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

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

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.

Study Overview

• Status: Completed
• Conditions: Anxiety
• Intervention / Treatment: Drug: Placebo; Drug: Tenoten

Detailed Description

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

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

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

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

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

• Study Type: Interventional
• Enrollment (Actual): 390
• Phase: Phase 4

Contacts and Locations

Study Locations

• Kazakhstan
  • Almaty, Kazakhstan, 050000
    • Kazakh National Medical University named after S.D. Asfendiyarov
  • Shymkent, Kazakhstan, 160019
    • South - Kazakhstan State Pharmaceutical Academy
• Russian Federation
  • Chelyabinsk, Russian Federation, 454048
    • Municipal Autonomous Healthcare Institution Order of the Red Banner of Labor City Clinical Hospital No. 1
  • Kazan', Russian Federation, 420012
    • Federal State Budgetary Educational Institution of Higher Education "Kazan Medical University" of the Ministry of Healthcare of the Russian Federation
  • Kazan', Russian Federation, 420101
    • The State Autonomic Health Care institution "Interregional clinical and diagnostical center"
  • Kazan', Russian Federation, 420110
    • LLC "City Center for Neurology and Pain Management"
  • Korolev, Russian Federation, 141060
    • Limited Liability Company "Family policlinic no. 4"
  • Moscow, Russian Federation, 117997
    • Pirogov Russian National Research Medical University
  • Moscow, Russian Federation, 115419
    • State Budget Health Care institution of Moscow the City "Scientific and practical psychoneurological center n.a. Z.P. Solovyov" of the Administration of Health Care of Moscow City
  • Moscow, Russian Federation, 115516
    • The State Budget Health Care institution of Moscow the City "City clinical hospital No. 12 of the Administration of Health Care of Moscow City"
  • Moscow, Russian Federation, 119992
    • The State Budget Educational institution of High Professional Training I.M. Sechenov First Moscow State Medical University of Ministry of Health Care of the Russian Federation, Hospital of nervous diseases A.Y. Kozhevnikov
  • Nizhny Novgorod, Russian Federation, 603126
    • State budgetary institution of public health services of the Nizhniy Novgorod region "Nizhegorod Regional Clinical Hospital named after NA Semashko"
  • Novosibirsk, Russian Federation, 630064
    • LLC "City Neurological Center" Sibneyromed "
  • Saint Petersburg, Russian Federation, 197022
    • Pavlov First Saint Petersburg State Medical University/Department of Neurology and Manual Medicine
  • Saint Petersburg, Russian Federation, 197022
    • Pavlov First Saint Petersburg State Medical University/Department of Neurology with Clinic
  • Samara, Russian Federation, 443096
    • State-Funded Healthcare Institution of the Samara Region "Samara City N.I. Pirogov Clinical Hospital №1"
  • Saratov, Russian Federation, 410012
    • Saratov State Medical University named after V. I. Razumovsky
  • Smolensk, Russian Federation, 214018
    • The State Budget Educational institution of High Professional Training Smolensk State Medical University of Ministry of Health Care of the Russian Federation, Smolensk regional clinical hospital
  • Vladimir, Russian Federation, 600023
    • The state budgetary health care institution of the Vladimir region "Regional Clinical Hospital"
  • Volgograd, Russian Federation, 400131
    • Volgograd State Medical University
  • Yaroslavl, Russian Federation, 150030
    • State Institution of Health of the Yaroslavl Region Clinical Hospital No. 8
  • Yaroslavl', Russian Federation, 150030
    • The State Health Care Institution Yaroslavl region "Clinical Hospital №8

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients of both sexes aged 18-45 years (inclusive).
2. Patients diagnosed with somatoform, stress-related, and other neurotic disorders (F43, F45, and F48), in accordance with the ICD-10 criteria.
3. A moderate and severe anxiety (HADS score ≥ 11) documented at screening.
4. Patients providing signed Informed Consent form for participation in the clinical trial.
5. 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:

1. Moderate and severe depression symptoms recorded at screening (HADS score ≥ 11).
2. Organic, including symptomatic, mental disorders (F00-09).
3. Mental and behavioural disorders due to psychoactive substance use (F10-19).
4. Schizophrenia, schizotypal and delusional disorders (F20-29).
5. Mood [affective] disorders(F30-39).
6. Phobic (F40) and other anxiety disorders (F41), obsessive-compulsive disorder (F42), dissociative [conversion] disorders (F44), depersonalization-derealization syndrome (F48.1).
7. Behavioral syndromes associated with physiological disturbances and physical factors (F50-59).
8. Disorders of adult personality and behavior (F60-69).
9. Intellectual disabilities (F70-79).
10. Inflammatory and traumatic brain injuries with permanent neurological deficit.
11. Prior diagnosis of a class III or IV cardiovascular disease (according to the New York Heart Association, 1964)
12. Malignant neoplasms/suspected malignant neoplasms.
13. An allergy/intolerance to any of the components of medications used in the treatment.
14. Malabsorption syndrome (including hereditary or acquired lactase or other disaccharidase deficiency) and galactosemia.
15. Any conditions that, from investigator's point of view, may affect the patient's ability to participate in the trial.
16. Hospitalizations or surgeries scheduled for any date during the participation in the study.
17. 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.
18. Use of drugs listed in "Prohibited therapy" within a month prior to enrollment.
19. Drug addiction, alcohol use in the amount over 2 units of alcohol a day.
20. Pregnant or breast-feeding women.
21. Participation in other clinical trials within 3 month prior to the enrollment in this study.
22. 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.
23. 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tenoten, 2 tablets twice daily (4 tablets/day); 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; Tablet for oral use.
Placebo Comparator: Placebo, 2 tablets twice daily (4 tablets/day); 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; Tablet for oral use.
Experimental: Tenoten, 2 tablets 4 times daily (8 tablets/day); 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; Tablet for oral use.
Placebo Comparator: Placebo, 2 tablets 4 times daily (8 tablets/day); 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; Tablet for oral use.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Materia Medica Holding
• Investigators: Principal Investigator: Vladimir Parfenov, DrMedSci, I.M. Sechenov First Moscow State Medical University (Sechenov University)

Publications and helpful links

General Publications

• Parfenov VA, Kamchatnov PR, Khasanova DR, Bogdanov EI, Lokshtanova TM, Amelin AV, Maslova NN, Pizova NV, Belskaya GN, Barantsevich ER, Duchshanova GA, Kamenova SU, Kolokolov OV, Glazunov AB. The randomized clinical trial results of the anxiety treatment in patients with somatoform dysfunction and neurotic disorders. Sci Rep. 2021 Dec 20;11(1):24282. doi: 10.1038/s41598-021-03727-5.

Study record dates

Study Major Dates

• Study Start (Actual): February 8, 2017
• Primary Completion (Actual): September 22, 2018
• Study Completion (Actual): September 22, 2018

Study Registration Dates

• First Submitted: January 26, 2017
• First Submitted That Met QC Criteria: January 26, 2017
• First Posted (Estimate): January 30, 2017

Study Record Updates

• Last Update Posted (Actual): December 31, 2020
• Last Update Submitted That Met QC Criteria: December 3, 2020
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Anxiety Disorders; Neurotic Disorders
• Other Study ID Numbers: MMH-TN-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No