical Practice requirements. 
11.2. Trial conduction 
All aspects of the clinical trial protocol must be adhered to during the clinical trial. If changes 
are necessary, they should be discussed without delay by the Investigator, CRA and Sponsor. 
Amendments to the clinical trial protocol must be made in writing and include a detailed 
justification for the changes. Amendments must be submitted to the Ministry of Health (MOH) 
and, once authorised by the MOH, to the LEC. 
Each deviation from the trial protocol must be documented and justified by the investigator (or 
person designated by the investigator) in the appropriate place in the eCRFs and Investigator 
Site Files. 
All other persons involved in the clinical trial process will be instructed by the investigator or 
CRA as to their tasks. This is the responsibility of the investigator. 
11.3. Monitoring 
Monitoring is the process of progress of a clinical trial control to ensure that it is conducted, 
documented and reported to the appropriate authorities in accordance with the Protocol and 
Good Clinical Practice guidelines. The person conducting the monitoring is approved by the 
Sponsor. The CRA is the primary link between the Sponsor and the Investigator. The CRA, as 
required by the Sponsor, shall ensure that the trial is properly conducted and documented. 
Quality control of trial execution is provided by the Principal Investigator and quality assurance 
is achieved by monitoring visits, the timing of which is determined by the Sponsor. 
The Sponsor's representative or designated individual will monitor the trial to ensure that: 
 
data is correct, accurate and complete; 
 
patient safety and rights are protected; 
 
the trial is conducted in accordance with the currently approved version of the protocol 
and any other trial agreements, the rules of Good Clinical Practice, and all applicable 
regulations. 
The CRA will periodically contact the investigator and perform visits to review all source 
data/records relevant to the trial, verify adherence to the protocol and the completeness, 
correctness and accuracy of all entries in the eCRF compared to the source data. The 
investigator will work with the CRA to resolve any discrepancies identified. 
In this trial, the monitoring visits to the investigational sites are planned to take place throughout 
the trial in accordance with the approved monitoring plan. 
11.4. Data identification 
All data contained in the eCRF should be supported by data in the patients' source 


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documentation. Source documentation represents source documents and records (laboratory 
records, techniques, case histories, outpatient charts, automated device records, documents 
completed during examinations) and includes source patient data. For identification purposes, 
all source documentation and data will be labelled with a patient number. 
11.5. Audit and inspection 
Audit - a comprehensive and independent examination of trial-related activities and 
documentation conducted to confirm compliance of those activities and procedures for 
collecting, analysing and reporting data with the protocol, the Sponsor's Standard Operating 
Procedures, Good Clinical Practice and regulatory requirements. 
Audit observations and findings should be documented. 
Inspection is the action of the Authorised Body to formally inspect documentation, equipment 
and other materials deemed by the Authorised Body to be relevant to the clinical trial that are 
located at the investigational site, the premises of the Sponsor and/or Contract Research 
Organisation, and other organisations deemed by the Authorised Body to be relevant to the trial. 
Upon completion of the review, a report shall be prepared and shall be made available to the 
Sponsor subject to confidentiality. 
To ensure compliance with the Good Clinical Practice Guidelines and all applicable regulatory 
requirements, at any time during or after completion of the trial, the Sponsor or regulatory 
authority may audit or inspect the Investigational site. In the case of an audit or inspection, the 
investigator (as well as the institution) must agree to allow the auditor(s) and inspector(s) direct 
access to all documents relevant to the trial and to schedule time for them and members of the 
trial team to discuss the relevant results or issues. 
The investigator will ensure that all source data and records pertaining to the trial are available 
to a qualified quality assurance auditor authorised by the Sponsor or to regulatory inspectors 
upon proper notification. The primary objectives of audits and inspections are to confirm that 
the rights and welfare of patients taking part in the trial are protected and that all the data 
relevant to the assessment of investigational products have been processed and reported in 
accordance with the Good Clinical Practice Guidelines and applicable regulatory requirements. 
12. ETHICAL AND LEGAL REQUIREMENTS 
12.1. General requirements 
Patient participation in the clinical trial is voluntary. The patient (patient's parents) has the right 
to refuse to participate (patient) in an ongoing trial at any stage of the trial. The trial is conducted 
in accordance with the principles set out in the WMA Declaration of Helsinki (adopted at the 
18th WMA Assembly in Helsinki in June 1964, revised 2013). 
Investigators recruited to participate in a clinical trial will provide the Sponsor with signed and 
dated summaries describing their clinical research experience, professional and scientific 
background prior to the commencement of the clinical trial. 
12.2. Ethical review 
Ethical review of clinical trials of medicinal products is conducted by the Ethics Council under 


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the Ministry of Health of the Russian Federation and the LEC of each investigational site. The 
Ethics Council and LECs are dedicated to protecting the rights, safety, and well-being of all 
patients participating in a clinical trial. The Ethics Council of the Ministry of Health of the 
Russian Federation and the LEC of each investigational site must assess the relevance of the 
investigator's qualifications to the proposed trial on the basis of the investigator's curriculum 
vitae. A list of all local ethics committees (for each participating Investigational site) as well as 
the committee chairperson(s) will be included in the clinical trial report. 
Investigators must ensure that the clinical trial is initiated and conducted under the supervision 
and approval of a LEC that complies with current Good Clinical Practice and applicable 
regulatory requirements. Before starting the trial, investigators must send copies of the protocol, 
informed consent forms, investigator brochures, investigator CV, Patient Diary and other 
documents that are reflected in the LEC requirements of each investigational site for approval 
to conduct the clinical trial. Prior to initiation of the trial at the site, the investigator must receive 
from the LEC full confirmation of approval of the protocol and other submitted documents in 
writing and dated. 
Investigators must not make any changes to the trial or the conduct of the trial without LEC 
approval unless these changes are necessary to address obvious immediate threats to the welfare 
of volunteers. Corrections of minor inaccuracies or minor changes to the protocol that do not 
carry ethical significance will be sent to the LEC for notification purposes. 
The investigator must immediately report to the LEC any changes in the trial, unexpected 
problems, including risks to volunteers or others, and any deviations from the protocol to 
address immediate risks to patients. 
As part of the LEC's requirements for continued review of approved studies, the investigator 
must provide the LEC with a final clinical trial report upon completion of the trial. 
12.3. Regulatory permission 
Permission to conduct a clinical trial is issued by the authorized body based on the results of 
expert examination of the documents required for obtaining permission to conduct the trial. 
Permission must be obtained before patients perform any trial procedures, including 
examination during screening to assess eligibility for the trial. 
12.4. Informed consent 
The patient's informed consent must be obtained and executed in accordance with local 
requirements, Good Clinical Practice and the ethical principles set out in the Declaration of 
Helsinki. 
Prior to obtaining informed consent, the investigator or the investigator's authorized person 
must provide the patient and the patient's parents with information in a language and with a 
level of sophistication that the patient and parents can understand, either verbally or in writing. 
Each patient (patient's parents) should have the opportunity to discuss the trial and its 
alternatives with the investigator. 
Prior to participation in the trial, the informed consent form must be personally signed and dated 
in duplicate by one of the patient's parents and the person who conducted the informed consent 
procedure (the investigator or a person authorized by the investigator). A dated copy of the 


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informed consent must be given to the patient's parent and a second copy must be attached to 
the clinical trial documents at the investigational site. When providing informed consent, the 
patient's parent must consent to direct access to the patient's medical records for monitoring and 
auditing in the trial and checks by the LEC and authorized bodies. 
The informed consent form is modified and amended when new information becomes available 
that may be relevant to the patient. An amended informed consent form must then be signed 
and dated by one of the patient's parents. 
The investigator will explain that patients (patient's parents) have every right to refuse 
(patient's) participation in the trial or withdraw consent at any time, without any consequences 
for their further treatment and without giving reasons. 
13. DATA MANAGEMENT AND RECORD KEEPING 
13.1. Data processing 
All documentation related to the trial, as well as information regarding patients participating in 
the trial, is strictly confidential. 
The investigator is responsible for providing accurate, complete and reliable data in the Case 
Report Forms and all required reports. 
All patient data obtained during the trial are first entered into the source documentation and 
then transferred to the Case Report Forms. The data contained in the eCRF must match the data 
in the source documentation. The eCRF must be completed no later than 5 days after the 
patient's visit to the Investigational site. The eCRF must be signed by the investigator or an 
authorized trial staff by marking it electronically. These signatures certify that the information 
contained in the eCRF is accurate. The Principal Investigator has ultimate personal 
responsibility for the accuracy and authenticity of all clinical and laboratory data entered into 
the eCRF. 
Informed consent from the patient's parents and inclusion of the patient in the trial should be 
reflected in the patient's source documentation. These data should include trial identification 
and dates of patient participation. 
13.2. Data storage 
All records and documents of the clinical trial, including Case Report Forms, Patient 
Information Sheets, Patient Lists, Investigator Site File are retained at the investigational sites 
where the trial is conducted for at least 15 years after completion of the trial. Archiving will be 
carried out at each Investigational site in accordance with each Investigational site's current 
archiving procedures. 
The investigator should take all possible steps to prevent accidental or premature destruction of 
records. If archiving of records at the Investigational site becomes impossible, the investigator 
must notify the Sponsor. 
14. FINANCING AND INSURANCE 
Prior to the start of the trial, a procedure is in place to insure the health of patients participating 
in a clinical trial of a medicinal product. In the event of injury to the patient's health related to 


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the clinical trial, the insurance company through which the Sponsor has contracted for insurance 
will reimburse all costs of necessary medical examination and treatment required as a result of 
direct exposure to the investigational product and/or medical manipulations administered in 
accordance with the Clinical Trial Protocol. 
The clinical trial is sponsored by RPC Pharmasoft LLC. In this trial, the health of all patients 
will be insured, for which purpose the Sponsor / Sponsor's representative has entered into a 
contract on life and health insurance of patients participating in a clinical trial of medicinal 
products with the insurance company IPJSC INGOSSTRAKH. 
15. USE OF INFORMATION AND PUBLICATIONS 
All previously unpublished information on investigational product studies and procedures used 
by the Sponsor is considered confidential. All rights to this information are solely owned by the 
Sponsor. The investigator agrees to use confidential information only within the scope of the 
trial; otherwise, only after written consent from the Sponsor. 
The investigator should be aware that data obtained in the course of the trial may be used by 
the sponsor company or its agent to provide data to other investigator or government 
organisations. It must be realised that all data obtained during the trial must be made available 
at the first request of the Sponsor. 
A representative of the Sponsor, as well as representatives of government agencies, should have 
access to any source documents, but the anonymity of trial subjects should be respected as a 
professional norm. 
16. FINAL REPORT 
The clinical trial report is prepared after statistical analysis and statistical report. The clinical 
trial report includes the clinical part of the trial and summarised results. The report shall be 
submitted by the contract research organisation responsible for the preparation of the final 
report to the Sponsor on an electronic medium for approval. The clinical trial report, as well as 
other clinical trial documents, is confidential information that cannot be disclosed by the 
investigators without the appropriate authorization of the Sponsor. 
17. APPENDICES 
17.1. SNAP-IV scale 
James M. Swanson, PhD, University of California, Irvine, CA 92715 
Child's Name: 
 
Gender  
Age: 
 
Class:  
 
Ethnic group (circle as appropriate): African American, Asian, Caucasian, Hispanic, Other 
 
 
By whom filled:  
Class Type: 
 
Number of people in the class  
 
For each statement, select the answer choice that best 
describes the child's behaviour 
Never 
Sometimes 
Often 
Very often 
1. Often unable to concentrate on details, causing 
ridiculous mistakes on school assignments 
- 
- 
- 
- 


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For each statement, select the answer choice that best 
describes the child's behaviour 
Never 
Sometimes 
Often 
Very often 
2. Often has difficulty sustaining attention for long 
periods of time on tasks or play activities 
- 
- 
- 
- 
3. Often does not listen when addressed 
- 
- 
- 
- 
4. Often unable to follow instructionsOR complete school 
assignments, daily chores, and other responsibilities 
- 
- 
- 
- 
5. Often finds it difficult to organize and carry out tasks in 
a rational way 
- 
- 
- 
- 
6. Often avoids, dislikes or does not agree to perform 
tasks that require prolonged mental effort 
- 
- 
- 
- 
7. Often loses things needed for tasks or activities (toys, 
books, pencils, etc.) 
- 
- 
- 
- 
8. Often easily distracted by extraneous stimuli 
- 
- 
- 
- 
9. Often forgetful in daily activities 
- 
- 
- 
- 
10. Often has difficulty maintaining attention when 
completing tasks or instructions 
- 
- 
- 
- 
11. Frequently moves arms or legs restlessly, fidgets in 
place 
- 
- 
- 
- 
12. Frequently leaves his/her seat in the classroom or 
similar behaviour in situations where sitting is required 
- 
- 
- 
- 
13. Often starts running or climbing somewhere, in 
situations where this is inappropriate 
- 
- 
- 
- 
14. Often makes a lot of noise during play and finds it 
difficult to spend leisure time in some quiet activity 
- 
- 
- 
- 
15. Often behaves as if he/she has a motor attached to 
him/her 
- 
- 
- 
- 
16, Often overly talkative 
- 
- 
- 
- 
17. Frequently shouts out an answer after not hearing the 
question all the way through 
- 
- 
- 
- 
18. Often struggles to wait his/her turn 
- 
- 
- 
- 
19, Often interrupts others or interferes (e.g. in 
conversations or games) 
- 
- 
- 
- 
20. Often unable to remain calm, sit still and restrain 
his/her impulses in the classroom or at home 
- 
- 
- 
- 
21. Often loses self-control 
- 
- 
- 
- 
22. Often argues with adults 
- 
- 
- 
- 
23. Often disobeys and refuses to comply with adult 
demands 
- 
- 
- 
- 
24. Often deliberately commits acts that annoy other 
people 
- 
- 
- 
- 
25. Often blames others for his/her mistakes and 
behavioural problems 
- 
- 
- 
- 


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For each statement, select the answer choice that best 
describes the child's behaviour 
Never 
Sometimes 
Often 
Very often 
26. Has hypersensitivity or is easily irritated by contact 
with others 
- 
- 
- 
- 
27. Often angry or resentful 
- 
- 
- 
- 
28. Can often be angry and vindictive 
- 
- 
- 
- 
29. Often quarrelsome 
- 
- 
- 
- 
30. Often demonstrates negative, defiant behaviour, 
disobedience or hostility towards authority figures 
- 
- 
- 
- 
31. Often makes noise (humming or making unintelligible 
noises) 
- 
- 
- 
- 
32. Often excitable, impulsive 
- 
- 
- 
- 
33. Can often cry easily 
- 
- 
- 
- 
34. Often unable to work in a group 
- 
- 
- 
- 
35. Often tries to "smarten up" 
- 
- 
- 
- 
36. Often restless and hyperactive. 
- 
- 
- 
- 
37. Often bothers other children 
- 
- 
- 
- 
38. Frequent and severe mood swings 
- 
- 
- 
- 
39. Often gets upset if his/her wish is not fulfilled 
immediately 
- 
- 
- 
- 
40. Often interferes with other children, teases them 
- 
- 
- 
- 
41. Often shows aggression towards other children 
(fighting, bullying) 
- 
- 
- 
- 
42. Often breaks things belonging to other people 
(vandalism) 
- 
- 
- 
- 
43. Lies frequently (e.g. stealing, cheating, forging, 
copying other people's work or manipulating others) 
- 
- 
- 
- 
44. Has frequent and serious misbehaviour (e.g. truancy, 
running away or completely ignoring classroom rules) 
- 
- 
- 
- 
45. Persistently violates the inherent rights of others or 
fundamental social norms 
- 
- 
- 
- 
46. Not always able to restrain aggressive impulses (may 
attack others or destroy their property) 
- 
- 
- 
- 
47. Has motor or verbal tics (sudden, rapid, repetitive, 
non-rhythmic motor or verbal activity) 
- 
- 
- 
- 
48. Presence of repetitive movements (waving arms, 
swaying torso or picking at skin) 
- 
- 
- 
- 
49. Having obsessive-compulsive thoughts - obsessions 
(e.g. persistent and intrusive inappropriate ideas, thoughts 
or impulses) 
- 
- 
- 
- 
50. Presence of compulsive behaviours - compulsions 
(behavioural or thought actions to reduce anxiety or 
tension) 
- 
- 
- 
- 
51. Often experiences a feeling of being "strung out", a 
state "on the verge of a nervous breakdown" 52. Often 
gets tired quickly 
- 
- 
- 
- 
53. Has difficulty concentrating or a "blank mind" 
- 
- 
- 
- 
54. Often irritable 
- 
- 
- 
- 


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For each statement, select the answer choice that best 
describes the child's behaviour 
Never 
Sometimes 
Often 
Very often 
55. Often feels muscle tension 
- 
- 
- 
- 
56. Often feels tense, anxious (premonition of trouble 
ahead) 
- 
- 
- 
- 
57. Frequent daytime sleepiness (unintentional falling 
asleep in inappropriate situations) 
- 
- 
- 
- 
58. Often over-emotional and seeking to be the centre of 
attention 
- 
- 
- 
- 
59. Frequent sense of grandiosity, need for admiration and 
lack of empathy 
- 
- 
- 
- 
60. Frequent instability in relations with others, reactive 
mood and impulsiveness in actions 
- 
- 
- 
- 
61. Periods of heightened self-esteem, sense of self-
importance lasting at least a week 
- 
- 
- 
- 
62. Periods of increased talkativeness, eagerness to strike 
up conversations lasting at least a week 
- 
- 
- 
- 
63. Periods, lasting at least a week, when there was an 
influx of thoughts or a spurt of ideas 
- 
- 
- 
- 
64. Periods of elevated expansive or euphoric mood 
lasting at least a week 
- 
- 
- 
- 
65. Periods of engagement in enjoyable but risky 
activities lasting at least a week 
- 
- 
- 
- 
66. Periods of depressed mood (sadness, hopelessness, 
despondency) of at least 2 weeks duration 
- 
- 
- 
- 
67. Periods of irritable or cranky mood (inadequate to the 
situation) lasting at least 2 weeks 
- 
- 
- 
- 
68. Intermittent distinct decline in interest or enjoyment in 
most activities for 2 weeks 
- 
- 
- 
- 
69. Periods of psychomotor agitation (more than usual) 
lasting at least 2 weeks 
- 
- 
- 
- 
70. Periods of psychomotor retardation (in most activities) 
of at least 2 weeks duration 
- 
- 
- 
- 
71. Periods of fatigue or lack of energy lasting at least 2 
weeks 
- 
- 
- 
- 
72. Intermittent feelings of worthlessness or inadequate 
feelings of excessive guilt lasting less than 2 weeks 
- 
- 
- 
- 
73. Intermittent decrease in attention and thinking ability 
for at least 2 weeks 
- 
- 
- 
- 
74. Consistently low self-esteem most of the time for at 
least a year 
- 
- 
- 
- 
75. Persistent decreased concentration or difficulty in 
making decisions most of the time for at least a year 
- 
- 
- 
- 
76. A constant feeling of hopelessness most of the time 
for at least a year 
- 
- 
- 
- 
77. Presently there is increased arousal (alertness and 
anxiety only) or increased startle response 
- 
- 
- 
- 
78, Currently experiencing irritability, outbursts of anger, 
or difficulty concentrating. 
- 
- 
- 
- 
79. There is now an emotional response (e.g. feelings of 
tension, anxiety, hopelessness, tears) to stress 
- 
- 
- 
- 
80. Behavioural reactions (e.g. fighting, vandalism, 
truancy) to stress are now observed 
- 
- 
- 
- 
81. Struggles to complete school assignments 
- 
- 
- 
- 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
76 
Protocol version 4.0 dated 15.10.2019. 
 
 
For each statement, select the answer choice that best 
describes the child's behaviour 
Never 
Sometimes 
Often 
Very often 
82. Has difficulty concentrating on a task throughout the 
lesson 
- 
- 
- 
- 
83. Struggles to complete schoolwork 
- 
- 
- 
- 
84. Struggles to maintain accuracy and neatness when 
completing written work at school 
- 
- 
- 
- 
85. Experiencing difficulties in group 
classesa nd discussions 
- 
- 
- 
- 
86. Has difficulty moving on to the next topic went to the 
next class 
- 
- 
- 
- 
87. Has difficulty in communicating with peers in the 
classroom 
- 
- 
- 
- 
88. Has difficulty communicating with school staff 
(teachers and other staff) 
- 
- 
- 
- 
89. Struggles to remain calm in the classroom 
- 
- 
- 
- 
90. Struggles to sit on the chair during the lesson 
- 
- 
- 
- 
17.2. Child Anxiety Scale (SCAS) - parental assessment 
Susan H. Spence, 2000 (translated into Russian by Professor N.N. Zavadenko) 
Completion date 
 
Your child's first and last name 
 
 
 
Your surname and initials, degree of relationship 
 
 
Please rate your child's condition for the past three months. 
For each item, select the most appropriate answer: 
"Never," "Sometimes," "Often," or "Always.". Circle the number in the appropriate column. 
 
Never 
Sometimes 
Often 
Always  
1. 
0 
1 
2 
3 
My child worries about everything 
2. 
0 
1 
2 
3 
My child is afraid of the dark 
3. 
0 
1 
2 
3 
When my child faces challenges, he/she complains of 
unusual sensations in the abdomen 
4. 
0 
1 
2 
3 
My child complains of feeling scared, frightened 
5. 
0 
1 
2 
3 
My child is afraid to stay home alone 
6. 
0 
1 
2 
3 
My child is afraid of tests and exams 
7. 
0 
1 
2 
3 
My child is afraid to use public toilets and baths 
8. 
0 
1 
2 
3 
It is painful for my child to be without me/parents 
9. 
0 
1 
2 
3 
My child is afraid of doing something stupid in public 
10. 
0 
1 
2 
3 
My child is worried that he/she won't do well at school 
11. 
0 
1 
2 
3 
My child is worried that something terrible will happen to 
someone in our family 
12. 
0 
1 
2 
3 
My child complains of suddenly feeling like he/she can't 
breathe, even though there is no reason for it 
13. 
0 
1 
2 
3 
My child is constantly checking that he/she has done 


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Clinical Trial protocol 
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Never 
Sometimes 
Often 
Always  
everything right (like turning off lights, appliances, or 
locking the door) 
14. 
0 
1 
2 
3 
My child gets anxious if he/she has to sleep alone at night 
15. 
0 
1 
2 
3 
My child has a hard time going to school in the morning 
because he/she feels anxious or afraid 
16. 
0 
1 
2 
3 
My child is afraid of dogs 
17. 
0 
1 
2 
3 
My child cannot get bad or stupid thoughts out of his/her 
head 
18. 
0 
1 
2 
3 
When my child faces challenges, he/she complains that 
his/her heart starts beating too fast (often) 
19. 
0 
1 
2 
3 
My child suddenly starts shaking or trembling when there 
is no reason to do so 
20. 
0 
1 
2 
3 
My child is afraid something bad will happen to him/her 
21. 
0 
1 
2 
3 
My child is afraid of going to doctors and dentists 
22. 
0 
1 
2 
3 
When faced with a problem, my child experiences doubt 
and hesitation 
23. 
0 
1 
2 
3 
My child is afraid of being at heights (like at the top of a 
steep mountain) or in lifts 
24. 
0 
1 
2 
3 
My child has special thoughts (techniques) to keep 
something bad from happening (like numbers or words) 
25. 
0 
1 
2 
3 
My child is scared when he/she has to ride in the car, bus 
or train 
26. 
0 
1 
2 
3 
My child worries about what other people think of him/her 
27. 
0 
1 
2 
3 
My child is afraid of being in crowds (e.g. shopping 
centres, cinemas, buses, sports grounds) 
28. 
0 
1 
2 
3 
In all unexpected situations, my child feels frightened even 
though there is no reason for it 
29. 
0 
1 
2 
3 
My child is afraid of insects and spiders 
30. 
0 
1 
2 
3 
My child complains of sudden dizziness or fainting spells 
for which there is no cause whatsoever 
31. 
0 
1 
2 
3 
My child experiences fear when he/she has to speak in front 
of the whole class 
32. 
0 
1 
2 
3 
My child complains that his/her heart starts beating too fast 
all of a sudden for no reason at all 
33. 
0 
1 
2 
3 
My child fears that he/she will suddenly panic, even though 
he/she really has nothing to fear 
34. 
0 
1 
2 
3 
My child is afraid of being in confined enclosed spaces 
such as a small room or tunnel 
35. 
0 
1 
2 
3 
My child does certain things over and over again (e.g., 
repeatedly washing hands, cleaning/wiping objects, 
arranging/laying things out in a certain order) 
36. 
0 
1 
2 
3 
My child is plagued by bad and silly intrusive thoughts or 
pictures that pop into his/her head 
37. 
0 
1 
2 
3 
My child needs to do certain things in a certain right way 
to prevent something bad from happening 
38. 
0 
1 
2 
3 
My child gets anxious when he/she has to stay out of the 
house all night 
39. 
 
 
 
 
Is there anything else your child fears/is afraid of? 
Please specify below exactly what it is and how it often 
happens 
0 
1 
2 
3 
1.  
 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
 
Never 
Sometimes 
Often 
Always  
0 
1 
2 
3 
2.  
 
0 
1 
2 
3 
3.  
 
 
 
 
 
 
 
 
17.3. ADHD Rating Scale-IV  
Circle the answer number that best describes the 
child's behaviour in the last 6 months 
Never 
rarely 
Sometimes 
Often 
Very often 
1. Cannot focus on details, which makes him/her make 
ridiculous mistakes when doing homework. 
0 
1 
2 
3 
2. Restless movement of arms or legs, fidgeting in place. 
0 
1 
2 
3 
3. Has difficulty holding attention for long periods of time 
while performing tasks or play activities. 
0 
1 
2 
3 
4. Leaves his/her seat in the classroom or similar 
behaviour in a situation where sitting is required. 
0 
1 
2 
3 
5. Does not listen when addressed. 
0 
1 
 
3 
6. Starts running or climbing somewhere, in situations 
where this is inappropriate. 
0 
1 
2 
3 
7. Does not follow the instructions received or does not 
follow through with what has been started. 
0 
1 
2 
3 
8. Experiences difficulty in spending leisure time in some 
quiet activity. 
0 
1 
2 
3 
9. Has difficulty in organising tasks and activities. 
0 
1 
2 
3 
10. Behaves as if he/she has a motor attached to it. 
0 
1 
2 
3 
11. Avoids tasks (e.g., classwork or homework) that 
require prolonged mental effort. 
0 
1 
 
3 
12. Overly talkative. 
0 
1 
2 
3 
13. Loses things needed to complete tasks or some 
activity. 
0 
1 
2 
3 
14. Shouts out the answer after not hearing the question 
all the way through. 
0 
1 
2 
3 
15. Easily distracted. 
0 
1 
2 
3 
16. Barely waiting his/her turn. 
0 
1 
2 
3 
17. Forgetful in day-to-day activities. 
0 
1 
 
3 
18. Interferes with other people's conversations, gets in 
the way. 
0 
1 
2 
3 
From ADHD Rating Scale IV: Checklists. Norms, and Clinical Interpretation, ©George J. Duaul, Thmas J. Power, 
Arthur D. Anastopoulos and Robert Reid. Reprinted by permission of the Guilford Press New York. 
17.4. Clinical Global Impressions-ADHD-Severity - CGI-ADHD-S 
  
"1" Normal, healthy 
 
The child is adequate in any environment 
 
No external structure is required 
 
No different from other children 
"2" Minimal disease severity 
 
Minor difficulties in any one setting 
 
If an external structure is required, it is only slightly 
 
Borderline deterioration 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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"3" Mild disease severity 
 
Some deterioration in any one environment 
"4" Moderate severity of the disease 
 
Some deterioration in at least two types of environments 
 
Significant difficulties at school and/or controlling one's behaviour 
"5" Extreme severity of the disease 
 
Deterioration in all kinds of environments 
 
Significant stress for others 
 
Social ties are disrupted 
"6" Severely ill 
 
Significant deterioration at all times in all types of environments 
 
Failure in academic/social environment 
 
Requires daily supervision for all or most of the day 
"7" One of the most difficult patients 
 
The most severe form of the disease 
 
Total insolvency even with constant supervision 
17.5. Clinical Global Impressions Scale - Improvement (CGI-I) 
Patient: 
Date: 
Doctor: 
 
Clinical global impression- global improvement 
Assess global improvement, even if, based on your clinical experience, you think it is 
related to medicinal drug only. 
How great are the changes compared to the patient's condition at the time of the first 
assessment? 
 
0 = No evaluation was carried out. 
 1 = very significant improvement - improvement on virtually all measures; good level of 
functioning; minimal symptom severity; demonstrates very significant change 
 2 = significant improvement - marked improvement with significant reduction in symptom 
severity; increased level of functioning, but some symptoms persisted 
 3 = slight improvement - slight improvement with a slight or clinically insignificant 
reduction in symptoms. Relatively small changes in clinical status, self-care and functional 
capacity relative to baseline level 
 4 = no change in symptomatology with little or no change in symptomatology 
 5 = slight deterioration, possibly clinically insignificant; may reflect a very slight change 
in clinical status of functional capacity relative to the BASELINE level 
 6 = significant deterioration - clinically significant increase in symptom severity and 
decline in functioning 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
80 
Protocol version 4.0 dated 15.10.2019. 
 
 
 7= very significant deterioration - marked exacerbation of symptoms and loss of function 
Adapted from Spearing M.K., Post R.M., Leverich G.S., et al. Modification of the Clinical 
Global Impressions (CSI) Scale tor use in bipolar illness (BP): the CGI BP Psychiatry Res 
1997; 73(3): 159-71. 
17.6. Patient diary 
(only the pages to be filled in are given) 
DAY 1 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 2 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 3 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 4 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 5 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 6 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 7 OF MEXIDOL®/PLACEBO 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
81 
Protocol version 4.0 dated 15.10.2019. 
 
 
ADMINISTRATION 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 8 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 9 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 10 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 11 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 12 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 13 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 14 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
 
DAY 15 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 16 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 17 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 18 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 19 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 20 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
D1 DAYS OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 22 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
83 
Protocol version 4.0 dated 15.10.2019. 
 
 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 23 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 24 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 25 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 26 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 27 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 28 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 29 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
DAY 30 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 31 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 32 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 33 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 34 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 35 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 36 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 37 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
85 
Protocol version 4.0 dated 15.10.2019. 
 
 
 
Yes  
No  
Yes  
No  
 
DAY 38 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 39 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 40 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 41 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
 
DAY 42 OF MEXIDOL®/PLACEBO 
ADMINISTRATION 
DATE _ _ _ / _ _ _ / _ _ _ _ _ _ 
_ _ _ _ _ 
Drug administration 
Morning 
Evening 
 
Yes  
No  
Yes  
No  
17.7. Assessment card for a child/adolescent with headache. 
(Visit 2 is filled out for the last 3 months, Visit 5 is filled out for the last 1.5 months (6 weeks)) 
Examination card for a child/adolescent with headache 
Date of examination 
Patient's full 
name 
 
 
Date of birth 
 
Age 
 
years 
months 
At what age did the headache first occur 
 
At what age did the headaches become frequent/severe 
 
FOR THE LAST 3 (1.5) MONTHS 
How often (how many times per month or week) there were the headaches (underline 
and write in the appropriate): 
1) every day or almost every day 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
2) several times a week; specify:__________ times a week 
3) about once a week 
4) 1 to 4 times a month; specify:__________ times a month 
4) once a month 
5) at least once a month 
How long the headache usually lasts (underline and insert as appropriate) 
1) 0-1 hour:  
minutes 
6) 2-3 days: 
 
twenty-four 
hours 
2) 1-6 hours: 
 
hours 
7) more than 3 days:  
twenty-four 
hours 
3) 6-12 hours: 
 
hours 
8) pain is constant 
4) 12-24 hours: 
 
hours 
9) duration varies greatly (specify: 
from____________ to_______________) 
5) 24-48 hours: 
 
hours 
What is the most common intensity of headache (underline the appropriate) 
Mild, moderate, tolerable, severe, intolerable 
Time of onset of headache (underline as appropriate) 
Morning, afternoon, evening, night, at different times 
Whether there are provoking factors for the headache: 
fatigue, emotional stress, odours (which:______________), sleep deprivation/ nighttime sleep 
disturbances, weather changes, habitual daily physical activity (which: climbing stairs, 
_________), other physical activity/exertion (which: ___________________________), 
coughing, skipping meals, alcohol consumption, menstruation, sudden head turns, other 
____________________________________________________________________ 
The nature of the headache (underline as appropriate) 
Aching, pressing, squeezing, tightening, cramping, throbbing, shooting  
Mixed character - specify___________________________________________ 
Headache localization 
Whole head, half of the head (__________________ side) 
Temporal, frontal- temporal, parieto-occipital, occipital clarification and comments 
________________________________________________________________________ 
Whether there are accompanying symptoms during the headache 
Nausea, vomiting, dizziness (systemic/nonsystemic), photophobia, phonophobia, lacrimation, 
eyelid swelling, sclera injection on the side of pain, pain or stiffness in the neck 
Other _________________________________________________________________ 
17.8. PedMIDAS questionnaire (to be completed only if the child has a 
headache) 
(Visit 2 is filled out for the last 3 months, Visit 5 is filled out for the last 1.5 months (6 
weeks)) 
 
Completion date 
 
Surname and 
first name 
 
 
Please answer each question about how your life has been affected by the headaches you 
have had in the past three (1.5) months 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
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Protocol version 4.0 dated 15.10.2019. 
 
 
The number of days on which there was some difficulty due to headache should be entered in 
the box. 
If there were no difficulties, 0 days are indicated. 
If the number of days is difficult to be exact, count them roughly but most reliably. 
1 How many school days have been completely missed at school 
(institution) due to headaches in the last 3 (1.5) months? 
 
 
 
 
days 
2 
How many school days were partially missed at school (institution) 
due to headaches in the last 3 (1.5) months? (not including 
completely missed days in the answer to question 1) 
 
 
 
 
days 
3 
How many days in the last three (1.5) months have you done less 
than half-heartedly at school because of a headache? (not including 
the days listed in the answers to questions 1 and 2) 
 
 
 
 
days 
4 
How many days in the last three (1.5) months have you been unable 
to do things at home (e.g., daily chores, homework, etc.) because of 
a headache? 
 
 
 
 
days 
5 
How many days in the last three (1.5) months have you been unable 
to participate in other activities (e.g., participate in games, walks, 
sports) because of a headache? 
 
 
 
 
days 
6 
How many days in the last three (1.5) months were you able to 
participate in these activities but did less than half-heartedly? (not 
including the days listed in the answer to question 5) 
 
 
 
 
days 
TOTAL 
 
 
 
 
days 
 
A 
How many days in the last three (1.5) months have you had a 
headache? (If the headache lasted more than one day, all days are 
counted) 
 
  
 
days 
B 
On a scale of 0 to 10 (put a vertical line), rate how much on average 
the headaches have been severe over the past 3 (1.5) months. 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
0 = no pain 
10 = pain 
 
unbearable 
C 
Rate on a scale of 0 to 10 points (put a vertical line) worst headaches 
you have had in the last three (1.5) months. How many times have it 
happened? ____________ 
How long did it last? _________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
0 = no pain 
10 = pain 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
88 
Protocol version 4.0 dated 15.10.2019. 
 
 
 
unbearable 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
89 
Protocol version 4.0 dated 15.10.2019. 
 
 
ADVERSE EVENTS AND MEDICAL DRUGS TAKEN 
Please indicate any significant changes in your child's medical condition and any new medications that have needed to be administered during the trial 
for any reason. 
If there are any problems, seek advice from a doctor at the investigational site. 
No. 
Symptom 
Date (dd/mm/yyyyy) 
and time (hh:min) of 
onset 
Date (dd/mm/yyyyy) 
and time (hh:min) of 
completion 
Has the medication 
been taken? 
Name of the medicinal 
product, dosage form, 
pharmaceutical form 
and dosage frequency 
example 
headache 
01.01.2016 (10.00) 
01.01.2016 (13.00) 
Yes V No  
Paracetamol 1 tablet, 
100 mg 
1. 
 
 
 
Yes  No  
 
2. 
 
 
 
Yes  No  
 
3. 
 
 
 
Yes  No  
 
4. 
 
 
 
Yes  No  
 
5. 
 
 
 
Yes  No  
 
6. 
 
 
 
Yes  No  
 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
90 
Protocol version 4.0 dated 15.10.2019. 
 
 
18. REFERENCE LIST 
1. 
Kotov A.S., Borisova M.N., Panteleeva M.V., Matyuk Y.V., Shatalin A.V. Attention 
deficit hyperactivity disorder. Clinical Lecture. Russian journal of paediatric neurology. 
2015;X(2):54-58. 
2. 
Zavadenko N.N. Hyperactivity and attention deficit in childhood: textbook. М.: 
Academy. 2005. 
3. 
Chutko L.S. Attention deficit hyperactivity disorder and related disorders. SPb: Hoka. 
2007. 
4. 
Skounti M., Giannoukas S., Dimitriou E., Nikolopoulou S., Linardakis E., Philalithis 
Prevalence of attention deficit hyperactivity disorder in schoolchildren in Athens, Greece. 
Association of ADHD subtypes with social and academic impairment. Atten Defic 
Hyperact Disord. 2010;2(3):127-132. 
5. 
Keen D., Hadijikoumi I. ADHD in children and adolescents. BMJ Clin Evid. 
2011;2011(Feb 4). 
6. 
Koren E.V., Kupriyanova T.A. FGBU "Federal Medical Research Centre of Psychiatry 
and Narcology named after V.P. Serbsky" of the Ministry of Health of Russia. 
Hyperkinetic disorders (ADHD). . Moscow. 2015. 
7. 
Zavadenko N.N. Attention deficit and hyperactivity disorder: modern principles of 
diagnosis and treatment. Issues in modern paediatrics. 2014;13(4):48-53. 
8. 
Sukhotina N.K., Egorova T.I. Evaluation scales of attention deficit hyperactivity disorder 
(ADHD). Journal of Clinical and Social Psychiatry. 2008(4):15-21. 
9. 
Potapova I.S., Khromina N.V., Protopopova M.V. The course of school adaptation in 
children with attention deficit hyperactivity disorder against the background of the use of 
Mexidol. Bulletin of Experimental Biology and Medicine. 2006;Suppl 1.:72-74. 
10. 
Askerova D.M. Application of mexidol in newborn children with syndrome of 
intrauterine developmental delay in the correction of hypoxic-ischaemic lesions of the 
central nervous system. Advances in modern natural science. 2011;5:50-52. 
11. 
Zvonareva E.V. Comparison of the effect of Mexidol and pantocalcin on clinical and 
functional manifestations of posthypoxic encephalopathy in infants. Bulletin of 
Experimental Biology and Medicine. 2012;Suppl 1:237-239. 
12. 
Tsypina L.G. Use of Mexidol in complex therapy of acute neuroinfections in children. 
Bulletin of Experimental Biology and Medicine. 2012;Suppl 1:246-252. 
13. 
Okuneva M.A. Use of Mexidol in correction of vegetative dysregulation syndrome as 
consequences of perinatal CNS lesions. Bulletin of Experimental Biology and Medicine. 
2012;Suppl 1:200-204. 
14. 
Guideline on the clinical investigation of medicinal products for the treatment of attention 
deficit hyperactivity disorder (ADHD). EMEA/CHMP/EWP/431734/2008. 2010. 
15. 
Shang CY, Pan YL, Lin HY, Huang LW, Gau SS. An Open-Label, Randomised Trial of 


RPC PHARMASOFT LLC  
Clinical Trial protocol 
Protocol PHS-ADHD-002-MEX-TAB 
Mexidol®, tablets, 125 mg 
 
CONFIDENTIAL 
 
91 
Protocol version 4.0 dated 15.10.2019. 
 
 
Methylphenidate 
and 
Atomoxetine 
Treatment 
in 
Children 
with 
Attention- 
Deficit/Hyperactivity Disorder. J Child Adolesc Psychopharmacol. 2015;25(7):566- 573. 
16. 
Chow S, Shao J, Wang H. Sample Size calculation in Clinical Research. 2nd edition. 
2008. 

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan  
 
A multicentre, double-blind, randomised, placebo-
controlled clinical trial in three parallel groups to evaluate 
the efficacy and safety of Mexidol® film-coated tablets, 125 
mg (RPC Pharmasoft LLC, Russia) in the treatment of 
attention deficit hyperactivity disorder (ADHD) in 
children aged 6-12 years under different dosing regimens 
(MEGA) 
 
 
 
 
 
 
NCT Number: NCT06854601 
 
 
 
 
 
 
Pharmasoft 
September 27, 2019 
 
 
 


 
 
ClinPharmDevelopment 
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Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 2 of 42 
 
Plan for statistical analysis of efficacy and safety parameters in 
the clinical trial 
“A multicentre, double-blind, randomised, placebo-controlled clinical trial 
in three parallel groups to evaluate the efficacy and safety of Mexidol® film-
coated tablets, 125 mg (RPC Pharmasoft LLC, Russia) in the treatment of 
attention deficit hyperactivity disorder (ADHD) in children aged 6-12 years 
under different dosing regimens (MEGA)” under protocol No. PHS-ADHD-
002-MEX-TAB, version 3.0 dated 19.07.2019. 
Yaroslavl - 2019 
 
 


 
 
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Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 3 of 42 
 
Approval sheet for the plan of statistical analysis of efficacy and safety parameters, 
version 1.0 dated 27.09.2019, in a multicentre, double-blind, randomised, placebo-
controlled clinical trial in three parallel groups to evaluate the safety and efficacy of 
Mexidol® film-coated tablets, 125 mg (RPC Pharmasoft LLC, Russia) in the treatment of 
attention deficit hyperactivity disorder (ADHD) in children aged 6-12 years under 
different dosing regimens (MEGA) under protocol No. PHS-ADHD-002-MEX-TAB, 
version 3.0 dated 19.07.2019. 
Project Manager 
Ekaterina Yuryevna Sharonova 
 
(signed) 
30.09.2019 
signature 
 
 
date 
 
Statistician 
 
 
Andrey Yuryevich Volin 
(signed) 
 
30.09.2019 
signature  
 
date 
 
Responsible Sponsor's representative  
 
 
 
 
 
signature 
 
date 
 
 


 
 
ClinPharmDevelopment 
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Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 4 of 42 
 
History of changes to the document 
Version number 
Date of issue 
Amendments 
Section 
Modifications made 
1.0 
27.09.2019 
New document 
 
 


 
 
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Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 5 of 42 
 
Table of Contents 
1. 
Trial background ................................................................................................................ 8 
2. 
Purpose of data statistical analysis ................................................................................... 10 
3. 
Deviations from protocol ................................................................................................. 11 
4. 
Trial procedures ................................................................................................................ 11 
5. 
Randomization ................................................................................................................. 12 
6. 
Main and additional trial parameters to be assessed in the course of the trial ................. 20 
7. 
Statistical hypothesis ........................................................................................................ 22 
8. 
Estimation of the required sample size ............................................................................ 23 
9. 
Statistical estimation of efficacy parameters .................................................................... 24 
10. 
Safety analysis .............................................................................................................. 25 
11. 
Patient populations to be analysed ............................................................................... 28 
12. 
Table templates ............................................................................................................ 29 
List of tables 
Table 1. Randomization scheme .............................................................................................. 12 
Table 2. Results of assessment of normality of distribution of indicators (template) .............. 29 
Table 3. Statistical analysis of the primary endpoint (template) .............................................. 32 
Table 4. Statistical analysis of secondary, endpoints (SNAP-GU, CGI-ADHD-S, SCAS, 
PedMIDAS and ADHD Rating Scale IV) (template) .............................................................. 33 
Table 5. Statistical analysis of secondary endpoints (CGI-Ι scale) (template) ........................ 34 
Table 6. Outcomes of the primary endpoint analysis ............................................................... 35 
Table 7. Baseline anthropometric indices (template) ............................................................... 35 
Table 8. Urinalysis values during the trial (template) .............................................................. 36 
Table 9. Results of the medical examination during the trial (template) ................................. 36 
Table 10. Comparison of vital signs when taking the Investigational product and the 
comparator product (template) ................................................................................................. 36 
Table 11. Results of statistical analysis of blood and urine test results (template) .................. 37 
Table 12. Summary table of the incidence of reported AEs in the group taking Mexidol by 
severity with randomization numbers of patients (N= ) ........................................................... 38 
Table 13. Summary table of the incidence of reported AEs in the group taking placebo by 
severity with randomization numbers of patients (N= ) ........................................................... 38 


 
 
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ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
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Table 14. Summary table of the incidence of reported AEs in the group taking Mexidol = 
placebo by severity with randomization numbers of patients (N= ) ........................................ 39 
Table 15. Summary table of the incidence of AEs after taking each investigational product . 39 
Table 16. List of all adverse events for each patient ................................................................ 39 
Table 17. Classification of AEs according to MedDRA v. 22.0 RU ....................................... 40 
Table 18. Summary table of the incidence of reported SAEs in the group taking Mexidol by 
severity with randomization numbers of patients (N= ) ........................................................... 40 
Table 19. Summary table of the incidence of reported SAEs in the group taking placebo by 
severity with randomization numbers of patients (N= ) ........................................................... 40 
Table 20. Summary table of the incidence of reported SAEs in the group taking 
Mexidol+placebo by severity with randomization numbers of patients (N= ) ........................ 41 
Table 21. Summary table of the incidence of SAEs after taking each investigational product…
 .................................................................................................................................................. 41 
Table 22. A list of all serious adverse events for each patient ................................................. 41 
Table 23. Classification of SAEs according to MedDRA v. .................................................... 42 
 
 


 
 
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Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
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List of abbreviations 
ADHD Rating Scale-IV; 
CGI-ADHD-S is a scale to assess the global clinical impression of ADHD severity; 
CGI-I - Clinical Global Impression-Improvement Scale; 
FAS - Full Analysis set; 
MedDRA - Medical Dictionary for Regulatory Activities; 
PP - Per Protocol; 
SNAP-IV - scale to assess the severity of ADHD; 
SCAS - Child Anxiety Scale - parental assessment; 
SOC - System Organ Class MedDRA; 
TESS - Treatment Emergent Signs and Symptoms; 
BP - Blood Pressure; 
ALT - alanine aminotransferase; 
AST - aspartate aminotransferase; 
GGT - gamma-glutamyltransferase; 
CI - confidence interval; 
BMI - Body Mass Index; 
eCRF - electronic case report form; 
AE - Adverse event; 
ADHD - attention deficit hyperactivity disorder; 
ESR - erythrocyte sedimentation rate; 
SAE - serious adverse event; 
RR - Respiratory rate; 
HR - Heart rate; 
ALP - alkaline phosphatase. 
The statistical tables will provide the following parameters for descriptive statistics: 
M - arithmetic mean; 
95% CI, L - the lower boundary of the 95% confidence interval; 
95% CI, U - the upper limit of the 95% confidence interval; 


 
 
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Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
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Me - median; 
Min - minimum value; 
Max - maximum value; 
Q1 - lower quartile; 
Q3 - upper quartile; 
Range - range of variation; 
QRange - interquartile range; 
SD - standard deviation; 
CV - coefficient of variation. 
1. Trial background 
Title: A multicentre, double-blind, randomised, placebo-controlled clinical trial in three 
parallel groups to evaluate the safety and efficacy of Mexidol® film-coated tablets, 125 mg 
(RPC Pharmasoft LLC, Russia) in the treatment of attention deficit hyperactivity disorder 
(ADHD) in children aged 6-12 years under different dosing regimens (MEGA). 
Protocol No.: PHS-ADHD-002-MEX-TAB 
Protocol version: 3.0 dated 19.7.2019. 
Sponsor: RPC PHARMASOFT LLC, Russia 
Investigational product: Mexidol® (ethylmethylhydroxypyridine succinate) film-coated 
tablets, 125 mg (RPC PHARMASOFT LLC, Russia). 
Comparator product: Placebo (RPC PHARMASOFT LLC, Russia). 
Trial design: 
A multicentre, prospective, double-blind, randomised in three parallel groups with a 1:1:1 ratio 
clinical trial to evaluate the efficacy and safety of Mexidol® film-coated tablets, 125 mg using 
placebo controls. Number of patients: 333 
Type of trial: phase II-III trial 
Trial purpose: 
Evaluation of efficacy and safety of two dosing regimens of Mexidol® film-coated tablets, 125 
mg (PRC Pharmasoft LLC, Russia) vs. placebo in children aged 6 to 12 years inclusive with 
attention deficit hyperactivity disorder (ADHD). 
Trial objectives: 
Primary objectives: 


 
 
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ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
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1. To evaluate the efficacy of Mexidol® film-coated tablets, 125 mg (PRC 
PHARMASOFT LLC, Russia) vs. placebo after 6 weeks from the beginning of therapy 
in relation to the average change in the total score on the "inattention" and 
"hyperactivity/impulsivity" subscales of the SNAP-IV scale when administered at a 
dose of 125 mg OD. 
2. To evaluate the efficacy of Mexidol® film-coated tablets, 125 mg (PRC 
PHARMASOFT LLC, Russia) vs. placebo after 6 weeks from the beginning of therapy 
in relation to the average change in the total score on the "inattention" and 
"hyperactivity/impulsivity" subscales of the SNAP-IV scale when administered at a 
dose of 125 mg BID. 
Secondary objectives: 
1. To evaluate the efficacy of Mexidol® film-coated tablets 125 mg (PRC 
PHARMASOFT LLC, Russia) vs. placebo after 6 weeks from the beginning of therapy 
when administered at a dose of 125 mg OD and 125 mg BID on the basis of the 
following parameters: 
a. Mean change on the SNAP-IV subscale - inattention; 
b. Mean change on SNAP-IV subscale - hyperactivity/impulsivity; 
c. Mean change on the SNAP-IV subscale - oppositional defiant disorder; 
d. Mean change on the SNAP-IV subscale - Conners' clinical index; 
e. Mean change on the Spence Children's Anxiety Scale (SCAS); 
f. Mean change on ADHD Rating Scale-IV; 
g. Clinical Global Impressions-ADHD-Severity scale (CGI-ADHD-S); 
h. Assessment of the dynamics of PedMIDAS questionnaire scores (number of days 
with restriction of daily activity due to headache, number of days with headache, 
average headache severity and maximum headache severity in scores); 
i. The Clinical Global Impressions Scale - Improvement (CGI-I) score. 
2. To evaluate the safety of Mexidol® film-coated tablets, 125 mg (RPC PHARMASOFT 
LLC, Russia) vs. placebo based on the assessment of frequency, severity and nature of 
adverse events. 
Criteria for assessing efficacy and safety: 
Given the purpose and primary objective of the present trial, the primary endpoint is the 
mean change in the sum of the total score on the inattention and hyperactivity/impulsivity 
subscales of the SNAP-IV scale after 6 weeks of therapy vs. baseline. 


 
 
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ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
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Secondary endpoints: 
 Mean change on the SNAP-IV inattention subscale after 6 weeks of therapy vs. baseline; 
 Mean change on SNAP-IV subscale hyperactivity/impulsivity after 6 weeks of therapy 
vs. baseline; 
 Mean change on the SNAP-IV subscale, oppositional defiant disorder, after 6 weeks of 
therapy vs. baseline; 
 Mean change on the SNAP-IV subscale - Conners' clinical index; 
 Mean change on the Spence children's anxiety scale (SCAS) after 6 weeks of therapy 
vs. baseline; 
 Mean change on ADHD Rating Scale-IV scores after 6 weeks of therapy vs. baseline; 
 Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scale score after 6 weeks 
of therapy vs. baseline; 
 Assessment of the dynamics of PedMIDAS questionnaire scores (number of days with 
restriction of daily activity due to headache, number of days with headache, average 
headache severity and maximum headache severity in scores); 
 Clinical Global Impressions Scale - Improvement (CGI-I) score after 6 weeks of therapy 
vs. baseline. 
The comparative efficacy of the investigational product and the comparator product on 
the primary endpoint will be assessed, with 95% confidence intervals calculated for the 
difference in mean changes in the sum of the total score on the inattention, 
hyperactivity/impulsivity subscales of the SNAP-IV scale. 
Safety endpoints: 
 Number of adverse events (AEs) and serious AEs (SAEs); 
 Frequency and severity of AEs/SAE associated with investigational product/placebo. 
Safety assessment will be based on patient and/or patient's parents interview, physical 
examination findings (including assessment of vital signs: BP, HR, RR), data from the Patient 
Diary and results of laboratory and instrumental examination (clinical and biochemical blood 
tests). 
The clinical trial is double-blind, meaning that the investigational site staff and patients 
participating in the trial will not know which therapy (Mexidol® + placebo therapy, Mexidol® 
alone, or placebo alone) patients will receive. 
2. Purpose of data statistical analysis 
The purpose of developing this Statistical Analysis Plan is to describe the planned data 
analysis for Protocol #PHS-ADHD-002-MEX-TAB, version 3.0 dated 19.07.2019 for inclusion 
of results in the Clinical Trial Report. 
The results obtained according to the planned statistical analysis of the data presented in 
this document will be used in the submission of the registration dossier for the drug to the 
regulatory authorities, as well as in the writing of publications on the materials of the conducted 


 
 
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Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
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clinical trial. 
This trial is being conducted in accordance with: 
 Clinical Trial Protocol, in strict compliance with the Constitution of the Russian 
Federation; 
 ethical principles of the 1964 Declaration of Helsinki of the World Medical Association, 
as revised in 2013. 
 Federal Law N 61-FZ dated 12 April 2010 "On Circulation of Medicines" (current 
version); 
 National Standard of the Russian Federation GOST R 52379-2005 "Good Clinical 
Practice"; 
 Order of the Ministry of Health of the Russian Federation No. 200n dated 01 April 2016 
"On Approval of the Rules of Good Clinical Practice"; 
 Resolution of the Government of the Russian Federation dated 13 September 2010 N 
714 "On Approval of Standard Rules for Compulsory Life and Health Insurance for 
Patients Participating in Clinical Trials of a Medicinal Product" (current version); 
 Order of the Ministry of Health of the Russian Federation No. 986n of 29 November 
2012 "On Approval of the Regulations on the Ethics Council"; 
 Decision of the Council of the Eurasian Economic Commission of 03.11.2016 No. 79 
"On Approval of the Rules of Good Clinical Practice of the Eurasian Economic Union". 
Statistical evaluation of efficacy and safety parameters will be performed in accordance 
with the Drug Evaluation Guidelines (Volume I. - FGBU NCESMP, Moscow, 2014), 
Guidelines on the principles of application of biostatistics in clinical trials of medicinal products 
(Annex to the recommendation of the EEC Collegium from 03.11.2020 No. 2014) and general 
recommendations on biomedical statistics (ICH Topic Е9 Statistical Principles for Clinical 
Trials, CPMP/ICH/363/96, 1998; Sergienko V.I., Bondareva I.B. Mathematical Statistics in 
Clinical Trials, Moscow: GEOSTAR-Media, 2006; Glantz S. Medical and Biological Statistics, 
Moscow: Practice, 1999). 
3. Deviations from protocol 
Deviations from the protocol in statistical analyses are not planned. However, if there is 
a deviation from the planned statistical analysis, all changes will be identified compared to the 
methods described in the statistical analysis plan. Similarly, if any additional changes are 
required after the analysis has been performed, this will be reflected in the Clinical Trial Report. 
4. Trial procedures 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 12 of 42 
 
 
5. Randomization 
Table 1. Randomization scheme 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
001 
1 
1 
1 
168 
2 
28 
6 
002 
3 
1 
2 
169 
3 
29 
1 
003 
2 
1 
3 
170 
3 
29 
2 
004 
3 
1 
4 
171 
1 
29 
3 
005 
2 
1 
5 
172 
2 
29 
4 
006 
1 
1 
6 
173 
1 
29 
5 
007 
3 
2 
1 
174 
2 
29 
6 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 13 of 42 
 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
008 
3 
2 
2 
175 
2 
30 
1 
009 
2 
2 
3 
176 
1 
30 
2 
010 
2 
2 
4 
177 
3 
30 
3 
011 
1 
2 
5 
178 
3 
30 
4 
012 
1 
2 
6 
179 
2 
30 
5 
013 
3 
3 
1 
180 
1 
30 
6 
014 
2 
3 
2 
181 
2 
31 
1 
015 
2 
3 
3 
182 
3 
31 
2 
016 
3 
3 
4 
183 
3 
31 
3 
017 
1 
3 
5 
184 
1 
31 
4 
018 
1 
3 
6 
185 
1 
31 
5 
019 
1 
4 
1 
186 
2 
31 
6 
020 
1 
4 
2 
187 
3 
32 
1 
021 
3 
4 
3 
188 
2 
32 
2 
022 
3 
4 
4 
189 
1 
32 
3 
023 
2 
4 
5 
190 
2 
32 
4 
024 
2 
4 
6 
191 
3 
32 
5 
025 
2 
5 
1 
192 
1 
32 
6 
026 
2 
5 
2 
193 
2 
33 
1 
027 
3 
5 
3 
194 
3 
33 
2 
028 
3 
5 
4 
195 
2 
33 
3 
029 
1 
5 
5 
196 
3 
33 
4 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 14 of 42 
 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
030 
1 
5 
6 
197 
1 
33 
5 
031 
2 
6 
1 
198 
1 
33 
6 
032 
2 
6 
2 
199 
3 
34 
1 
033 
3 
6 
3 
200 
2 
34 
2 
034 
1 
6 
4 
201 
2 
34 
3 
035 
3 
6 
5 
202 
3 
34 
4 
036 
1 
6 
6 
203 
1 
34 
5 
037 
1 
7 
1 
204 
1 
34 
6 
038 
1 
7 
2 
205 
1 
35 
1 
039 
3 
7 
3 
206 
1 
35 
2 
040 
2 
7 
4 
207 
2 
35 
3 
041 
3 
7 
5 
208 
3 
35 
4 
042 
2 
7 
6 
209 
2 
35 
5 
043 
3 
8 
1 
210 
3 
35 
6 
044 
3 
8 
2 
211 
2 
36 
1 
045 
2 
8 
3 
212 
2 
36 
2 
046 
2 
8 
4 
213 
1 
36 
3 
047 
1 
8 
5 
214 
1 
36 
4 
048 
1 
8 
6 
215 
3 
36 
5 
049 
1 
9 
1 
216 
3 
36 
6 
050 
2 
9 
2 
217 
1 
37 
1 
051 
2 
9 
3 
218 
2 
37 
2 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 15 of 42 
 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
052 
1 
9 
4 
219 
3 
37 
3 
053 
3 
9 
5 
220 
2 
37 
4 
054 
3 
9 
6 
221 
3 
37 
5 
055 
1 
10 
1 
222 
1 
37 
6 
056 
3 
10 
2 
223 
3 
38 
1 
057 
1 
10 
3 
224 
2 
38 
2 
058 
2 
10 
4 
225 
1 
38 
3 
059 
2 
10 
5 
226 
1 
38 
4 
060 
3 
10 
6 
227 
3 
38 
5 
061 
3 
11 
1 
228 
2 
38 
6 
062 
2 
11 
2 
229 
1 
39 
1 
063 
1 
11 
3 
230 
2 
39 
2 
064 
2 
11 
4 
231 
2 
39 
3 
065 
3 
11 
5 
232 
1 
39 
4 
066 
1 
11 
6 
233 
3 
39 
5 
067 
3 
12 
1 
234 
3 
39 
6 
068 
2 
12 
2 
235 
1 
40 
1 
069 
1 
12 
3 
236 
3 
40 
2 
070 
3 
12 
4 
237 
2 
40 
3 
071 
1 
12 
5 
238 
3 
40 
4 
072 
2 
12 
6 
239 
2 
40 
5 
073 
2 
13 
1 
240 
1 
40 
6 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 16 of 42 
 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
074 
2 
13 
2 
241 
3 
41 
1 
075 
1 
13 
3 
242 
3 
41 
2 
076 
3 
13 
4 
243 
2 
41 
3 
077 
3 
13 
5 
244 
1 
41 
4 
078 
1 
13 
6 
245 
1 
41 
5 
079 
3 
14 
1 
246 
2 
41 
6 
080 
2 
14 
2 
247 
3 
42 
1 
081 
2 
14 
3 
248 
1 
42 
2 
082 
1 
14 
4 
249 
1 
42 
3 
083 
3 
14 
5 
250 
2 
42 
4 
084 
1 
14 
6 
251 
3 
42 
5 
085 
2 
15 
1 
252 
2 
42 
6 
086 
_ 3 
15 
2 
253 
2 
43 
1 
087 
1 
15 
3 
254 
3 
43 
2 
088 
1 
15 
4 
255 
2 
43 
3 
089 
3 
15 
5 
256 
1 
43 
4 
090 
2 
15 
6 
257 
1 
43 
5 
091 
2 
16 
1 
258 
3 
43 
6 
092 
1 
16 
2 
259 
1 
44 
1 
093 
3 
16 
3 
260 
2 
44 
2 
094 
3 
16 
4 
261 
1 
44 
3 
095 
1 
16 
5 
262 
3 
44 
4 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 17 of 42 
 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
096 
2 
16 
6 
263 
2 
44 
5 
097 
1 
17 
1 
264 
3 
44 
6 
098 
1 
17 
2 
265 
1 
45 
1 
099 
2 
17 
3 
266 
1 
45 
2 
100 
2 
17 
4 
267 
2 
45 
3 
101 
3 
17 
5 
268 
3 
45 
4 
102 
3 
17 
6 
269 
3 
45 
5 
103 
2 
18 
1 
270 
2 
45 
6 
104 
1 
18 
2 
271 
3 
46 
1 
105 
2 
18 
3 
272 
2 
46 
2 
106 
3 
18 
4 
273 
1 
46 
3 
107 
1 
18 
5 
274 
1 
46 
4 
108 
3 
18 
6 
275 
3 
46 
5 
109 
1 
19 
1 
276 
2 
46 
6 
110 
1 
19 
2 
277 
1 
47 
1 
111 
2 
19 
3 
278 
3 
47 
2 
112 
2 
19 
4 
279 
2 
47 
3 
113 
3 
19 
5 
280 
3 
47 
4 
114 
3 
19 
6 
281 
2 
47 
5 
115 
3 
20 
1 
282 
I 
47 
6 
116 
3 
20 
2 
283 
2 
48 
1 
117 
1 
20 
3 
284 
1 
48 
2 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 18 of 42 
 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
118 
2 
20 
4 
285 
3 
48 
3 
119 
1 
20 
5 
286 
3 
48 
4 
120 
2 
20 
6 
287 
2 
48 
5 
121 
2 
21 
1 
288 
1 
48 
6 
122 
2 
21 
2 
289 
1 
49 
1 
123 
3 
21 
3 
290 
2 
49 
2 
124 
3 
21 
4 
291 
1 
49 
3 
125 
1 
21 
5 
292 
3 
49 
4 
126 
1 
21 
6 
293 
3 
49 
5 
127 
2 
22 
1 
294 
2 
49 
6 
128 
1 
22 
2 
295 
2 
50 
1 
129 
2 
22 
3 
296 
3 
50 
2 
130 
3 
22 
4 
297 
2 
50 
3 
131 
3 
22 
5 
298 
1 
50 
4 
132 
1 
22 
6 
299 
3 
50 
5 
133 
2 
23 
1 
300 
1 
50 
6 
134 
1 
23 
2 
301 
2 
51 
1 
135 
3 
23 
3 
302 
1 
51 
2 
136 
3 
23 
4 
303 
3 
51 
3 
137 
1 
23 
5 
304 
3 
51 
4 
138 
2 
23 
6 
305 
1 
51 
5 
139 
1 
24 
1 
306 
2 
51 
6 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 19 of 42 
 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
140 
2 
24 
2 
307 
2 
52 
1 
141 
1 
24 
3 
308 
3 
52 
2 
142 
3 
24 
4 
309 
3 
52 
3 
143 
2 
24 
5 
310 
1 
52 
4 
144 
3 
24 
6 
311 
1 
52 
5 
145 
3 
25 
1 
312 
2 
52 
6 
146 
3 
25 
2 
313 
3 
53 
1 
147 
2 
25 
3 
314 
1 
53 
2 
148 
2 
25 
4 
315 
3 
53 
3 
149 
1 
25 
5 
316 
1 
53 
4 
150 
1 
25 
6 
317 
2 
53 
5 
151 
1 
26 
1 
318 
2 
53 
6 
152 
2 
26 
2 
319 
2 
54 
1 
153 
1 
26 
3 
320 
3 
54 
2 
154 
2 
26 
4 
321 
3 
54 
3 
155 
3 
26 
5 
322 
1 
54 
4 
156 
3 
26 
6 
323 
2 
54 
5 
157 
2 
27 
1 
324 
1 
54 
6 
158 
3 
27 
2 
325 
3 
55 
1 
159 
3 
27 
3 
326 
2 
55 
2 
160 
2 
27 
4 
327 
2 
55 
3 
161 
1 
27 
5 
328 
1 
55 
4 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 20 of 42 
 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
Patient randomization 
number 
Group 
Block number 
Order number within 
the block 
162 
1 
27 
6 
329 
1 
55 
5 
163 
1 
28 
1 
330 
3 
55 
6 
164 
1 
28 
2 
331 
1 
56 
1 
165 
2 
28 
3 
332 
3 
56 
2 
166 
3 
28 
4 
333 
2 
56 
3 
167 
3 
28 
5 
- 
- 
- 
- 
6. 
Main and additional trial parameters to be assessed in the 
course of the trial 
The FAS and PP populations will be used for efficacy analyses, with the FAS population 
planned to be used as the main population. The criterion chosen as the primary criterion for 
efficacy evaluation is: 
 Mean change in the total score on the inattention and hyperactivity/impulsivity 
subscales of the SNAP-IV scale after 6 weeks of therapy vs. baseline. 
Two-sided confidence intervals will be used as part of the primary efficacy analyses. The 
primary population for this analysis will be the FAS population. Differences will be considered 
statistically significant at the p level <0.05. 
As a sensitivity analysis, the analysis of the primary variable in the ITT population will 
be repeated in the per protocol (PP) population. 95% confidence intervals will also be presented. 
The secondary efficacy evaluation criteria chosen are: 
 Mean change on the SNAP-IV inattention subscale after 6 weeks of therapy vs. baseline; 
 Mean change on SNAP-IV subscale hyperactivity/impulsivity after 6 weeks of therapy 
vs. baseline; 
 Mean change on the SNAP-IV subscale, oppositional defiant disorder, after 6 weeks of 
therapy vs. baseline; 
 Mean change on the SNAP-IV subscale - Conners' clinical index; 
 Mean change on the Spence children's anxiety scale (SCAS) after 6 weeks of therapy 
vs. baseline; 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 21 of 42 
 
 Mean change on ADHD Rating Scale-IV scores after 6 weeks of therapy vs. baseline; 
 Clinical Global Impressions-ADHD-Severity (CGI-ADHD-S) scale score after 6 weeks 
of therapy vs. baseline; 
 Assessment of the dynamics of PedMIDAS questionnaire scores (number of days with 
restriction of daily activity due to headache, number of days with headache, average 
headache severity and maximum headache severity in scores); 
 The Clinical Global Impressions Scale - Improvement (CGI-I) score after 6 weeks of 
therapy vs. baseline. 
Two-sided confidence intervals will be used to assess treatment efficacy (primary and 
secondary efficacy criteria). A conclusion on superiority can be made if the upper bound of the 
two-sided 95% confidence interval for the difference in mean changes in SNAP-IV scores of 
Mexidol® vs. placebo is negative. 
For primary and secondary efficacy criteria, differences will be considered statistically 
significant at the p-value level of <0.05. 
The χ-square test or Fisher's exact test will be used to assess differences in event rates. 
The χ-square test or Fisher's exact test will also be used to assess differences in patient 
adherence. 
Demographic and baseline characteristics will be characterized using descriptive 
statistical methods for the analysis sample as a whole and for therapeutic subgroups, with 
testing of the null hypothesis of no differences between the trial groups at baseline. Descriptive 
statistics for data whose distribution follows the law of normal distribution will be presented 
using the arithmetic mean and standard deviation. For otherwise distributed data, descriptive 
statistics will be presented using non-parametric measures (median/mode, quartiles). The 
assessment of normality of distribution for interval indicators will be determined by the 
Shapiro-Wilk test. 
Concomitant therapy drugs will be coded by generic name using the WHO dictionary of 
medicines. Medications will be listed by treatment group. 
No interim statistical analyses of efficacy are planned as part of this trial. Statistical 
analysis of the results will be done after the trial is completed. 
All safety data will be analysed on the safety population. 
Further analysis of AEs, including SAEs, will consist of determining the total number of 
AEs, total number of patients with AEs, number of AEs associated with the trial therapy, 
number of AEs that required cancellation of therapy or changes in therapy parameters, and 
number of patient-initiated dropouts. 
The frequency and severity of both all AEs and drug-related AEs (i.e., with an estimated 
association of at least "possible") will be presented for system organ classes (SOC - System 
Organ Class MedDRA - the highest level of classification of AEs, taking into account etiology, 
localization of manifestations and classification objectives). 
AEs will be coded according to MedDRA and will be classified using System Organ 
Classes and preferred term (SOC - System Organ Class MedDRA - the highest level of 
classification of AEs taking into account the etiology, localization of manifestations and 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 22 of 42 
 
classification objectives). The protocol provides for the recording of all AEs that occur to the 
patient after the first administration of the trial therapy and until the end of the patient's 
participation in the trial. Frequency tables with data on discontinuation of therapy or changes 
in therapy parameters due to AEs will be presented. The choice of statistical criterion will be 
determined by the conformity/nonconformity to the normal distribution law and the 
dependence/independence of the samples being compared. Comparisons of safety performance 
between trial groups will be made using the χ-square test (for qualitative data) and the t-test for 
data whose distribution follows the law of normal distribution, or its non-parametric analogue 
(for data whose distribution does not follow the law of normal distribution). The Mann-Whitney 
U-test will be used as the non-paramatric analogue of the t-criterion. 
Data obtained before the start and at the end of the trial will be compared to assess safety 
parameters. 
To assess the robustness of the trial results, a sensitivity analysis will be performed on the 
main efficacy parameter: "Mean change in the total score on the inattention, 
hyperactivity/impulsivity subscale of the SNAP-IV scale after 6 weeks of therapy vs. baseline". 
Since sensitivity analysis aims to assess the impact on the trial results of deviations from 
the methods of analysis used, as well as the impact of missing data values and a priori 
assumptions in order to identify the results that are most dependent on questionable or untenable 
assumptions, this trial includes an assessment of the impact of the following factors on the main 
conclusion of the trial: 
 Investigational site: planned analysis adjusted for the covariate “Site” using a 
generalized linear model (GLM) to assess the consistency of the results with the analysis 
without introducing one; 
 Analysed populations: in addition to the main analysis in the FAS population, a 
secondary analysis in the PP population is planned to assess the consistency of the 
results with the main analysis; 
 Various assessments for treatment success: secondary efficacy endpoints were 
planned to support the results of the primary efficacy analysis using the t-test - for data 
whose distribution conforms to the law of normal distribution, or the Mann-Whitney U-
test for data whose distribution does not conform to the law of normal distribution. 
 Missing data: analyses of full cases and post-hoc analyses using the last observation 
carry forward method (LOCF) to assess consistency of results are assumed. 
The feasibility of using a number of statistical methods will be assessed after data 
collection has been completed, as the nature of the data distribution, sample homogeneity, etc. 
is not known in advance. During the course of the analysis, the list of methods to be used may 
be modified and supplemented if necessary for the qualitative processing of the data. 
7. Statistical hypothesis 
In accordance with the purpose of the trial, statistical analysis of the results is planned to 
compare the efficacy of the therapy regimen including Mexidol® in the treatment of attention 
deficit hyperactivity disorder (ADHD) in children 6-12 years old at different dosing regimens 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 23 of 42 
 
with the efficacy of the regimen including placebo and a combination of the investigational 
product and placebo. 
The main efficacy criterion is the mean change in the total score on the inattention and 
hyperactivity/impulsivity subscales of the SNAP-IV scale after 6 weeks of therapy vs. baseline. 
Descriptive statistics for this indicator will be given and the following statistical hypotheses 
will be tested: 
Η0 : μp=μT; 
Η1: μт<μр 
μT - mean change in SNAP-IV score in the experimental group (group 1 Mexidol®, 125 
mg OD, or group 2 (Mexidol®, 125 mg BID); 
μΡ - mean change in SNAP-IV score in control group 3 (placebo). 
The sign "<" is associated with the fact that the change has a negative value. 
Comparison of the values of the two groups of patients will be performed by calculating 
the 95% confidence interval for the difference of μ1 (μ2) and μ0 values. A conclusion on 
superiority can be made if the upper bound of the two-sided 95% confidence interval for the 
difference in mean changes in SNAP-IV scores of Mexidol® vs. placebo is negative. 
Testing of the null statistical hypothesis can be done using one-factor analysis of variance 
with Dunnett's posterior criterion and evaluation of contrasts or similar applicable statistical 
analysis method. 
The χ-square test or Fisher's exact test will be used to assess differences in event rates. 
The χ-square test or Fisher's exact test will also be used to assess differences in patient 
adherence. 
8. Estimation of the required sample size 
The sample size calculation is based on the guidelines outlined in Chow S, Shao J, Wang 
H. Sample Size calculation in Clinical Research. 2nd edition. 2008. 
The present trial assumes a 1:1:1 distribution of patients into groups (μ1=μ2=μ0). 
The following input data are used in the calculations: 
1. The significance level is 95% (respectively, the I error is 0.05). Since the boundaries 
of the 95% confidence interval must be two-sided and testing of the superiority 
hypothesis is one-sided, a one-sided error I of 0.025 will be applied to test the 
hypothesis, which is equivalent to an error of 0.05 for a two-sided test. 
2. Acceptable trial power is at least 80 per cent; 
3. The mean change in SNAP-IV score in the placebo group is -2.0 points, and the 
standard deviation for the change is 4.70 points. 
4. The mean change in SNAP-IV score in the Mexidol® group is -4.5 points, and the 
standard deviation for the change is 7.515 points. 
5. The modulus of the difference in mean SNAP-IV scores between the Mexidol and 
placebo groups is 2.5 points 
Thus, based on the calculations based on the data above, the number of patients to 
complete the trial according to the protocol was at least 100 in each group or a total of at least 


 
 
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CONFIDENTIAL 
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300. Assuming a 10% drop-out rate during follow-up, the trial is planned to include 333 patients 
(111 in each group). 
9. Statistical estimation of efficacy parameters 
Statistical processing of the data obtained during the trial will be carried out using 
specialised software, namely the programming language for statistical data processing R and 
StatSoft® Statistica v.12 (and above) statistical package. 
Statistical analyses will be performed for data obtained from all included patients who 
received at least one dose of the investigational product. The data obtained will be summarised 
using discrete groups with case frequencies and percentages. 
Descriptive statistics will be presented at each visit for all quantitative safety data from 
the trial. 
Indicators of descriptive statistics used in this trial will include: 
for quantitative data: 
 arithmetic mean (M); 
 standard deviation (SD); 
 median (Me); 
 interquartile range (QRange); 
 minimum (Min); 
 maximum (Max); 
for ordinal data: 
 median (Me); 
 interquartile range (QRange); 
 minimum (Min); 
 maximum (Max); 
for categorical data: 
 frequency; 
 portion (%). 
In addition, calculation of 95% confidence intervals (95% CI, L; 95% CI, U) and range 
will be used. 
The Shapiro-Wilk test will be used to assess the normality of the distribution for 
indicators with interval type of scale. Pearson's χ2 (chi-square) exact test or Fisher's exact test 
(in case the absolute frequency of a trait is 5 or less) will be used to compare groups on 
qualitative traits. 
To test the null hypothesis of no difference between groups for qualitative features not 
specified as direct measures of efficacy (secondary endpoints) as well as qualitative measures 
of safety, testing of the null hypothesis of no difference between groups is planned using the χ2 
test or Fisher's exact test. 
The feasibility of using a number of statistical methods will be assessed after data 
collection has been completed, as the nature of the data distribution, sample homogeneity, etc. 


 
 
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Plan for statistical analysis of efficacy and safety parameters 
 
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CONFIDENTIAL 
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is not known in advance. During the course of the analysis, the list of methods to be used may 
be modified and supplemented if necessary for the qualitative processing of the data. All 
deviations from the statistical plan of the survey as well as their causes will be detailed in the 
statistical report. 
10. Safety analysis 
The protocol provides for the recording of all AEs that occur to the patient after the first 
administration of the trial therapy and until the end of the patient's participation in the trial. AEs 
will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). 
Further analysis of AEs, including SAEs, will consist of determining the total number of AEs, 
total number of patients with AEs, number of AEs associated with the trial therapy, number of 
AEs that required cancellation of therapy or changes in therapy parameters, and number of 
patient-initiated dropouts. 
The frequency and severity of both all AEs and drug-related AEs (i.e., with an estimated 
association of at least "possible") will be presented for system organ classes (SOC - System 
Organ Class MedDRA - the highest level of classification of AEs, taking into account etiology, 
localization of manifestations and classification objectives). 
Frequency tables with data on discontinuation of therapy or changes in therapy 
parameters due to AEs will be presented. 
Data obtained before the start and at the end of the trial will be compared to assess safety 
parameters. 
The statistical report on the results of this trial will include tables showing the dynamics 
of clinical manifestations and instrumental examination data, the dynamics of vital functional 
parameters and comparison of the results of clinical and biochemical blood analysis and general 
urine analysis. The results of the evaluation of the incidence of adverse events will be given. 
The following safety assessment parameters will be analysed: the number of adverse 
events (AEs) and serious AEs (SAEs) and the incidence of AEs/SAEs associated with the 
investigational product/placebo. 
All data will be analyzed on the safety population. 
The identification of AEs, including serious AEs, will consist of determining the total 
number of AEs; 
 total number of patients with AEs; 
 number of AEs with a possible and higher degree of association with the 
investigational product/procedure; 
 number of AEs that required discontinuation of therapy; 
The frequency and severity of all AEs and drug-related AEs (i.e., with an estimated 
association of at least "possible"), will be summarized for body systems. Data on patient 
dropouts from the trial due to the development of AEs (if any) will be tabulated. 
The trial will record all AEs that occur in a patient after a single dose of investigational 
products in the specified dose. 
Adverse event (AE) - an adverse event (AE) is any adverse change in the health status 


 
 
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Plan for statistical analysis of efficacy and safety parameters 
 
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19.07.2019. 
CONFIDENTIAL 
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of a patient or subject of a clinical trial to whom a medicinal (investigational) product has been 
administered, regardless of the causal relationship with its use. 
An adverse event may be any unfavourable and unintended change (including a deviation 
of a laboratory indicator from the norm), symptom or disease, the time of occurrence of which 
does not exclude a causal relationship with the use of the medicinal product, regardless of the 
presence or absence of a relationship with the use of the medicinal product. 
If any adverse events develop, the investigator should complete the relevant pages of the 
patient's CRF, assess the appropriateness of the patient's continued participation in the trial. 
Adverse events will be recorded from the time the first dose of the investigational product is 
administered to the patient in the trial until completion of the trial. 
The severity of AEs is assessed as follows: 
The investigator assesses the severity of an adverse event according to the Common 
Terminology Criteria for Adverse Events (CTCAE) current version at the time of the trial. If an 
adverse event cannot be classified according to the СТСАЕ criteria, the investigator will choose 
the closest description of the severity of the adverse event from those given in the classification 
based on personal clinical experience: 
Degree of 
severity 
Category 
Definition/Description 
1 
Mild 
No symptoms or mild symptoms, only clinical or diagnostic 
follow-up is required; no intervention is indicated 
2 
Moderate 
Only minimal, localised or non-invasive interventions are 
indicated; limitation of daily living activities 
3 
Severe 
Severe or clinically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disability; limitation of self-care in activities of daily 
living 
4 
Life-threatening/ Disability 
to work 
Life-threatening consequences, urgent intervention required 
5 
Fatal 
Death associated with an adverse event 
"Severe" adverse event will not necessarily be “serious" in nature, “serious" adverse event 
will not necessarily be "severe" by definition. 
The association of an AE with the use of investigational products will be assessed using World 
Health Organisation (WHO) criteria: 
 Definite. Clinical manifestations of an AE, including abnormalities of laboratory 
parameters occurring during the period of drug administration, which cannot be 
explained by the presence of existing diseases and the influence of other factors and 
chemical compounds. Manifestations of adverse reaction regress after drug withdrawal 
and occur with repeated administration. 
 Probable. Clinical manifestations of an AE that include changes in laboratory values 
that are temporally related to the use of the investigational product, that are unlikely to 
be related to comorbidities or other factors, and that regress with drug withdrawal. The 
response to rechallenge is unknown. 
 Possible. Clinical manifestations of an AE that include changes in laboratory values that 


 
 
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Plan for statistical analysis of efficacy and safety parameters 
 
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ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 27 of 42 
 
are temporally related to drug administration but can be explained by the presence of 
comorbidities or the administration of other drugs and chemical compounds. 
Information on response to drug withdrawal is unclear. 
 Doubtful. Clinical manifestations of an AE that include changes in laboratory values 
that occur in the absence of a clear temporal relationship to drug administration; other 
factors (drugs, diseases, chemicals) are present that may be responsible for their 
occurrence. 
 Conditional. Clinical manifestations of an AE involving abnormalities of laboratory 
indications categorised as 'adverse reactions' that need further data (for accurate 
assessment) or these obtained data are currently being analysed. 
 Unclassifiable. Reports of a suspected adverse reaction cannot be evaluated because 
there is insufficient or conflicting information. 
The occurrence of an adverse event will be considered to be related to the investigational 
product if the relationship is considered by the investigator as definite, probable, possible. 
Serious adverse event (SAE) - "Serious" adverse event is defined as any adverse medical event 
that, regardless of the dose of the medicinal product: 
 resulted in death; 
 was life-threatening; 
 has caused severe or permanent disability or incapacity for work; 
 required an inpatient admission (other than a previously planned admission) or causes 
an extension of the current hospitalization; 
 resulted in a congenital anomaly/developmental defect; 
 required medical intervention to prevent the above conditions; 
 there has been transmission of an infectious agent through a medicinal product. 
In addition, a serious adverse event includes any event that does not formally fit the above 
criteria but is a significant medical event from the investigator's point of view. 
"Serious" adverse reaction is a serious adverse event with a causal relationship (possible, 
probable, or credible) to the use of the investigational product; 
All other AEs that do not meet these criteria will be considered as “non-serious". 
If a patient develops an AE or SAE, it is mandatory that the appropriate forms are 
completed for the patient and attached to the patient's CRF. The safety assessment population 
will be used for all safety analyses. 
Early withdrawn patients will be present in the patient list, and summarized by the main 
reason for withdrawal, and for each treatment group. Missing or omitted data will not be 
replaced. 
Clinical laboratory assessments will be presented with descriptive statistics by trial visit 
indicating changes from baseline. Laboratory abnormalities outside of normal values will be 
noted. Lists and summary descriptions of clinically significant haematological laboratory 
abnormalities will be presented. The feasibility of using a number of statistical methods will be 
assessed after data collection has been completed, as the nature of the data distribution, sample 


 
 
ClinPharmDevelopment 
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Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
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homogeneity, etc. is not known in advance. During the course of the analysis, the list of methods 
to be used may be modified and supplemented if necessary for the qualitative processing of the 
data. All deviations from the statistical plan of the survey as well as their causes will be detailed 
in the statistical report. 
Vital signs will also be presented with descriptive statistics showing changes from 
baseline. 
Data harmonisation, if possible, will be done by converting values to commonly used or 
most common units of measurement in the dataset. In case the units of measurement cannot be 
harmonised, the data will be presented as tables without further statistical treatment. 
Based on the results of the trial, after the final statistical analysis, a conclusion will be 
made about the efficacy and safety of Mexidol® vs. placebo. 
11. Patient populations to be analysed 
The following groups will be used for the analysis: 
1. Safety population - will include all patients who have taken at least one dose of the 
investigational product; 
2. Full analysis set (FAS) population - will include all randomized patients who have 
taken at least one dose of the investigational product and who have an assessed response to 
therapy after 6 weeks of therapy. This will be the main population for efficacy analyses; 
3. Per protocol population (PP) is a subgroup of the FAS population that will include 
patients in the absence of significant protocol deviations regarding inclusion/non-inclusion 
criteria, adherence to therapy, and use of concomitant therapy. This will be an additional 
population used for efficacy analyses. 
Efficacy analyses will be performed on the FAS population as well as on the PP 
population of all patients who completed the trial according to the protocol in order to validate 
the results obtained. 
The final Clinical Trial Report will include data on all patients included in the trial, 
including those who dropped out at any time without explanation. 
In general, any deviation from the protocol may be accepted only in an urgent case or 
after obtaining written agreement from the Sponsor and subject to approval by the Ethics 
Committee. Any deviation from the protocol should be clearly explained in the source 
documentation and in the eCRF. Classification of protocol deviations will be made by the 
Sponsor's medical expert before the database lock. Deviations from the protocol will be 
considered significant in the following cases (the list may be expanded in a subsequent 
evaluation of protocol deviations): 
 skip of visit 4; 
 violation of inclusion / non-inclusion criteria; 
 violation of the exclusion criteria; 
 taking the investigational product/placebo <80% or >120% of the total number of tablets 
prescribed; 
 administration of prohibited drugs. 


 
 
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Plan for statistical analysis of efficacy and safety parameters 
 
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ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
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In the absence of data at Visit 4 when data are available at Visit 5, these patients will not 
be included in the FAS and РР populations, but will be analysed in the safety population. 
In the presence of data at Visit 4 and the presence of the other listed significant protocol 
deviations, these patients will be included in the full analysis population, safety population, but 
excluded from the protocol population. 
12. Table templates 
Table 2. Results of assessment of normality of distribution of indicators (template) 
Indicators 
Stage 
Investigational products 
Mexidol® 
Placebo 
Mexidol®+ Placebo 
W 
р 
Distribution 
W р 
Distribution 
W р 
Distribution 
Age 
Visit 1 (Day-
14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Height 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Body weight 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
BMI 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
HR 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 5 (Day 
50+3) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
CHD 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 5 (Day 
50+3) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Systolic BP 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 5 (Day 
50+3) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Diastolic BP 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than 
Visit 5 (Day 
50+3) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Haemoglobin 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 30 of 42 
 
Indicators 
Stage 
Investigational products 
Mexidol® 
Placebo 
Mexidol®+ Placebo 
W 
р 
Distribution 
W р 
Distribution 
W р 
Distribution 
Haematocrit 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Erythrocyte 
count 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Platelet count 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
White blood cell 
count 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Eosinophils 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Basophils 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Stab neutrophils 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Segmented 
neutrophils 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Lymphocytes 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Monocytes 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
ESR 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Total protein 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 31 of 42 
 
Indicators 
Stage 
Investigational products 
Mexidol® 
Placebo 
Mexidol®+ Placebo 
W 
р 
Distribution 
W р 
Distribution 
W р 
Distribution 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Albumin 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Glucose 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
ALT 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
AST 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Total bilirubin 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Alkaline 
phosphatase 
(ALP) 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Amylase 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Creatinine 
Visit 1 (Day 
-14-1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Visit 4 (Day 
43+1) 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Urine pH 
20 weeks 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
24 weeks 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
Urine specific 
gravity 
28 weeks 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
32 weeks 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 
 
 
normal/other 
than normal 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
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Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-ADHD-002-MEX- TAB, 
version 3.0 dated 19.07.2019. 
CONFIDENTIAL 
page 32 of 42 
 
Table 3. Statistical analysis of the primary endpoint (template) 
Total score on the "inattention" and 
"hyperactivity/impulsivity" subscales of 
the SNAP IV scale 
Mexidol® 
Placebo 
Mexidol®+ Placebo 
Visit 2 
(Day 1) 
Visit 5 
(Day 43+1) 
Dynamics 
Visit 2 
(Day 1) 
Visit 5 
(Day 43+1) 
Dynamics 
Visit 2 
(Day 1) 
Visit 5 
(Day 43+1) 
Dynamics 
Abs. 
% 
Abs. 
% 
Abs. 
% 
N 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
95% CI, L 
 
 
 
 
 
 
 
 
 
 
 
 
95% CI, U 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
Q1 
 
 
 
 
 
 
 
 
 
 
 
 
Q3 
 
 
 
 
 
 
 
 
 
 
 
 
Range 
 
 
 
 
 
 
 
 
 
 
 
 
Q Range 
 
 
 
 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
 
 
 
 
CV 
 
 
 
 
 
 
 
 
 
 
 
 
Intragroup comparison: comparison of data at the end of therapy with data at the start of therapy (statistical criterion"1) (p-level value) 
Comparison of drugs (statistical test2) (p-value) 
Indicator span diagram/ indicator scatter diagram 
 
 
______________________ 
1 T-test for related samples or Wilcoxon test depending on the type of distribution of the indicator 
2 T-test for independent samples or Mann-Whitney test depending on the type of distribution of the indicator 


 
 
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CONFIDENTIAL 
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Table 4. Statistical analysis of secondary, endpoints (SNAP-GU, CGI-ADHD-S, SCAS, PedMIDAS and ADHD Rating Scale IV) (template) 
Indicator3 
Mexidol® 
Placebo 
Mexidol®+ Placebo 
Visit 2 (Day 
1) 
Visit 5 (Day 
43+1) 
Dynamics 
Visit 2 (Day 
1) 
Visit 5 (Day 
43+1) 
Dynamics 
Visit 2 (Day 
1) 
Visit 5 (Day 
43+1) 
Dynamics 
Abs. 
% 
Abs. 
% 
Abs. 
% 
N 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
95% CI, L 
 
 
 
 
 
 
 
 
 
 
 
 
95% CI, U 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
Q1 
 
 
 
 
 
 
 
 
 
 
 
 
Q3 
 
 
 
 
 
 
 
 
 
 
 
 
Range 
 
 
 
 
 
 
 
 
 
 
 
 
QRange 
 
 
 
 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
 
 
 
 
CV 
 
 
 
 
 
 
 
 
 
 
 
 
Intragroup comparison: comparison of data at the end of therapy with data at the start of therapy (statistical criterion"4) (p-level value) 
Comparison of drugs (statistical test5) (p-value) 
Indicator span diagram/ indicator scatter diagram 
______________________ 
3 - SNAP-IV subscale score - "inattention." 
- SNAP-IV subscale score - "hyperactivity/impulsivity." 
- SNAP-IV subscale score - oppositional defiant disorder; 
 - SNAP-IV subscale score - Conners index; 
Clinical Global Impressions-ADHD-Severity scale (CGI-ADHD-S). 
- Spence children's anxiety scale (SCAS) scores after 6 weeks of therapy compared to baseline; 
PedMIDAS questionnaire score 
- ADHD Rating Scale-IV score after 6 weeks of therapy compared with baseline. 
4 T-test for related samples or Wilcoxon test depending on the type of distribution of the indicator 
5 T-test for independent samples or Mann-Whitney test depending on the type of distribution of the indicator 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-ADHD-002-MEX- TAB, 
version 3.0 dated 19.07.2019. 
CONFIDENTIAL 
page 34 of 42 
 
Table 5. Statistical analysis of secondary endpoints (CGI-Ι scale) (template) 
The Clinical Global Impressions Scale - 
Improvement (CGI-I) score. 
Investigational products 
Mexidol® 
Placebo 
Mexidol®+ Placebo 
N 
 
 
 
Mean 
 
 
 
95% CI, L 
 
 
 
95% CI, U 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1 
 
 
 
Q3 
 
 
 
Range 
 
 
 
Q Range 
 
 
 
SD 
 
 
 
CV 
 
 
 
Comparison of drugs (statistical test6) (p-value) 
Indicator span diagram/ indicator scatter diagram 
 
 
______________________ 
6 T-test for independent samples or Mann-Whitney test depending on the type of distribution of the indicator 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-ADHD-002-MEX- TAB, 
version 3.0 dated 19.07.2019. 
CONFIDENTIAL 
page 35 of 42 
 
Table 6. Outcomes of the primary endpoint analysis 
Total score on the "inattention" and 
"hyperactivity/impulsivity" subscales of 
the SNAP-IV scale 
Inter-group differences 
Mexidol® vs. Mexidol®+Placebo 
Mexidol® vs. Placebo 
Statistical criterion 
 
 
 
 
p-level 
 
 
 
 
CI for difference in variances 
 
 
 
 
Superiority is proven (Yes/No) 
 
 
 
 
Table 7. Baseline anthropometric indices (template) 
Indicator 
Mexidol® 
Placebo 
Mexidol® + Placebo 
General data 
Age, years 
Body 
weight, 
kg 
Height, 
cm 
BMI Age, years 
Body 
weight, 
kg 
Height, 
cm 
BMI Age, years 
Body 
weight, 
kg 
Height, 
cm 
BMI Age, years 
Body 
weight, 
kg 
Height, 
cm 
BMI 
N 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
95% CI, L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
95% CI, U 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Range 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QRange 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CV 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 36 of 42 
 
Table 8. Urinalysis values during the trial7 (template) 
Indicator 
Visit 
Mexidol® 
Placebo 
Mexidol®+ Placebo 
Normal 
Abs. 
 
 
 
% 
 
 
 
Deviations from normal 
(clinically insignificant) 
Abs. 
 
 
 
% 
 
 
 
Deviations from normal 
(clinically significant) 
Abs. 
 
 
 
% 
 
 
 
Inter-group differences 
Statistical criterion 
p-level 
 
Table 9. Results of the medical examination during the trial (template) 
Indicator8 
Investigational product 
Visit 1 (Day -14 -1) 
Visit 5 (Day 43+1) 
Visit 6 (Day 50+3) 
Normal 
Abs. 
 
 
 
% 
 
 
 
Deviations from normal (clinically 
insignificant) 
Abs. 
 
 
 
% 
 
 
 
Deviations from normal 
Abs. 
 
 
 
(clinically significant) 
% 
 
 
 
Comparison of drugs (statistical test9) (p-value) 
Table 10. Comparison of vital signs when taking the investigational product and the 
comparator product (template) 
Indicator10 
Investigational product 
Visit 1 (Day -14 -1) 
Visit 5 (Day 43+1) 
Visit 6 (Day 50+3) 
N 
 
 
 
______________________ 
7 Applicable for categorical indicators 
8 General condition 
- Skin condition 
- Musculoskeletal system 
- Lymph nodes 
- Thyroid gland 
- Upper respiratory tract and lungs 
- Heart, blood vessels 
- Abdominal organs, kidneys 
- Neuropsychiatric status 
9 Pearson's χ2 test/Fisher's exact test 
10 BP, HR, RR. 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-
ADHD-002-MEX- TAB, version 3.0 dated 
19.07.2019. 
CONFIDENTIAL 
page 37 of 42 
 
Indicator10 
Investigational product 
Visit 1 (Day -14 -1) 
Visit 5 (Day 43+1) 
Visit 6 (Day 50+3) 
Mean 
 
 
 
95% CI, L 
 
 
 
95% CI, U 
 
 
 
Median 
 
 
 
Min 
 
 
 
Max 
 
 
 
Q1 
 
 
 
Q3 
 
 
 
Range 
 
 
 
QRange 
 
 
 
SD 
 
 
 
CV 
 
 
 
Intragroup comparison: comparison of data at the end of therapy with data at the start of therapy (statistical 
criterion"11) (p-level value) 
Comparison of drugs (statistical test12) (p-value) 
Indicator span diagram/ indicator scatter diagram 
Table 11. Results of statistical analysis of blood and urine test results (template) 
Indicator13 
Investigational product 
Visit 1 (Day -14 -1) 
Visit 5 (Day 43+1) 
N 
 
 
Mean 
 
 
95% CI, L 
 
 
95% CI, U 
 
 
Median 
 
 
Min 
 
 
Max 
 
 
Q1 
 
 
Q3 
 
 
Range 
 
 
QRange 
 
 
SD 
 
 
CV 
 
 
Intragroup comparison: comparison of data at the end of therapy with data at the start of therapy (statistical 
criterion"14) (p-level value) 
Comparison of drugs (statistical test15) (p-value) 
Indicator span diagram/ indicator scatter diagram 
______________________ 
11 T-test for related samples or Wilcoxon test depending on the type of distribution of the indicator 
12 T-test for independent samples or Mann-Whitney test depending on the type of distribution of the indicator 
13 Interval indicators measured according to the clinical trial protocol 
14 T-test for related samples or Wilcoxon test depending on the type of distribution of the indicator 
15 T-test for independent samples or Mann-Whitney test depending on the type of distribution of the indicator 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-ADHD-002-MEX- TAB, 
version 3.0 dated 19.07.2019. 
CONFIDENTIAL 
page 38 of 42 
 
Table 12. Summary table of the incidence of reported AEs in the group taking Mexidol by severity with randomization numbers of patients (N= )16 
AE/code, PT according to 
MedDRA version 
Mild AE 
Medium AE 
Moderate AE 
Life-threatening AE 
Fatal AE 
Total 
Total 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R+UR 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cataract/10007739 Cataracta 
 
 
13 /611617 
 
 
 
 
 
 
 
1 
 
1 
Vascular system 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypertensive crisis/10020802 
 
 
 
 
 
1/793818  
 
 
 
 
 
1 
1 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 13. Summary table of the incidence of reported AEs in the group taking placebo by severity with randomization numbers of patients (N= )19 
Adverse eventcode PT level 
according to MedDRA version 
Mild AE 
Medium AE 
Moderate AE 
Life-threatening AE 
Fatal AE 
Total 
Total 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R+UR 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascular system 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
______________________ 
16 R - AE related to the investigational product: UR - AE unrelated to the investigational product; R+UR - sum of related and unrelated AEs; nm - degree of relationship, where n is 
the number of AEs; m 1 - definite relationship; m 2 - probable relationship; m 3 - possible relationship 
17 13/6116 means - one AE with a degree of possible relationship; 6116 - the patient's randomisation number 
18 1/7938 means - one unrelated AE, 7938 -  randomization number of the patient 
19 R - AE related to the investigational product: UR - AE unrelated to the investigational product; R+UR - sum of related and unrelated AEs; nm - degree of relationship, where n is 
the number of AEs; m 1 - definite relationship; m 2 - probable relationship; m 3 - possible relationship;  for an example of filling in, see Table 12 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-ADHD-002-MEX- TAB, 
version 3.0 dated 19.07.2019. 
CONFIDENTIAL 
page 39 of 42 
 
Table 14. Summary table of the incidence of reported AEs in the group taking Mexidol = placebo by severity with randomization numbers of patients 
(N= )20 
Adverse eventcode PT level 
according to MedDRA version 
Mild AE 
Medium AE 
Moderate AE 
Life-threatening AE 
Fatal AE 
Total 
Total 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R+UR 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascular system 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 15. Summary table of the incidence of AEs after taking each investigational product 
Adverse eventcode PT level according to MedDRA version 
Mexidol N= 
Mexidol+placebo Ν= 
Placebo Ν= 
P-value (Statistical criterion) 
n 
% 
n 
% 
n 
% 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascular system 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 16. List of all adverse events for each patient 
Site 
numb
er 
Randomization 
number, full name 
Demographic 
data 
AE/code, PT 
according to 
MedDRA 
version 
AE onset 
Severity 
Seriousn
ess 
Relatio
nship 
Actions taken 
in relation to 
the patient 
Actions 
taken in 
relation to 
the 
investigation
al product 
Concomit
ant 
therapy 
Date the 
AE 
resolved 
Outco
me 
 
 
Age, y 
 
 
 
 
 
 
 
 
 
 
 
gender 
 
 
 
 
 
 
 
 
 
 
 
______________________ 
20 A - AE associated with the investigational product: UR - AE unrelated to the investigational product; R+UR - sum of related and unrelated AEs; nm - degree of relationship, where n is the 
number of AEs; m 1 - definite relationship; m 2 - probable relationship; m 3 - possible relationship;  for an example of filling in, see Table 12 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-ADHD-002-MEX- TAB, 
version 3.0 dated 19.07.2019. 
CONFIDENTIAL 
page 40 of 42 
 
Weight, kg 
 
 
 
 
 
 
 
 
 
 
 
Height, cm 
 
 
 
 
 
 
 
 
 
 
 
race 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 17. Classification of AEs according to MedDRA v. 22.0 RU 
Randomization number, initials 
AE 
MedDRA AE code, SOC 
level 
MedDRA AE term, SOC 
level 
MedDRA AE code, PT 
level 
MedDRA AE term, PT 
level 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 18. Summary table of the incidence of reported SAEs in the group taking Mexidol by severity with randomization numbers of patients (N= )21 
Adverse event/code, РТ level 
according to MedDRA version 
Mild AE 
Medium AE 
Moderate AE 
Life-threatening 
AE 
Fatal AE 
Total 
Total 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R+UR 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascular system 
 
 
 
 
 
 
 
 
 
 
 
 
 
--- 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 19. Summary table of the incidence of reported SAEs in the group taking placebo by severity with randomization numbers of patients (N= )22 
Adverse event/code PT level according to MedDRA version 
Mexidol N= 
Mexidol+placebo Ν= 
Placebo Ν= 
P-value (Statistical criterion) 
n 
% 
n 
% 
n 
% 
______________________ 
21 A - SAE associated with the investigational product: UR - SAE unrelated to the investigational product; R+UR - sum of related and unrelated SAEs; nm - degree of relationship, where n is the number of AEs; m 1 - definite 
relationship; m 2 - probable relationship; m 3 - possible relationship;  for an example of filling in, see Table 12 
 
 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-ADHD-002-MEX- TAB, 
version 3.0 dated 19.07.2019. 
CONFIDENTIAL 
page 41 of 42 
 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascular system 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
Table 20. Summary table of the incidence of reported SAEs in the group taking Mexidol+placebo by severity with randomization numbers of patients 
(N= )23 
Adverse event/code, РТ level 
according to MedDRA version 
Mild AE 
Medium AE 
Moderate AE 
Life-threatening AE 
Fatal AE 
Total 
Total 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R 
UR 
R+UR 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascular system 
 
 
 
 
 
 
 
 
 
 
 
 
 
... 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 21. Summary table of the incidence of SAEs after taking each investigational product 
Adverse event/code PT level according to MedDRA version 
Mexidol N= 
Placebo Ν= 
P-value (Statistical 
criterion) 
n 
% 
η 
% 
Eyes 
 
 
 
 
 
 
 
 
 
 
 
Vascular system 
 
 
 
 
 
... 
 
 
 
 
 
Table 22. A list of all serious adverse events for each patient 
Site 
numb
er 
Randomization 
number, full name 
Demographic 
data 
SAE/code, 
PT 
according 
AE onset 
Severity 
Seriousn
ess 
Relations
hip 
Actions 
taken in 
relation 
Actions 
taken in 
relation to 
Concomita
nt therapy 
Date the AE 
resolved 
Outco
me 
______________________ 
23 A - SAE associated with the investigational product: UR - SAE unrelated to the investigational product; R+UR - sum of related and unrelated SAEs; nm - degree of relationship, where n is the number of AEs; m 1 - definite 
relationship; m 2 - probable relationship; m 3 - possible relationship;  for an example of filling in, see Table 12 


 
 
ClinPharmDevelopment 
ST-04-FRM-02 
Version 1 of 26.11.2018 
Plan for statistical analysis of efficacy and safety parameters 
 
Version 1.0 of 27.9.2019 
Protocol-specific version for protocol #PHS-ADHD-002-MEX- TAB, 
version 3.0 dated 19.07.2019. 
CONFIDENTIAL 
page 42 of 42 
 
to 
MedDRA 
version 
to the 
patient 
the 
investigation
al product 
 
 
Age, y 
 
 
 
 
 
 
 
 
 
 
 
gender 
 
 
 
 
 
 
 
 
 
 
 
Weight, kg 
 
 
 
 
 
 
 
 
 
 
 
Height, cm 
 
 
 
 
 
 
 
 
 
 
 
race 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 23. Classification of SAEs according to MedDRA version 
Randomization number, initials 
SAE 
SAE MedDRA code, 
SOC level 
SAE MedDRA term, 
SOC level 
SAE MedDRA code, PT 
level 
SAE MedDRA term, PT 
level