| 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 |
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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 | PT |
| E.1.2 | Classification code | 10061536 |
| E.1.2 | Term | Parkinson's disease |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 |
Part A:
- Compare the PK of buccal apomorphine with the PK of subcutaneous apomorphine to determine the dose of buccal apomorphine to be used for Part B and C.
- To assess the dose proportionality/linearity of buccal apomorphine over a range of 2-6 mg or 2-8 mg, depending on results of the interim PK and safety (AEs) analysis.
Part B:
- Compare the PK of buccal apomorphine with the PK of sublingual apomorphine (Kynmobi).
- Examine the (local) tolerability of the buccal administration of apomorphine relative to the sublingual administration of apomorphine.
Part C:
- Characterize the 12-week safety and (local) tolerability of (multiple) daily dosing with buccal apomorphine.
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| E.2.2 | Secondary objectives of the trial |
Part A:
- Explore the safety and (local) tolerability of buccal apomorphine.
Part B:
- Characterize the occurrence of AEs (e.g. dyskinesia, nausea) in relation to apomorphine plasma concentrations after buccal and sublingual administration.
Part C:
- Patient preference for buccal or subcutaneous administration.
- Patient-reported efficacy (within 30 minutes) of buccal apomorphine administration.
- Assess the ratio between the self-chosen, at-home buccal apomorphine dose used during the study and the subcutaneous apomorphine dose used prior to the study.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part A
1) Male or female, 30-85 years of age, inclusive at screening.
4) Clinical diagnosis (confirmed by a neurologist) of Parkinson’s disease and classified by the investigator as Hoehn and Yahr stage I to IV in the ON state.
5) Having clear, self-described motor fluctuations as assessed by the 9-symptom Wearing-off Questionnaire (WOQ-9): at least one motor symptom (Question 1, 2, 4, 6, 9) indicated to improve after the subject’s next anti-Parkinson medication dose.
6) Mini-Mental State Examination (MMSE) score ≥ 20 and assessed by the investigator or qualified designee as able to provide informed consent.
Part B and C
1) Male or female, 30-85 years of age, inclusive at screening.
4) Clinical diagnosis (confirmed by a neurologist) of Parkinson’s disease and classified by the investigator as Hoehn and Yahr stage I to III in the ON state.
5) Mini-Mental State Examination (MMSE) score ≥ 20 and assessed by the investigator or qualified designee as able to provide informed consent.
8) On a stable dose of 1 to 4 mg subcutaneous apomorphine (APO-GO PEN) for the management of OFF episodes for at least 4 weeks prior to first study drug administration.
9) Subject’s at-home subcutaneous apomorphine injection location is the abdomen.
11) Subjects who experience motor fluctuations (as assessed by the 9-symptom Wearing-off Questionnaire (WOQ-9): at least one motor symptom (Question 1, 2, 4, 6, 9) indicated to improve after the subject’s next anti-Parkinson medication dose) with recognizable OFF periods at least once per day.
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| E.4 | Principal exclusion criteria |
Part A and B:
1) Atypical or secondary parkinsonism e.g., multiple-system atrophy or progressive supranuclear palsy, or evidence of drug-induced parkinsonism.
2) Subjects with a borderline QT interval corrected for heart rate according to Fridericia's formula (QTcF) of >450 ms for male and >470 ms for female, PR interval > 220 msec or QRS duration > 120 msec at screening or history of long QT syndrome.
6) Currently taking medication that can influence the efficacy of apomorphine in the opinion of the investigator, such as dopamine antagonists and dopamine depleting drugs, with the exception of domperidone.
Part B
As in part A, but with the following differences:
2) Subjects with a borderline QT interval corrected for heart rate according to Fridericia’s formula (QTcF) of >450 ms for male and >470 ms for female, PR interval > 220 msec or QRS duration > 120 msec at screening or prior to first dose, or history of long QT syndrome.
3) Contraindications to the excipients of the buccal or sublingual apomorphine formulation, or contraindications to domperidone.
12) Elevated hepatic panel, defined as serum levels of ALT, AST, GGT, ALP or TBL higher than 2 times the upper limit of normal.
19) Use of any apomorphine formulation in the 4 weeks prior to first dosing.
20) Use of 5HT3 antagonists.
Part C:
1) Atypical or secondary parkinsonism e.g., multiple-system atrophy or progressive supranuclear palsy, or evidence of drug-induced parkinsonism.
2) Subjects with a borderline QT interval corrected for heart rate according to Fridericia’s formula (QTcF) of >450 ms for male and >470 ms for female, PR interval > 220 msec or QRS duration > 120 msec at screening or history of long QT syndrome.
4) Use of apomorphine formulations other than subcutaneous injections in the 4 weeks prior to first dosing.
7) Currently taking medication that can influence the efficacy of apomorphine in the opinion of the investigator, such as dopamine antagonists and dopamine depleting drugs, with the exception of domperidone. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary part A
- Apomorphine plasma concentrations
o Derived parameters including but not limited to Cmax, Tmax, Tlag, T1/2, AUC
o Dose-normalized AUC and Cmax
o Ratio of buccal to subcutaneous AUC and Cmax
Primary part B
- Apomorphine plasma concentrations (parameters as above, with the only change that in part B the ratio of buccal to sublingual AUC and Cmax will be calculated)
- Treatment-emergent (serious) adverse events ((S)AEs).
- Concomitant medication
- Clinical laboratory tests
o Haematology
o Chemistry
o Coagulation
o Urinalysis
- Vital signs
o Pulse Rate (bpm)
o Systolic blood pressure (mmHg)
o Diastolic blood pressure (mmHg)
o Orthostatic hypotension (delta mmHg sit-sta)
o Respiratory rate (breaths/min)
o Pulse oximetry (SpO2) (%)
- ECG
o Heart Rate (HR) (bpm), PR, QRS, QT, QTcF
Primary part C
- Treatment-emergent (S)AEs
- Concomitant medication
- Clinical laboratory tests (as above)
- Vital signs (as above)
- ECG (as above)
- C-SSRS
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from pre dose to end of treatment |
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| E.5.2 | Secondary end point(s) |
Secondary Part A
- Treatment-emergent (S)AEs
- Concomitant medication
- Clinical laboratory tests (as above)
- Vital signs (as above)
- ECG (as above)
Secondary part B
- Apomorphine plasma concentrations (parameters as above for part A)
- Treatment-emergent (S)AEs
Secondary part C
- Percentage of patients in each response category (refer to Appendix I: no improvement/ slight improvement /moderate improvement/ full ON response within 30 minutes after administration of buccal apomorphine) as based on interview by phone and on patient diaries.
- Question during phone call which determines patient preference for buccal or subcutaneous administration.
- Average buccal dose used in Part C of the study
- Daily used subcutaneous dose in clinical practice before entering the study |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| from pre dose to end of treatment |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | Yes |
| E.6.9 | Dose response | No |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | Yes |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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