Efficacy and Safety of Vespireit, Sustained-release Tablets, in Patients With Autonomic Dysfunction Syndrome Accompanied by Functional Vertigo

Open Multicenter Randomized Clinical Trial to Evaluate the Efficacy and Safety of Vespireit, Prolonged-release Tablets (Valenta Pharm JSC, Russia) and Arlevert, Tablets (Menarini International Operations Luxembourg S.A., Luxembourg) in Patients With Autonomic Dysfunction Syndrome Accompanied by Functional Vertigo

Study of efficacy and safety of Vespireit, prolonged-release tablets, 15 mg (Valenta Pharm JSC, Russia) in comparison with Arlevert, tablets, 40 mg + 20 mg (Menarini International Operations Luxembourg S.A., Luxembourg) in patients with autonomic dysfunction syndrome accompanied by functional vertigo.

Study Overview

• Status: Recruiting
• Conditions: Vertigo; Autonomic Dysfunction
• Intervention / Treatment: Drug: Vespireit; Drug: Arlevert

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Phase 4

Contacts and Locations

Study Locations

• Russian Federation
  • Bryansk, Russian Federation, 241050
    • Recruiting
    • Central Clinic LLC
    • Contact: Marina A Agafonova, MD, PhD; Phone Number: +7-4832-72-58-28; Email: agafonova.marina.sm@mail.ru
  • Kirov, Russian Federation, 610027
    • Recruiting
    • Federal State Budgetary Educational Institution of Higher Education "Kirov State Medical University" of the Ministry of Healthcare of the Russian Federation
    • Contact: Nadezhda S Trushnikova, MD; Phone Number: +7-8332-62-75-68; Email: uddefola@mail.ru
  • Moscow, Russian Federation, 109263
    • Recruiting
    • State Budgetary Institution of Healthcare of the City of Moscow "V.P. Demikhov City Clinical Hospital of the Department of Healthcare of the City of Moscow"
    • Contact: Kamila B Gadjialieva, MD; Phone Number: +7-925-710-00-97; Email: demikhovadzm@mail.ru
  • Smolensk, Russian Federation, 214025
    • Recruiting
    • Private Healthcare Institution "Clinical Hospital "RZD-Medicine" of the city of Smolensk"
    • Contact: Natalia A Belyaeva, MD; Phone Number: +7-4812-24-50-60; Email: n.makar1973@mail.ru

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient signing and dating the Informed Consent Form.
2. Women and men between the ages of 18 and 65 inclusive at the time of signing the Informed Consent Form.
3. Clinical diagnosis: G90.8 Other disorders of autonomic nervous system or G90.9 Disorder of autonomic nervous system, unspecified.
4. Presence of chronic (functional) vertigo established in accordance with the diagnostic criteria of the Barani Society: total DHI score ≥ 31 points; mean MVS score ≥ 1.5 points.
5. For women with preserved reproductive potential, a negative pregnancy test and consent to use an authorized method of contraception throughout the entire period of study participation, starting from Visit 0, and for 3 weeks after the end of the study; for men, consent to use an authorized method of contraception throughout the entire period of study participation and for 3 weeks after the end of the study.

The authorized contraceptive methods in this study are: intrauterine device, barrier method, or dual barrier method (condom or occlusive cap (diaphragm or cervical/vaginal cap) plus spermicide)). Hormonal contraception was not permitted due to insufficient data on drug interactions of buspirone.

Women with fertility failure (menopausal (defined as no menstruation for at least 2 years or more) or documented surgical sterilization (hysterectomy, bilateral ovariectomy, tubal ligation)) and men with documented infertility or vasectomy will also be eligible for the study.

Non-inclusion Criteria:

1. Known or suspected hypersensitivity to the active substance or any of the excipients of the study medication.
2. Lactose intolerance, lactase deficiency, glucose-galactose malabsorption.
3. A cumulative score > 2 on the Suicide Risk Assessment Scale (SRAS).
4. Chronic heart failure III-IV functional classes according to the New York Heart Association (NYHA) classification, angina pectoris III-IV functional classes.
5. Presence of uncompensated peripheral vestibular hyporeflexia due to previous vestibular neuronitis, labyrinthitis, labyrinth trauma.
6. Presence at the time of screening of exacerbation of vestibular diseases with episodic vestibular syndrome.
7. Meniere's disease.
8. Established diagnosis of bilateral vestibular insufficiency.
9. Syncopal and presyncopal conditions at the time of screening.
10. Acute cardiovascular disease or surgical interventions (myocardial infarction, angioplasty, aortocoronary/mammary coronary heart bypass, unstable angina, and others) less than 6 months prior to the date of the Screening Visit.
11. Acute cerebral circulatory disorders and/or transient ischemic attacks less than 6 months prior to the date of the Screening Visit.
12. Hemodynamically significant cardiac rhythm and conduction abnormalities, including a history of cardiac rhythm and conduction abnormalities.
13. An installed artificial pacemaker.
14. Clinically significant ECG abnormalities;
15. Established diagnosis of liver failure, including history and/or altered laboratory values: increase in aspartateaminotransferase (AST), alanineaminotransferase (ALT) more than 2.5 times relative to the upper limit of normal, increase in total bilirubin more than 1.5 times above the upper limit of normal;
16. Established diagnosis of renal failure of any severity and/or creatinine clearance calculated by the Cockcroft-Gault formula at screening < 80 ml/min in women and < 90 ml/min in men.
17. Pyloroduodenal obstruction based on history.
18. Prostatic hyperplasia of the prostate gland.
19. Thyroid function disorder according to examination and clinical and laboratory tests.
20. Parkinson's disease according to anamnesis.
21. Severe ischemic heart disease.
22. Uncontrolled hypertension with systolic blood pressure > 180 mm Hg and/or diastolic blood pressure > 110 mm Hg, or blood pressure (BP) at screening ≥140/90 or ≤ 100/60 mm Hg.
23. Uncontrolled diabetes mellitus, diabetes mellitus in decompensation.
24. Myasthenia gravis.
25. Closed-angle glaucoma.
26. Suspicion of elevated intraocular pressure at the time of screening.
27. Systemic connective tissue diseases.
28. Autoimmune diseases.
29. History or suspicion of elevated intracranial pressure.
30. Urinary retention due to a history of urethral and/or prostate disease.
31. Need for surgical and/or endovascular treatment in the next 15 months.
32. Epilepsy or convulsive seizures, including history of seizures.
33. Alcoholism, drug dependence, substance abuse in the history and/or at the time of screening (alcoholism - use of more than 30 ml of ethyl alcohol per day during the last 6 months; drug dependence - use of any narcotic substances in any doses during the last 6 months; substance abuse - use of any psychoactive substances in any doses during the last 6 months).
34. History of schizophrenia, schizoaffective disorder, bipolar disorder.
35. Tuberculosis, hepatitis B and C, HIV infection, syphilis, history or by screening.
36. Conditions after surgical operations, if less than 6 months have passed since the operation.
37. Therapy for cognitive impairment, balance disorders, and dizziness 21 days or less prior to Visit 1-1 date.
38. Use of an irreversible MAO inhibitor within 14 days or a reversible MAO inhibitor within 1 day prior to Visit 1-1.
39. Therapy with the following drugs and drug groups: 7 days or less before screening: Selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SSRIs); Cinnarizine and/or dimenhydrinate preparations; Cytochrome P450 3A4 (Cytochrome P450 3A4, CYP3A4) inhibitors and inducers: Erythromycin, itraconazole, nefazodone, diltiazem, verapamil, etc.; Cimetidine, warfarin, phenytoin, propranolol. Monoamine oxidase inhibitors (MAOIs): concomitant use of MAO inhibitors is prohibited, as well as taking the drug earlier than 14 days after withdrawal of an irreversible MAO inhibitor, or less than 1 day after withdrawal of a reversible MAO inhibitor.
40. Presence of a history of malignant neoplasm, except in patients who have had no disease in the past 5 years, patients with completely cured basal cell skin cancer, or completely cured carcinoma in situ.
41. Decompensated somatic diseases that, in the opinion of the investigator, would prevent the patient from complying with the regimen prescribed by the study protocol, or would prevent assessment of the efficacy of therapy and compliance according to the protocol, or could skew the results of the study.
42. Decompensated neuropsychiatric diseases, including multiple sclerosis, Parkinson's disease, endogenous depression, and others, which in the opinion of the investigator would prevent the patient from complying with the regimen prescribed by the study protocol, or would prevent assessment of therapy efficacy and compliance according to the protocol, or could skew the results of the study.
43. Women in pregnancy or lactation; women planning pregnancy within the next 15 months.
44. Patients who require concomitant therapy prohibited in this study.
45. Participation in another clinical trial within the last 3 months prior to the date of the Screening Visit.
46. Patient's unwillingness or inability to comply with protocol procedures (in the opinion of the investigator).
47. Other conditions that, in the opinion of the Investigator, preclude the patient's inclusion in the study.
48. The patient is diagnosed with COVID-19 disease at the time of screening or Randomization Visit; or the presence of symptoms of acute respiratory infections or COVID-19 within 14 days prior to screening and a positive rapid test for COVID-19 at screening.

Exclusion criteria:

1. The patient's desire to discontinue participation in the study.
2. A decision by the investigator that continued participation in the study is contrary to the patient's best interests.
3. The patient is included in the study in violation of the inclusion and non-inclusion criteria.
4. A decision by the investigator's physician to exclude the patient from the study due to lack of adequate cooperation of the patient with the investigator's physician during the study.
5. Diagnosis of acute (vestibular neuronitis, acute labyrinthitis, traumatic vestibulopathy, stroke with lesions of central and peripheral vestibular structures and others) and/or episodic vestibular syndromes (benign positional paroxysmal vertigo, Meniere's disease, vestibular migraine and others), bilateral vestibulopathy.
6. Skipping taking the study drug (3 consecutive tablets or more than 6 tablets for each period of therapy).
7. Omission of the comparison drug (9 consecutive tablets or more than 17 tablets per therapy period).
8. An adverse event requiring withdrawal of investigational therapy or limiting protocol procedures.
9. The need to prescribe to the patient drugs from the "Prohibited Concomitant Therapies" section.
10. Loss of communication with the patient.
11. Pregnancy of the patient.
12. Ineffectiveness of therapy (increase from baseline or no decrease in DHI total score and MVS mean score by 25% or more from baseline after another course of therapy).
13. The patient was diagnosed with COVID-19 disease during the periods of primary and repeated therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Vespireit, prolonged-release tablets, 15 mg; Dosage regimen: 1 tablet once a day at approximately the same time in the morning after meals for 28 days. The drug is taken orally, whole, without breaking and not chewing.	Drug: Vespireit; Buspirone
Active Comparator: Arlevert, tablets, 40 mg + 20 mg; Dosage regimen: 1 tablet 3 times a day at approximately the same time after meals for 28 days. The drug is taken orally, whole, without breaking and not chewing.	Drug: Arlevert; Dimenhydrinate + Cinnarizine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mean vertigo score (MVS) at Visit 1-3 of the Primary Therapy Period relative to baseline at Visit 1-1	Difference in MVS assessed on Visit 1-3 and 1-1 (12-item scale with score from 0 to 4 for each item; higher scores mean a worse outcome)	Day 1 - Day 28±1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in mean MVS score at Visit 1-2 of the Primary Therapy Period relative to baseline at Visit 1-1.	Assessment performed using MVS (12-item scale with score from 0 to 4 for each item; higher scores mean a worse outcome)	Day 1 - Day 28±1
Change in mean MVS score at Visits 2-2, 2-3, and 2-4 of the Retreatment Period compared with Visit 2-1.	Assessment performed using MVS (12-item scale with score from 0 to 4 for each item; higher scores mean a worse outcome)	Day 1 - Day 42 ±1 (retreatment period)
Change in mean MVS score at the visit of completion of study participation compared with the score at Visit 1-1 in patients who completed the study according to the protocol (PP(response)).	Assessment performed using MVS (12-item scale with score from 0 to 4 for each item; higher scores mean a worse outcome)	Day 1 - Day 28±1
Percentage of patients with a ≥50% reduction in total DHI score on Visit 1-3 of the Primary Therapy Period relative to Visit 1-1.	Assessment performed using DHI (25-item self-report questionnaire with total score from 0 to 100; higher scores mean a worse outcome)	Day 1 - Day 28±1
Percentage of patients with a ≥50% reduction in total DHI score on Visits 2-3 and 2-4 of the Retreatment Period relative to Visit 2-1.	Assessment performed using DHI (25-item self-report questionnaire with total score from 0 to 100; higher scores mean a worse outcome)	Day 1 - Day 42 ±1 (retreatment period)
Percentage of patients with a ≥25% reduction in total DHI score on Visit 1-3 of the Primary Therapy Period relative to Visit 1-1.	Assessment performed using DHI (25-item self-report questionnaire with total score from 0 to 100; higher scores mean a worse outcome)	Day 1 - Day 28±1
Percentage of patients with a ≥25% reduction in total DHI score on Visits 2-3 and 2-4 of the Retreatment Period relative to Visit 2-1.	Assessment performed using DHI (25-item self-report questionnaire with total score from 0 to 100; higher scores mean a worse outcome)	Day 1 - Day 42 ±1 (retreatment period)
Change in total score on the DHI at Visit 1-3 of the Primary Therapy Period compared with Visit 1-1.	Assessment performed using DHI (25-item self-report questionnaire with total score from 0 to 100; higher scores mean a worse outcome)	Day 1 - Day 28±1
Change in total score on the DHI at Visits 2-3 and 2-4 of the Retreatment Period compared with Visit 2-1.	Assessment performed using DHI (25-item self-report questionnaire with total score from 0 to 100; higher scores mean a worse outcome)	Day 1 - Day 42 ±1 (retreatment period)
Change in total score on the DHI at the study participation completion visit compared to the score at Visit 1-1 in patients who completed the study according to the protocol (PP(response)).	Assessment performed using DHI (25-item self-report questionnaire with total score from 0 to 100; higher scores mean a worse outcome)	Day 1 - Day 28±1
Change in digital rating scalescore from Visit 1-1 to Visits 1-2 and 1-3 in the Primary Treatment Period.	Assessment performed using digital rating scale (from minimum of 0 to maximum of 10 points; higher scores mean a worse outcome)	Day 1 - Day 28±1
Change in digital rating scale score from Visit 2-1 to Visits 2-2, 2-3, and 2-4 in the Retreatment Period.	Assessment performed using digital rating scale (from minimum of 0 to maximum of 10 points; higher scores mean a worse outcome)	Day 1 - Day 42 ±1 (retreatment period)
Assessment of quality of life in patients with autonomic dysfunction syndrome accompanied by functional vertigo using the EQ-5D questionnaire at Visit 1-3 of the Primary Therapy Period.	Assessment performed using EQ-5D questionnaire (5-item self-report questionnaire with total score from 0 to 100; higher scores mean a better outcome)	Day 1 - Day 28±1
Assessment of quality of life in patients with autonomic dysfunction syndrome accompanied by functional vertigo using the EQ-5D questionnaire at Visits 2-3 and 2-4 of the Retreatment Period.	Assessment performed using EQ-5D questionnaire (5-item self-report questionnaire with total score from 0 to 100; higher scores mean a better outcome)	Day 1 - Day 42 ±1 (retreatment period)
Change in total score on the Hamilton Anxiety Rating Scale HARS at Visit 1-3 of the Primary Treatment Period compared with Visit 1-1.	Assessment performed using HARS (21-item scale with total score from 0 to 56; higher scores mean a worse outcome)	Day 1 - Day 28±1
Change in total score on the Hamilton Anxiety Rating Scale HARS at Visits 2-3 and 2-4 of the Retreatment Period compared with Visit 2-1.	Assessment performed using HARS (21-item scale with total score from 0 to 56; higher scores mean a worse outcome)	Day 1 - Day 42 ±1 (retreatment period)
Change in VSS-SF total score at Visit 1-3 of the Primary Therapy Period relative to baseline at Visit 1-1.	Assessment performed using VSS-SF score (15-item scale with score from 0 to 4 for each item; higher scores mean a worse outcome)	Day 1 - Day 28±1
Change in VSS-SF total score at Visits 2- 3 and 2-4 of the Retreatment Period compared with Visit 2-1.	Assessment performed using VSS-SF score (15-item scale with score from 0 to 4 for each item; higher scores mean a worse outcome)	Day 1 - Day 42 ±1 (retreatment period)
Change in VSS-SF total score at the study participation completion visit compared with the score at Visit 1-1 in patients who completed the study according to protocol (PP(response)).	Assessment performed using VSS-SF score (15-item scale with score from 0 to 4 for each item; higher scores mean a worse outcome)	From Day 1 to the end of the study
Evaluation of therapy efficacy on the CGI-i scale by the patient at Visits 1-2 and 1-3 in the Primary Therapy Period.	Assessment performed using CGI-i scale (scale from 0 to 7; higher scores mean a worse outcome)	Day 1 - Day 28±1
Evaluation of therapy efficacy on the CGI-i scale by the physician at Visits 1-2 and 1-3 in the Primary Therapy Period.	Assessment performed using CGI-i scale (scale from 0 to 7; higher scores mean a worse outcome)	Day 1 - Day 28±1
Evaluation of therapy efficacy on the CGI-i scale by the patient at Visits 2-2, 2-3, and 2-4 in the Retreatment Period.	Assessment performed using CGI-i scale (scale from 0 to 7; higher scores mean a worse outcome)	Day 1 - Day 42 ±1 (retreatment period)
Evaluation of the effectiveness of therapy on the CGI-i scale by the physician at Visits 2-2, 2-3, 2-4 in the Re-Treatment Period.	Assessment performed using CGI-i scale (scale from 0 to 7; higher scores mean a worse outcome)	Day 1 - Day 42 ±1 (retreatment period)
Proportion of patients with exacerbation (relapse) of the disease after treatment in the Primary Treatment Period during the entire follow-up period (until the visit of completion of participation in the study)	An exacerbation (relapse) is defined as a total DHI score ≥ 31 points	From Day 1 to the end of the study
Duration of remission period after treatment in the Primary Therapy Period. Remission means absence of episodes of exacerbations (relapses)	The duration of the remission period is the time from the day of completion of primary therapy to the day of the visit confirming an exacerbation (relapse) or to the day of completion of the study (if there is no exacerbation (relapse))	From Day 1 to the end of the study
Clinically significant abnormalities on physical and/or neurologic examination	Number and percentage of patients with clinically significant abnormalities found during physical and/or neurologic examination	Day 1 - Day 28±1 (primary treatment period), Day 1 - Day 42 ±1 (retreatment period)
Adverse events (AEs)	Frequency of AEs for all treatment periods stratified by severity and frequency	Day 1 - Day 28±1 (primary treatment period), Day 1 - Day 42 ±1 (retreatment period)
Serious adverse events (SAEs)	Frequency of SAEs	Day 1 - Day 28±1 (primary treatment period), Day 1 - Day 42 ±1 (retreatment period)
Adverse reactions	Frequency of AEs and SAEs associated with the use of study medications	Day 1 - Day 28±1 (primary treatment period), Day 1 - Day 42 ±1 (retreatment period)
Рatients with at least one AE	Proportion of patients with at least one AE registered	Day 1 - Day 28±1 (primary treatment period), Day 1 - Day 42 ±1 (retreatment period)
Patients discontinued due to AE	Percentage of patients who discontinued treatment due to the occurrence of AE	Day 1 - Day 28±1 (primary treatment period), Day 1 - Day 42 ±1 (retreatment period)

Collaborators and Investigators

• Sponsor: Valenta Pharm JSC

Study record dates

Study Major Dates

• Study Start (Actual): January 24, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 13, 2024
• First Submitted That Met QC Criteria: March 13, 2024
• First Posted (Actual): March 20, 2024

Study Record Updates

• Last Update Posted (Actual): March 20, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Otorhinolaryngologic Diseases; Labyrinth Diseases; Ear Diseases; Vestibular Diseases; Sensation Disorders; Vertigo; Dizziness; Primary Dysautonomias; Autonomic Nervous System Diseases
• Other Study ID Numbers: BUSP-04-04-2023

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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