Tenoten® in the Treatment of Somatoform, Stress-related and Other Neurotic Disorders

Study Overview
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Brief Summary
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The purposes of this study are: To further examine the efficacy and safety of Tenoten® in the treatment of anxiety in patients with somatoform, stress-related and other neurotic disorders. To compare the efficacy of two dosing regimens of Tenoten® (4 tablets daily vs.8 tablets daily, both for 12 weeks) in the treatment of anxiety in patients with somatoform, stress-related and other neurotic disorders.

Detailed Description
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Design: an international, a multicenter, double-blind, randomized, parallel group placebo-controlled trial to evaluate efficacy and safety of study treatment. The study will enroll outpatient subjects of both genders aged 18-45 years with verified diagnoses of somatoform, stress-related and other neurotic disorders (F43, F45, F48) and signs of clinically relevant anxiety according to The Hospital Anxiety and Depression scale (HADS). After signing the informed consent form to participate in the clinical study the subject will be interviewed (complaints, medical history, concomitant therapy) and objective examination will be performed; the subject will fill HADS scale. The severity of anxiety at screening should be ≥ 11 according to HADS. If the subject meets inclusion criteria and has no exclusion criteria he/she will be enrolled into the study. The investigator will determine the severity of anxiety using НАМ-А scale; the subject will fill EQ-5D-3L questionnaire. At Visit 1 (Day 1) the subject will be randomized into one of the treatment groups: Group 1: Tenoten® at 2 tablets twice daily (4 tablets/day); Group 2: Placebo at 2 tablets twice daily (4 tablets/day); Group 3: Tenoten® at 2 tablets 4 daily (8 tablets/day). Group 4: Placebo at 2 tablets 4 daily (8 tablets/day). The first dose should be administered at Visit 1 after the visit procedures are completed. Further administration of the study product will be made according to the dosing scheme. The subject will administer the study product and will be followed for 12 weeks during which additional three visits will be made. At Visit 2 (Week 4), Visit 3 (Week 8) and Visit 4 (Week 12) the physician will record patients' complaints and physical examination data, fill HAM-A scale, check the study and concomitant therapy, assess treatment safety and patient compliance with the study treatment. At the final Visit 4 the subject will fill EQ-5D-3L questionnaire and the investigator will fill the Clinical Global Impression Scale Efficacy Index (CGI-EI). Subjects will be allowed to take symptomatic therapy and medications for their co-morbidities during the study, except for the medicines listed in Prohibited therapy.

Official Title
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International Multicenter, Double-blind, Randomized Placebo-controlled Phase IV Clinical Trial of Different Dosing Regimens of Tenoten® in the Treatment of Anxiety in Patients With Somatoform, Stress-related and Other Neurotic Disorders

Conditions
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Anxiety

Intervention / Treatment
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* Drug: Tenoten
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of both sexes aged 18-45 years (inclusive). Patients diagnosed with somatoform, stress-related, and other neurotic disorders (F43, F45, and F48), in accordance with the ICD-10 criteria. A moderate and severe anxiety (HADS score ≥ 11) documented at screening. Patients providing signed Informed Consent form for participation in the clinical trial. Patients of reproductive age (of both sexes) using contraceptives and contraceptive methods during the study and for 30 days after the end of participation in the trial. Exclusion Criteria: Moderate and severe depression symptoms recorded at screening (HADS score ≥ 11). Organic, including symptomatic, mental disorders (F00-09). Mental and behavioural disorders due to psychoactive substance use (F10-19). Schizophrenia, schizotypal and delusional disorders (F20-29). Mood [affective] disorders(F30-39). Phobic (F40) and other anxiety disorders (F41), obsessive-compulsive disorder (F42), dissociative [conversion] disorders (F44), depersonalization-derealization syndrome (F48.1). Behavioral syndromes associated with physiological disturbances and physical factors (F50-59). Disorders of adult personality and behavior (F60-69). Intellectual disabilities (F70-79). Inflammatory and traumatic brain injuries with permanent neurological deficit. Prior diagnosis of a class III or IV cardiovascular disease (according to the New York Heart Association, 1964) Malignant neoplasms/suspected malignant neoplasms. An allergy/intolerance to any of the components of medications used in the treatment. Malabsorption syndrome (including hereditary or acquired lactase or other disaccharidase deficiency) and galactosemia. Any conditions that, from investigator's point of view, may affect the patient's ability to participate in the trial. Hospitalizations or surgeries scheduled for any date during the participation in the study. Patients who, from investigator's point of view, will fail to comply with the observation requirements of the trial or with the dosing regimen of the study drugs. Use of drugs listed in Prohibited therapy within a month prior to enrollment. Drug addiction, alcohol use in the amount over 2 units of alcohol a day. Pregnant or breast-feeding women. Participation in other clinical trials within 3 month prior to the enrollment in this study. Patients are related to the research personnel of the investigative site who are directly involved in the trial, or patients who are the immediate family member of the researcher. The 'immediate family member' includes husband/wife, parents, children or brothers (or sisters), regardless of whether they are natural or adopted. Patients working for OOO NPF MATERIA MEDICA HOLDING, i.e. the company's employee, temporary contract worker, or appointed official responsible for carrying out the research (or the immediate relative).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tenoten, 2 tablets twice daily (4 tablets/day)<br>Tablet for oral use. Dose per administration: 2 tablets. 2 tablets twice daily (4 tablets/day). The tablets should be held in the mouth until dissolution, without meal. | Drug: Tenoten<br>* Tablet for oral use.<br>|
| Placebo Comparator: Placebo, 2 tablets twice daily (4 tablets/day)<br>Tablet for oral use. Dose per administration: 2 tablets. 2 tablets twice daily (4 tablets/day). The tablets should be held in the mouth until dissolution, without meal. | Drug: Placebo<br>* Tablet for oral use.<br>|
| Experimental: Tenoten, 2 tablets 4 times daily (8 tablets/day)<br>Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 4 times daily (8 tablets/days). The tablets should be held in the mouth until dissolution, without meal. | Drug: Tenoten<br>* Tablet for oral use.<br>|
| Placebo Comparator: Placebo, 2 tablets 4 times daily (8 tablets/day)<br>Tablet for oral use. Dose per administration: 2 tablets. 2 tablets 4 times daily (8 tablets/days). The tablets should be held in the mouth until dissolution, without meal. | Drug: Placebo<br>* Tablet for oral use.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Mean HAM-A Score at 12 Weeks of Treatment: 1. Group 1 (Tenoten®, 4 Tablets a Day); 2. Group 3 (Tenoten®, 8 Tablets a Day). | The Hamilton Anxiety Rating Scale (HAM-A). Personality questionnaire designed to identify constitutive anxiety and situational anxiety. The scale consists of 14 items and measures both psychic anxiety and somatic anxiety. Total score is in range 0-56. Includes the symptoms of anxious mood, phobic, emotional, sleep disorders, depressive mood, somatic symptoms - muscular (pain, convulsions, etc.), sensory (e.g. tinnitus), cardiovascular, respiratory, gastrointestinal, genitourinary, neurovegetative. Major role belongs to behaviour during this interview. Anxiety scoring: ≤13 - no anxiety; 14-17 - mild anxiety disorder; 18-24 - moderate anxiety disorder; ≥25 - severe anxiety. Higher values represent a worse outcome | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Mean HAM-A Score at 4 Weeks of Treatment: 1.1. Group 1 (Tenoten®, 4 Tablets a Day); 1.2. Group 3 (Tenoten®, 8 Tablets a Day). | The Hamilton Anxiety Rating Scale (HAM-A). Personality questionnaire designed to identify constitutive anxiety and situational anxiety. The scale consists of 14 items and measures both psychic anxiety and somatic anxiety. Total score is in range 0-56. Includes the symptoms of anxious mood, phobic, emotional, sleep disorders, depressive mood, somatic symptoms - muscular (pain, convulsions, etc.), sensory (e.g. tinnitus), cardiovascular, respiratory, gastrointestinal, genitourinary, neurovegetative. Major role belongs to behaviour during this interview. Anxiety scoring: ≤13 - no anxiety; 14-17 - mild anxiety disorder; 18-24 - moderate anxiety disorder; ≥25 - severe anxiety. Higher values represent a worse outcome | 4 weeks | 
| The Mean HAM-A Score at 8 Weeks of Treatment: 2.1. Group 1 (Tenoten®, 4 Tablets a Day); 2.2. Group 3 (Tenoten®, 8 Tablets a Day). | The Hamilton Anxiety Rating Scale (HAM-A). Personality questionnaire designed to identify constitutive anxiety and situational anxiety. The scale consists of 14 items and measures both psychic anxiety and somatic anxiety. Total score is in range 0-56. Includes the symptoms of anxious mood, phobic, emotional, sleep disorders, depressive mood, somatic symptoms - muscular (pain, convulsions, etc.), sensory (e.g. tinnitus), cardiovascular, respiratory, gastrointestinal, genitourinary, neurovegetative. Major role belongs to behaviour during this interview. Anxiety scoring: ≤13 - no anxiety; 14-17 - mild anxiety disorder; 18-24 - moderate anxiety disorder; ≥25 - severe anxiety. Higher values represent a worse outcome | 8 weeks | 
| Percentage of Patients Had at Least a 50% Improvement in the HAM-A Score: 3.1. Group 1 (Tenoten® 4 Tablets a Day): After 4, 8 and 12 Weeks; 3.2. Group 3 (Tenoten® 8 Tablets a Day): After 4, 8 and 12 Weeks. | The Hamilton Anxiety Rating Scale (HAM-A). Personality questionnaire designed to identify constitutive anxiety and situational anxiety. The scale consists of 14 items and measures both psychic anxiety and somatic anxiety. Total score is in range 0-56. Includes the symptoms of anxious mood, phobic, emotional, sleep disorders, depressive mood, somatic symptoms - muscular (pain, convulsions, etc.), sensory (e.g. tinnitus), cardiovascular, respiratory, gastrointestinal, genitourinary, neurovegetative. Major role belongs to behaviour during this interview. Anxiety scoring: ≤13 - no anxiety; 14-17 - mild anxiety disorder; 18-24 - moderate anxiety disorder; ≥25 - severe anxiety. Higher values represent a worse outcome | 4,8,12 weeks | 
| Percentage of Patients With no Anxiety (HAM-A Score <14) in: 4.1. Group 1 (Tenoten®, 4 Tablets a Day); After 4, 8 and 12 Weeks; 4.3. Group 3 (Tenoten®, 4 Tablets a Day); After 4, 8 and 12 Weeks. | The Hamilton Anxiety Rating Scale (HAM-A). Personality questionnaire designed to identify constitutive anxiety and situational anxiety. The scale consists of 14 items and measures both psychic anxiety and somatic anxiety. Total score is in range 0-56. Includes the symptoms of anxious mood, phobic, emotional, sleep disorders, depressive mood, somatic symptoms - muscular (pain, convulsions, etc.), sensory (e.g. tinnitus), cardiovascular, respiratory, gastrointestinal, genitourinary, neurovegetative. Major role belongs to behaviour during this interview. Anxiety scoring: ≤13 - no anxiety; 14-17 - mild anxiety disorder; 18-24 - moderate anxiety disorder; ≥25 - severe anxiety. Higher values represent a worse outcome | 4,8,12 weeks | 
| Change From Baseline in the Total EQ-5D-3L Score at 12 Weeks of Treatment in Patients From: 5.1. Group 1 (Tenoten®, 4 Tablets a Day); 5.2. Group 3 (Tenoten®, 8 Tablets a Day). | European Quality of Life Instrument questionnaire (EQ-5D-3L) is designed for the evaluation of the quality of life.The score ranges between 5-15. Higher values represent a worse outcome. | 12 weeks | 
| Total CGI Scores in Patients From: 6.1. Group 1 (Tenoten®, 4 Tablets a Day); 6.2. Group 3 (Tenoten®, 8 Tablets a Day). | Clinical Global Impession (CGI) provides a brief assessment of the clinician's view of the patient's global functioning prior to and after initiating a study medication. Total range 0-16. Higher values represent a worse outcome | 12 weeks |