| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| vertigo (giddiness) after the removal of a tumour of the balance and hearing nerve |
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| 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 |
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| 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 |
Primary Objective of Part A:
Three doses of AM-125 will be tested. The aim is to identify two safe and effective doses of AM-125, which will be further tested in Part B.
Also, to see how effective AM-125 is compared to placebo, in improving the symptoms of vestibular dysfunction (such as vertigo (giddiness)), and improving vestibular compensation following neurosurgery affecting the vestibular nerve, such as vestibular schwannoma resection, labyrinthectomy or vestibular neurectomy.
Primary Objective of Part B:
To evaluate how effective the two chosen doses from Part A are compared to placebo, in reducing the symptoms of vestibular dysfunction and improving vestibular compensation, following surgery.
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives of Part A:
To compare the effects of oral betahistine against AM-125 in improving the symptoms of vestibular dysfunction (such as vertigo) and improving vestibular compensation, following neurosurgery.
Secondary Objectives of Part A & Part B:
The overall purpose of this trial is to collect information about how safe and how well tolerated AM-125 is, in treating acute peripheral vertigo after neurosurgery. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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 ≥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.
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| E.4 | Principal exclusion criteria |
1. Prior radiotherapy (gamma knife, intensity modulated radiation therapy) irradiating the brain-stem with more than 4Gv.
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 orthopedic 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 in another investigational medicinal product or prior treatment with another investigational medicinal product within 30 days prior to randomization.
17. Any treatment with a monoamine oxidase (MAO) inhibitor that is ongoing or concomitant during the IMP treatment period.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoints for Part A:
1) Improvement of time standing on foam (eyes closed) from TV (baseline) to FUV2;
2) Improvement in tandem Romberg test (eyes closed) from TV (baseline) to FUV2;
Primary efficacy endpoint of Part B:
1) Based on the outcome of Part A, one of the two primary efficacy endpoints will be selected as primary efficacy endpoint in Part B. The other one will become the secondary efficacy endpoint in Part B. The selection of the primary endpoint will be based on the relative reliability and sensitivity to change.
Primary safety endpoint of Part A and B:
1) Frequency of occurrence of moderate-severe nasal symptoms at treatment visit or any follow up visit and overall. |
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| 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 endpoints of Part B
End of Part A and Part B for primary safety endpoint of Part A and Part B |
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints for Part A and Part B:
1) Improvement of time standing on foam (eyes closed) from TV (baseline) to FUV1, FUV3 and FUV4;
2) Improvement in tandem Romberg test (eyes closed) from TV (baseline) to FUV1, FUV3 and FUV4;
3) Improvement in tandem gait from TV (baseline) to all FUVs;
4) Improvement of subjective visual vertical deviation from TV (baseline) to all FUVs.
Secondary efficacy endpoint of Part B:
One of the primary efficacy from Part A will become a secondary efficacy endpoint in Part B.
1) Improvement of time standing on foam (eyes closed) from TV (baseline) to FUV2;
OR
2) Improvement in tandem Romberg test (eyes closed) from TV (baseline) to FUV2.
Secondary safety endpoint of Part A and B:
1) Frequency of occurrence of any nasal symptoms at treatment visit or any follow up visit and overall;
2) Occurrence of adverse events after intranasal administration.
Secondary safety endpoint of Part A (only):
1) Occurrence of adverse events after oral administration. |
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| 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 endpoint of Part A and B |
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| 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 the oral treatment in Part A (PR3) |
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| 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 | 3 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Poland |
| Slovakia |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | No |
| 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
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| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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