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

Open-label, Multicenter, Randomized Controlled Phase 4 Trial Evaluating the Efficacy and Safety of Vespireit, Prolonged-release Tablets (Valenta Pharm JSC, Russia) Versus Arlevert, Tablets (Menarini International Operations Luxembourg S.A., Luxembourg) in Patients With Autonomic Dysfunction Syndrome Accompanied by Functional Vertigo.

This study aims to evaluate the 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.

Inclusion Criteria:

1. Patient signed and dated the Informed Consent Form.
2. Males and females ≥18 to ≤ 65 years of age 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. Diagnosed chronic functional vertigo per Barani Society criteria: total DHI score ≥ 31 points; mean MVS score ≥ 1.5 points.
5. For women of childbearing 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.

Postmenopausal women (≥2 years of amenorrhea) or women who are surgically sterile (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 investigational drugs.
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.
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 suspected 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 procedures, if less than 6 months have passed since the intervention.
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. Female patients who are pregnant or breastfeeding or planning pregnancy within the next 15 months.
44. Patients requiring prohibited concomitant medications.
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 judgment 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 decision 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 active comparator (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.
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.