Clinical trial NCT03159611
Conditions: Sequelae of Perinatal Brain Injury
Sponsor: Materia Medica Holding
Start date: 2016-02-19; Completion date: 2018-02-09
Enrollment: 182 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Purpose of the study:

* To assess the clinical efficacy of Tenoten for children liquid dosage form therapy (10 oral drops per day for 12 weeks) in Infants with Sequelae of Perinatal Brain Injury (mild-to-moderate cerebral hypoxia-ischaemia and/or mild-to-moderate intracranial haemorrhage).
* To assess the safety of Tenoten for children liquid dosage form therapy (10 oral drops per day for 12 weeks) in Infants with Sequelae of Perinatal Brain Injury (mild-to-moderate cerebral hypoxia-ischaemia and/or mild-to-moderate intracranial haemorrhage).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Tenoten for children intervention 2: Placebo
Intervention descriptions: intervention 1: Oral. 10 drops daily, at the same time in the morning, 15 minutes before feeding. intervention 2: Oral. 10 drops daily, at the same time in the morning, 15 minutes before feeding.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol No. MMH-TD-004 
19-Jul-2017 
CONFIDENTIAL  
 
Page 1 of 8 
Protocol Summary 
 
This document represents the protocol summary for the study on human subjects. The 
study will be carried out in accordance with ICH GCP, National Standard of the Russian 
Federation GOST 52379-2005 "Good Clinical Practice", Helsinki Declaration of World Medical 
Association, relevant requirements of the regulatory authorities as well as the study procedures. 
Title of Study 
Multicenter double-blind placebo-controlled parallel-group randomized clinical study of efficacy 
and safety of Tenoten for children liquid dosage form therapy in infants with sequelae of 
perinatal brain injury. 
 
Phase: III 
Sponsor: OOO "NPF "Materia Medica Holding", Moscow, Russia 
Protocol No. MMH-TD-004 
 
Study purposes 
 To assess the clinical efficacy of Tenoten for children liquid dosage form therapy (10 oral 
drops per day for 12 weeks) in infants with sequelae of perinatal brain injury (mild-to-
moderate cerebral hypoxia-ischemia and/or mild-to-moderate intracranial hemorrhage). 
 To assess the safety of Tenoten for children liquid dosage form therapy (10 oral drops per day 
for 12 weeks) in infants with sequelae of perinatal brain injury (mild-to-moderate cerebral 
hypoxia-ischemia and/or mild-to-moderate intracranial hemorrhage).  
Endpoints  
Primary endpoint 
1. Percentage of patients with a 4 and more point increase of the total score according to 
Jurba-Mastyukova psychomotor development scale by the end of the treatment course 
compared to baseline. 
Secondary endpoints 
1. Percentage of patients with normal psychomotor development (≥ 27 scores on Jurba-
Mastyukova scale) by the end of the treatment course compared to baseline. 
2. Mean Cognitive adaptive test/Clinical linguistic and auditory milestone scale 
(CAT/CLAMS) by the end of the treatment course compared to baseline. 


Protocol No. MMH-TD-004 
19-Jul-2017 
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3. Percentage of patients with normal psychomotor development (CATS/CLAMS + Gross 
motor developmental quotients score ≥ 75) by the end of the treatment course compared 
to baseline. 
4. Clinical Global Impression scale - Efficacy Index (CGI-EI) score by the end of the 
treatment course. 
Safety assessment  
 Adverse events during the treatment, their severity, treatment relatedness, and 
outcomes. 
Study design  
Study design: multicenter, double-blind, placebo-controlled, parallel-group, randomized 
clinical study to assess efficacy and safety of the study therapy.  
The study will enroll children of both genders aged from 29 days (end of neonatal period) 
up to 9 months on outpatient neurologist's observation due to sequelae of perinatal brain injury 
(mild-to-moderate cerebral hypoxia-ischemia and/or mild-to-moderate intracranial hemorrhage). 
The subjects of the study are not to be scheduled for any other treatments besides the 
investigated therapy within 12 weeks of the trial.  
After parent/adoptive parent has signed the patient information sheet (informed consent 
form) the subject’s medical history will be collected, physical examination will be performed, 
body weight, length, and head circumference will be measured. The infant neurological status 
will be assessed including psychomotor development according to Jurba-Mastyukova scale and 
Clinical Adaptive Test/Clinical Linguistic and Auditory Milestone (CAT/CLAMS) scale. 
Concomitant therapy will be recorded. If the subject meets inclusion criteria and has no 
exclusion criteria he/she will be included in the study and randomized at Visit 1 into one of the 
two groups: group 1 will receive Tenoten for children (oral drops) 10 oral drops per day for 12 
weeks; group 2 - Placebo 10 oral drops per day for 12 weeks.  
The subject will be observed for 12 weeks during which he/she will be examined by 
neurologist every 4 weeks (Visits 2, 3 and 4) in order to evaluate changes in physical and 
neuropsychological development, changes in neurological status, and to record potential adverse 
events, study treatment compliance.  
At the final visit (Visit 4, Week 12) the neurologist will evaluate motor and mental 
development, fill in Jurba-Mastyukova and CAT/CLAMS scales, record adverse events, and 
assess the therapy compliance. Then the Clinical Global Impression – Efficacy Index (CGI-EI) 
scale will be filled in. 


Protocol No. MMH-TD-004 
19-Jul-2017 
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Music therapy, herbal baths, gymnastics and tactile stimulation based on the child's age are 
allowed during the study.  
If the prohibited medicines are required for patients they will be withdrawn from the study 
and it will be considered as the absence of efficacy.   
Inclusion and exclusion criteria 
Inclusion criteria 
1. 
Full-term infants aged 29 days to 9 months1. 
2. 
Diagnosis of sequelae of perinatal brain injury (mild-to-moderate cerebral hypoxia-ischemia 
and/or mild-to-moderate intracranial hemorrhage). 
3. 
Jurba-Mastyukova total score < 27 and > 12. 
4. 
Physical development parameters within 25-27 centiles. 
5. 
Neurologist's outpatient observation. 
6. 
Information sheet (informed consent form) for parents/adoptive parents for participation in 
the clinical study signed by the child's parents/adoptive parents. 
Exclusion criteria 
1. 
Previously diagnosed lesions, diseases and conditions: 
1.1. Cerebral ischemia (grade III). 
1.2. Intraventricular hemorrhage (grade III). 
1.3. Metabolic and toxic disorders affecting central nervous system (persistent neonatal 
hypoglycemia, hyperbilirubinemia associated with elevated indirect bilirubin, and 
other severe conditions). 
1.4. Intracranial birth injury, focal impairments due to brain injuries (pareses and 
paralyses). 
1.5. Sequelae of birth injury to spinal cord, cranial nerves and peripheral nervous system 
(peripheral pareses and paralyses). 
1.6. Different types of hydrocephalus. 
1.7. Symptomatic epilepsy and epileptic syndromes. 
1.8. Sequelae of perinatal central nervous system (CNS) infectious diseases (injury to 
CNS caused by neonatal sepsis, encephalitis, meningitis, meningoencephalitis, 
ventriculitis). 
1.9. Infectious diseases including congenital diseases (cytomegalovirus infection, rubella, 
herpesvirus or enterovirus infection, toxoplasmosis, syphilis, HIV infection, etc.).  
                                               
1 Full-term neonates, i.e. born at gestation term of 38-42 weeks with birth weight > 2500 g. 


Protocol No. MMH-TD-004 
19-Jul-2017 
CONFIDENTIAL  
 
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1.10. Chronic respiratory diseases originating in the perinatal period, including 
bronchopulmonary dysplasia. 
1.11. Hereditary metabolic diseases including glycogen storage disease (glycogenoses, 
E74.0), galactose metabolism disorders (galactosemia, Е74.2), other carbohydrate 
metabolism 
disorders 
(Е74), 
glucosaminoglycan 
metabolism 
disorders 
(mucopolysaccharidoses, 
Е76), 
aromatic 
amino-acid 
metabolism 
disorders 
(phenylketonuria, tyrosinemia, etc, Е70), branched-chain amino-acid and fatty-acid 
metabolism disorders (maple-syrup-urine disease, Е71), mitochondrial myopathy 
(G71.3). 
1.12. Neurogenerative diseases including Huntington disease (G10), copper metabolism 
disorder (Wilson disease, Е83.0). 
1.13. Chromosomal abnormalities. 
1.14. Congenital anomalies [malformations] and deformities including congenital 
anomalies of nervous system and malformations of internal organs.  
1.15. Congenital endocrine diseases (congenital hypothyroidism, hypoparathyroidism, 
adrenocortical dysfunction). 
1.16. Malignant neoplasm / suspected malignant neoplasm.  
2. 
Acute infectious disease, exacerbation / decompensation of diseases that may prevent the 
patients’ participation in the clinical study. 
3. 
Allergy/intolerance of any of the study treatment medications components. 
4. 
Drug addiction, alcohol use in the volume over 2 alcohol units/day by the subject's 
parent(s)/adoptive parent(s). 
5. 
Mental disorders of the patient’s parent(s)/adoptive parent(s).  
6. 
Participation in other clinical studies for a period prior to and during the course of this trial. 
7. 
Other conditions complicating the subject's participation in the study (cannot make regular 
medical visits, moving, etc.). 
8. 
Subjects whose parent(s)/adoptive parent(s), from the investigator’s point of view, will not 
follow the study requirements or comply with the dosing regimen.  
9. 
Patients whose parent(s)/adoptive parent(s) are related research staff of the clinical 
investigative site who are directly involved in the study or is a close relative of the 
investigator. Close relatives include spouse, parents, children or brothers (sisters) 
regardless of whether they are biological or adoptive ones. 
10. 
Patients whose parent(s)/adoptive parent(s) is working in OOO “NPF “Materia Medica 
Holding”, i.e. is the company official, temporary contract worker or an appointed official 
responsible for the study or their close relatives.  


Protocol No. MMH-TD-004 
19-Jul-2017 
CONFIDENTIAL  
 
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Discontinuation criteria  
1. 
Inability or refusal of parent(s)/adoptive parent(s) to compliance the protocol. 
2. 
Necessity in the products not allowed within the study. 
3. 
Development of an adverse event requiring the product discontinuation. 
4. 
Parents’/adoptive parents’ wish to terminate the study early due to lack of therapeutic 
efficacy or for any other reason. 
5. 
Cases not specified by the protocol when, according to the investigator, further subject’s 
participation is dangerous. 
6. 
Enrollment of an ineligible subject. 
Number of subjects 
Signing informed consent by the parent(s)/adoptive parent(s) of 184 patients is planned; 
this is supposed to assure completion of all protocol procedures by at least 144 subjects. 
Treatment 
 
Group 1 
Name: Tenoten for children 
Active ingredient (per 1.0 mL): affinity purified antibodies to brain-specific S-100 protein - 
0.006 g* 
* administered as a mixture of three active water dilutions of the substance diluted respectively 
10012, 10030, 10050 times 
Excipients: Maltitol − 0.06 g; glycerol − 0.03 g; potassium sorbate − 0.00165 g; citric acid 
anhydrous – 0.0002 g; purified water − up to 1.0 mL 
Dosage: Per os. 10 drops (0.5 mL) once daily 15 min prior to morning feeding approximately at 
the same time. Prior to administration the drops may be diluted in small amount (1-5 mL) of 
boiled water of room temperature 
Dosage form: Oral drops 
Description: Colourless or almost colourless clear fluid 
Storage conditions: Store protected from light at temperature below 25°С. Keep out of the reach 
of children. Do not freeze 
 
Group 2 
Name: Placebo 
Active ingredient (per 1.0 mL): NA 
Excipients: Maltitol − 0.06 g; glycerol − 0.03 g; potassium sorbate − 0.00165 g; citric acid 
anhydrous – 0.0002 g; purified water − up to 1.0 mL 
Dosage: Placebo using Tenoten for children scheme. 
Dosage form: Oral drops 
Description: Colourless or almost colourless clear fluid 
Storage conditions: Store protected from light at temperature below 25°С. Keep out of the reach 
of children. Do not freeze 
 
Treatment period 
Tenoten for children/Placebo treatment period is 12 weeks. 


Protocol No. MMH-TD-004 
19-Jul-2017 
CONFIDENTIAL  
 
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Basic therapy 
All subjects participating in the study will receive non-drug therapy in home conditions: 
music therapy, herbal baths, gymnastics and tactile stimulation based on the child's age. 
Prohibited concomitant therapy 
The following products (ATC group is specified in brackets) are not allowed 15 days prior 
to enrollment and throughout the study: 
1. 
Psycholeptics (ATC group N05) including anxiolytics (tranquilizers), hypnotics and 
sedative products. 
2. 
Psychoanaleptics (ATC group N06) including psychostimulants and nootropic agents: 
 
pyrrolidine derivatives (racemates) – piracetam, etiracetam, aniracetam, etc.; 
 
pyridoxine derivatives - pyritinol, biotredin; 
 
GABA derivatives and analogues – gamma-aminobutyric acid, nicotinoyl gamma-
aminobutyric acid, gamma-amino-beta-phenylbutyric acid hydrochloride, hopantenic 
acid, calcium gamma-hydrobutyrate; 
 
ginkgo biloba; 
 
neuropeptides and their analogues - methionyl-glutamyl-histidyl-phenylalanyl-
prolyl-glycyl-proline; 
 
amino acids and substances affecting excitatory amino acid system - glycine, 
pyridoxine + threonine;  
 
polypeptides and organic composites - live stock cerebral cortical polypeptides, 
cerebrolysin; 
 
substances from other pharmacological groups with nootropic effect (general tonic 
agents and adaptogenes - acetylasparaginic acid, melatonin, lecithin, etc.). 
3. 
Antiepileptic drugs (ATC group N03A). 
4. 
Anticholinergic drugs (ATC group N04A). 
5. 
Dopaminergic drugs (ATC group N04B). 
6. 
Muscle relaxants (ATC group M03). 
7. 
Antihypoxants and antioxidants (ethylmethylhydroxypyridine succinate, citicoline, etc.). 
8. 
Agents improving metabolism and energy supply to tissues reducing tissue hypoxia 
(cytoflavin, corylip, eltacin, inosine, etc.). 
9. 
Homeopathic products.  
10. 
Vitamins and vitamin-like agents (ATC groups A11E, A11D, A11HA) − thiamine (vitamin 
В1), pyridoxine (vitamin В6), pyridoxal phosphate, nicotinic acid (vitamin РР), pantothenic 
(vitamin В5) and pangamic (vitamin В15) acids. 
11. 
Products previously causing allergic reactions in the subjects. 


Protocol No. MMH-TD-004 
19-Jul-2017 
CONFIDENTIAL  
 
Page 7 of 8 
 
 
Study design scheme 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule of study procedures  
Procedure/visit  
Visit 1 
(Screening, 
Day 0) 
Visit 2
(Week 4±5 
days) 
Visit 3
(Week 8±5 
days) 
Visit 4
(Week 12±5 
days) 
Signing patient information sheet
+ 
 
 
 
Collection of complaints
+ 
+ 
+ 
+ 
Collection of medical history
+ 
 
 
 
Objective examination
+ 
+ 
+ 
+ 
Neurological status
+ 
+ 
+ 
+ 
Body weight measurement
+ 
 
 
+ 
Body length measurement
+ 
 
 
+ 
Head circumference measurement
+ 
 
 
+ 
Evaluation of physical development
by centile tables 
+ 
 
 
+ 
Evaluation of psychomotor 
development using Jurba-Mastyukova 
scale 
+ 
+ 
+ 
+ 
Evaluation of psychomotor 
development using CAT/CLAMS 
scale 
+ 
+ 
+ 
+ 
Recording concomitant therapy
+ 
+ 
+ 
+ 
Evaluation of compliance with 
inclusion/exclusion criteria 
+ 
 
 
 
Randomization and prescription of the 
study therapy 
+ 
 
 
 
Drug issue
+ 
+ 
+ 
 
Accounting and return of the product, 
determination of compliance  
 
+ 
+ 
+ 
CGI score
 
 
 
+ 
Therapeutic safety evaluation
 
+ 
+ 
+ 
Group 1: Tenoten for children for 12 weeks 
SCREENING
Visit 3
(Week 8±5 days) 
Visit 1
(Day 0) 
12 weeks 
Visit 4 
(Week 12±5 days) 
Visit 2
(Week 4±5 days) 
Group 2: Placebo for 12 weeks 
RANDOMIZATION
Non-pharmacological therapy for group 1 and 2 subjects:
music therapy on a daily basis (predominantly cradle songs), herbal baths every other day 
(10 baths per month), daily gymnastics and tactile stimulation (based on the child's age) 


Protocol No. MMH-TD-004 
19-Jul-2017 
CONFIDENTIAL  
 
Page 8 of 8 
 
Statistical Analyses 
The following rules and assumptions were taking into account when calculating the sample 
size: power of statistical criteria is equal to 80% (probability of non-missing the effect is equal to 
0.8); probability of error of the first kind is < 5% (probability of erroneous decision on the effect 
presence < 0.05). The statistical criteria used are two-sided, sample size is based on the 
assumption of the expected effects according to the primary outcome measure claimed in the 
protocol.  
It is supposed that the difference between proportions of subjects with increased Jurba-
Mastyukova total score ≥ 4 scores by the end of the treatment course in Tenoten for children 
group compared to equivalent proportion of subjects in Placebo group is no less than 22% in 
favour of Tenoten for children.  
Given the statistical terms mentioned above, the size of each group will be 72 subjects (PP 
analysis, total = 144). 
Supposing potential withdrawal of at least 22% subjects at screening and during the study 
for various reasons, at least 92 subjects in each group (184 in total) will be required to be 
recruited with their parents/adoptive parents signing informed consent form.  
Safety and tolerability analysis of the study therapy will be based on the data from all 
randomized subjects who have received at least one dose of the study product/placebo. Efficacy 
analysis will be based on the two samples - FAS (Full Analysis Set) and PP (Per Protocol set): 
ITT-analysis and PP-analysis, respectively.  
SAS-9.4 software will be used for statistical analysis including various parametric and 
nonparametric tests.