| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of acute peripheral vertigo |
| Liečba akútneho periférneho vertiga |
|
| E.1.1.1 | Medical condition in easily understood language |
| Treatment of vertigo (giddiness) after removal of a tumor of the balance and hearing nerve |
| Liečba vertiga (závratu) po odstránení nádoru nervu rovnováhy a sluchu |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10059614 |
| E.1.2 | Term | Vestibular vertigo |
| E.1.2 | System Organ Class | 100000004854 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of Part A is
a. to explore and provide an estimate of the dose response curve for AM-125, and
b. to evaluate the efficacy of AM-125 compared to placebo in reducing the symptoms of vestibular dysfunction and accelerating vestibular compensation following neurosurgery.
The primary objective of Part B is to evaluate the efficacy of two selected doses of AM-125 versus placebo, as determined based on the results from Part A, in reducing the symptoms of vestibular dysfunction and accelerating vestibular compensation following neurosurgery compared to placebo.
|
|
| E.2.2 | Secondary objectives of the trial |
The secondary objective of Part A is to compare the treatment effect of oral betahistine (open label) versus AM-125 in reducing the symptoms of vestibular dysfunction and accelerating vestibular compensation following neurosurgery.
The secondary objective of both Part A and Part B is to describe the safety and tolerability of AM-125 in the treatment of acute peripheral vertigo following neurosurgery.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects have to meet all of the following inclusion criteria to be eligible for enrolment into the study:
1. Scheduled for neurosurgery (vestibular schwannoma resection, labyrinthectomy or vestibular neurectomy)
2. Small to moderately large vestibular schwannoma (Koos grade I-III; Samii grade T1-T3b; ≤ 30 mm in diameter in cerebellopontine angle) that does not displace the brainstem, documented by magnetic resonance imaging not older than six months.
or
Indication for labyrinthectomy or vestibular neurectomy.
3. Confirmed vestibular function on both sides (> 6 deg/sec sum of bithermal max. slow phase velocity on the affected side in caloric video/electronystagmography (VNG/ENG) and > 10 deg/sec sum of bithermal max. slow phase velocity on the contralateral side).
4. Presence of symptoms of acute peripheral vertigo:
• Subjective symptoms of vertigo (rating of at least “two” in EEV questionnaire question 1: illusion of movement)
• Spontaneous nystagmus beating towards the contralateral side.
SVV deviation > 2.5°from the true vertical.
5. Age at SV (screening visit) ≥18 years and ≤70 years.
6. Negative urine pregnancy test for women of childbearing potential.
7. Willing and able to attend the study visits.
8. Able to read and understand study documents, to complete the relevant questionnaires and rating scales and follow Investigator instructions.
9. Signed informed consent. |
|
| E.4 | Principal exclusion criteria |
1. Prior radiotherapy (gamma knife, intensity modulated radiation therapy) irradiating the brain-stem with more than 4 Gy.
2. Any ongoing other peripheral vestibular disorder (e.g. Meniere’s disease, benign paroxysmal vertigo, vestibular neuritis) or central vestibular disorder (e.g. vestibular migraine, central vertigo).
3. Vestibular rehabilitation therapy or presurgical gentamicin therapy (i.e. “pre-habilitation therapy”) within the past three months prior to neurosurgery.
4. Any clinically relevant nasal obstruction or pathology precluding effective and/or safe intranasal delivery.
5. Diagnosis of phaeochromocytoma.
6. Ongoing upper respiratory tract infection or allergic rhinitis (symptomatic).
7. Any treatment with antihistamines, anti-emetics or benzodiazepines that is ongoing or planned during the IMP treatment period.
8. Any history of clinically relevant drug hypersensitivity, urticaria, or other severe allergic diathesis as well as current moderate or severe allergic disorders or hay fever.
9. Subjects with diagnosed anxiety disorders, depression, schizophrenia or other significant psychiatric diseases requiring current drug treatment or subjects who required treatment in the previous three months prior to enrolment for any of these diseases.
10. Any clinically relevant respiratory, cardiovascular, neurological disorder (e.g. neurofibromatosis type 2, except vertigo), relevant orthopaedic or visual limitation, relevant abnormality in laboratory test or physical examination or other abnormality that in the opinion of the Investigator or Sponsor may pose a safety risk to a subject in this study, which may confound efficacy or safety assessment, or may interfere with study participation.
11. Any clinically relevant complication during or after neurosurgery that in the opinion of the Investigator or Sponsor may pose a safety risk to a subject in this study, which may confound efficacy or safety assessment, or may interfere with study participation.
12. Known hypersensitivity, allergy or intolerance to the study medication or any history of severe, abnormal drug reaction.
13. History within the past two years or presence of drug abuse or alcoholism.
14. Women who are breast-feeding, pregnant or who are planning to become pregnant during the study.
15. Women of childbearing potential who are unwilling or unable to use an effective method of avoiding pregnancy from the SV until the end of the study. Effective methods of avoiding pregnancy are contraceptive methods with a Pearl index of less than 1 used consistently and correctly (including implantable, injectable, oral and transdermal contraceptives, intrauterine devices, or a sterile sexual partner, or being abstinent).
16. Concurrent treatment with another investigational medicinal product or prior treatment with another investigational medicinal product within 30 days prior to randomization. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint
•Improvement in tandem Romberg test (eyes closed) from TV (baseline) to FUV4.
Primary safety endpoint
•Frequency of occurrence of moderate-severe nasal symptoms at TV or any FUV and overall. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of Part A for primary efficacy endpoints of Part A.
End of Part B for primary efficacy endpoint of Part B.
End of Part A and Part B for primary safety endpoint of Part A and B.
|
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoint
•Improvement of time standing on foam (eyes closed) from TV (baseline) to FUV2.
Secondary efficacy endpoints
•Improvement of time standing on foam (eyes closed) from TV (baseline) to FUV1, FUV3 and FUV4;
•Improvement in tandem Romberg test (eyes closed) from TV (baseline) to FUV1, FUV2 and FUV3;
•Improvement in tandem gait from TV (baseline) to all FUVs;
•Improvement of subjective visual vertical deviation from TV (baseline) to all FUVs;
•Change in the frequency of horizontal spontaneous nystagmus from TV (baseline to all FUVs.
Secondary safety endpoints
•Frequency of occurrence of any nasal symptoms at TV or any FUV and overall;
•Occurrence of adverse events after intranasal administration;
•Occurence of adverse events after oral administration. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of Part A for secondary efficacy endpoints of Part A.
End of Part B for secondary efficacy endpoints of Part B.
End of Part A and/or Part B for secondary safety endpoints of Part A and
B. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Open-label arm for oral treatment in Part A (PR2) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Canada |
| Czechia |
| France |
| Germany |
| Italy |
| Poland |
| Slovakia |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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