Efficacy and Safety of Tenoten for Children in the Treatment of Specific Developmental Disorders of Scholastic Skills in Children

A multicenter, double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy and safety of the study treatment.

The study will enroll the school children (boys and girls) of grades 1, 2 and 3 of a regular school aged 7-9 years old (grade 1 school children will be enrolled at the beginning of the second half of the year) complaining of difficult learning classified according to ICD-10 as specific developmental disorders of scholastic skills (F81) including:

• specific reading disorder (F81.0);
• specific spelling disorder (F81.1);
• specific disorder of arithmetical skills (F81.2);
• mixed disorder of scholastic skills (F81.3);
• disorder simultaneously meeting criteria of F81.2+F81.0 or F81.2+F81.1, or F81.2+F81.0+F81.1.

The developmental disorders of scholastic skills will be verified by a doctor (either a neurologist or psychiatrist) according to reading, spelling, and counting tests. The children may have any concomitant diseases not considered as exclusion criteria and not requiring therapy during the following 12 weeks using the products specified in section "Forbidden concomitant therapy". Specific additional educational programs should not be performed within 12 weeks after enrollment either.

On signing information sheet (informed consent form) by the parent/adopter the patients will be examined by a neurologist or psychiatrist and tested for reading skills (method by L.A. Fotekova, Т.V. Akhutina, 2002;), spelling skills (method by L.A. Fotekova, Т.V. Akhutina, 2002) and counting skills (subtest No. 3 "Arithmetic" WISC test), and concomitant therapy will be recorded.

If inclusion criteria are met and non-inclusion criteria are absent at Visit 1, the patient will be enrolled in the trial and randomized into one of the two groups: 1 tablet of Tenoten for children three times daily for 3 months (group 1) or the same dosing regimen of Placebo (group 2).

At Visit 1 the parents/adopters will receive the study product for 12-week treatment period and a diary to report any potential adverse events and cases of concomitant therapy.

Six weeks later (Week 6±3 days) a "Phone visit" (Visit 2) will be made in order to interview parents about the patient's condition, the presence/absence of concomitant diseases, adverse events.

At Visit 3 (Week 12±3 days) repeated testing of reading, spelling and counting skills will be made, complaints, data on concomitant diseases, concomitant therapy, and adverse events will be collected. The investigator will evaluate the subject's compliance and fill in the Clinical Global Impression Scale to calculate Efficacy Index (CGI-EI).

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

Inclusion criteria

• Children of either gender aged 7 to 9 years old.
• School children of grades 1-3 (grade 1 children will be enrolled at the beginning of the second half of the year) in regular schools with state accreditation with principal educational program of elementary general education in compliance with Federal State Educational Standard of the Russian Federation.
• Beginning of the second half of the year (only for 1st grades).
• Specific developmental disorder of scholastic skills such as:

• specific reading disorder (F81.0);
• specific spelling disorder (F81.1);
• specific disorder of arithmetical skills (F81.2);
• mixed disorder of scholastic skills (F81.3; i.e. meeting the criteria for one of the following combinations: F81.2+F81.0, F81.2+F81.1, or F81.2+F81.0+F81.1).
• Reading score of 15 to 35 on the Reading Skills test (L.A. Fotekova, T.V. Akhutina, 2002).
• Spelling score of 15 to 30 on the Spelling Skills test (L.A. Fotekova, T.V. Akhutina, 2002).
• Counting score of 5 to 15 on subtest No. 3 "Arithmetic" (of Wechsler Intelligence Scale for Children).
• Availability of a patient information sheet (Informed Consent form) signed by the parent/adopter to confirm the child's participation in the clinical trial.

Exclusion criteria

• History of the diseases:

• Diseases of the nervous system, including

• inflammatory diseases of the central nervous system;
• systemic atrophies;
• extrapyramidal and movement disorders;
• degenerative diseases of the nervous system;
• demyelinating diseases of the central nervous system;
• episodic and paroxysmal disorders;
• polyneuropathies;
• diseases of myoneural junction and muscle;
• cerebral palsy.
• Congenital malformations of the nervous system (excl. Spina bifida without hydrocephalus)
• Diseases and congenital malformations of the eye causing impairment of vision.
• Diseases and congenital malformations of the ear causing impairment of hearing.
• Organic mental disorders.
• Mental retardation ranging from mild to profound.
• Stuttering (stammering).
• Obsessive-compulsive disorder.
• Pervasive developmental disorders including:

• childhood autism;
• atypical autism;
• Rett syndrome;
• overactive disorder associated with mental retardation and stereotyped movements;
• Asperger syndrome.
• Phakomatoses (tuberous sclerosis, neurofibromatosis).
• Postconcussional syndrome.
• Hereditary metabolic diseases, including glycogen storage disease (glycogenosis), disorders of galactose metabolism (galactosemia), other disorders of carbohydrate metabolism, disorders of glycosaminoglycan metabolism (mucopolysaccharidoses), disorders of aromatic amino-acid metabolism (phenylketonuria, tyrosinemia, etc.), disorders of branched-chain amino-acid metabolism and fatty-acid metabolism (maple-syrup-urine disease), mitochondrial myopathy.
• Chromosomal abnormalities.
• Administration of the products specified in section "Forbidden concomitant therapy" within the previous 4 weeks.
• Necessity in pharmacotherapy for underlying and/or concomitant disease during the following 12 weeks.
• Acute infectious disease or exacerbation/decompensation of a disease affecting the patient's ability to participate in the trial.
• Malignant neoplasm/suspected malignant neoplasm.
• Allergy/intolerance to any of the components of medications used in the treatment.
• Malabsorption syndrome including congenital or acquired lactase deficiency (or another disaccharidase deficiency), and galactosemia.
• Mental disorders of patient's parent(s)/adopter(s).
• Use of drugs or alcohol by the patient's parents/adopters at > 2 alcohol units a day (1 unit of alcohol is equivalent to 0.33 L of lager/150 mL of unfortified wine, or 40 mL of Ethyl Alcohol).
• Participation in other clinical trials in the previous 3 months.
• Patients whose parent(s)/adopter(s), from the investigator's point of view, will fail to comply with the observation requirements of the trial or with the dose regimen of the investigational drug.
• Patients whose parent(s)/adopter(s) are related to any of the on-site research personnel directly involved in the conduct of the trial or are an immediate relative of the study investigator. "Immediate relative" means husband, wife, parent, son, daughter, brother, or sister (regardless of whether they are natural or adopted).
• Patients whose parent(s)/adopter(s) work for OOO "NPF "MATERIA MEDICA HOLDING" (i.e., is the company's employee, temporary contract worker, or, designated officials responsible for carrying out the research or any immediate relatives of the aforementioned).