An Exploratory Study Investigating Safety, Tolerability and Pharmacokinetics of Ascending Doses of Lu AE04621 in Parkinson Disease Patients

Study Overview
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Brief Summary
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To evaluate the safety, tolerability, pharmacokinetics, and efficacy of the Lu AE04621 and metabolite after ascending oral doses of Lu AE04621 in patients with Parkinson's Disease.

Detailed Description
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The study comprised 5 cohorts (Cohorts 1 to 5), with each cohort consisting of 3 patients with Parkinson's disease (men and/or women). Each patient will be treated for 3 or 4 days, with increasing dose each day. Dosing regimen will be decided at a dosing conferences. Dose levels can be increased, maintained or reduced both between cohorts but also within same cohort. The results are presented by dose level and reflect the actual doses administered. A follow-up safety visit was scheduled approximately 7 days after the last dose of IMP.

Official Title
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Interventional, Open-label, Exploratory Study Investigating the Safety, Tolerability, Pharmacokinetics, and Efficacy of Lu AE04621 and the Active Metabolite Lu AA40326 After Ascending Oral Doses of Lu AE04621 to Patients With Parkinson's Disease

Conditions
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Parkinson Disease

Intervention / Treatment
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* Drug: 0.04 mg Lu AE04621
* Drug: 0.08 mg Lu AE04621
* Drug: 0.2 mg Lu AE04621
* Drug: 0.4 mg Lu AE04621
* Drug: 0.6 mg Lu AE04621
* Drug: 0.8 mg Lu AE04621
* Drug: 1.0 mg Lu AE04621
* Drug: 1.2 mg Lu AE04621


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The patient is diagnosed with idiopathic Parkinson Disease (consistent with the UK Parkinson's Disease Society Brain Bank Criteria for the Diagnosis of PD). The patient's Hoehn and Yahr Staging score is ≤ 3 in the ON state. The patient experiences motor fluctuations with at least 2.5 hours of OFF periods in the awake time and has predictable morning OFF episodes, which have been consistent within the past 4 weeks. The patient currently has a good response to L-DOPA and has been receiving a stable dose of L-DOPA (≥3 doses per day of standard L-DOPA or ≥3 doses per day of Carbidopa and L-DOPA, Extended-Release Capsules) during at least four weeks prior to screening. Exclusion Criteria: The patient has cognitive impairment, defined as a Mini Mental State Examination(MMSE) score ≤ 26 at the Screening Visit. The patient has severe disabling dyskinesia The patient takes or has taken disallowed recent or concomitant medication (CYP2D6 inhibitors, CYP 3A4 substrate, Dopamine agonists, 5 HT3 antagonists, Anti-viral (Amantadine)) Other protocol defined inclusion and exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: The study comprised 5 cohorts (Cohorts 1 to 5), with each cohort consisting of 3 patients (men and/or women). The dosing regimen planned for Cohort 1 was a dose of 0.2 mg Lu AE04621 on Day 1 followed by a dose of 0.4 mg Lu AE04621 on Day 2, and a dose of 0.6 mg Lu AE04621 on Day 3. • The dosing regimen planned for Cohort 2 was 0.4 mg Lu AE04621 on Day 1 followed by a dose of 0.6 mg Lu AE04621 on Day 2, and a dose of 0.8 mg Lu AE04621 on Day 3. The dosing regimen planned for Cohort 3 was 0.2 mg Lu AE04621 on Day 1 followed by a dose of 0.4 mg Lu AE04621 on Day 2, a dose of 0.6 mg Lu AE04621 on Day 3, and a dose of 1.0 mg Lu AE04621 on Day 4. The dosing regimen planned for Cohorts 4 and 5 was 0.2 mg Lu AE04621 on Day 1 followed by a dose of 0.4 mg Lu AE04621 on Day 2, a dose of 0.6 mg Lu AE04621 on Day 3, and a dose of 1.2 mg Lu AE04621 on Day 4. The results are presented by dose groups and are based on the actual doses administered.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.04 mg Lu AE04621<br>Patients having received a dose of 0.04 mg, independent of which Cohort they belong to. | Drug: 0.04 mg Lu AE04621<br>* 0.04 mg dose group<br>|
| Experimental: 0.08 mg Lu AE04621<br>Patients having received a dose of 0.08 mg, independent of which Cohort they belong to. | Drug: 0.08 mg Lu AE04621<br>* 0.08mg dose group<br>|
| Experimental: 0.2 mg Lu AE04621<br>Patients having received a dose of 0.2 mg, independent of which Cohort they belong to. | Drug: 0.2 mg Lu AE04621<br>* 0.2 mg dose group<br>|
| Experimental: 0.4 mg Lu AE04621<br>Patients having received a dose of 1.2 mg, independent of which Cohort they belong to. | Drug: 0.4 mg Lu AE04621<br>* 0.4 mg dose group<br>|
| Experimental: 0.6 mg Lu AE04621<br>Patients having received a dose of 0.6 mg, independent of which Cohort they belong to. | Drug: 0.6 mg Lu AE04621<br>* 0.6 mg dose group<br>|
| Experimental: 0.8 mg Lu AE04621<br>Patients having received a dose of 0.8 mg, independent of which Cohort they belong to. | Drug: 0.8 mg Lu AE04621<br>* 0.8 mg dose group<br>|
| Experimental: 1.0 mg Lu AE04621<br>Patients having received a dose of 1.0 mg, independent of which Cohort they belong to. | Drug: 1.0 mg Lu AE04621<br>* 1.0 mg dose group<br>|
| Experimental: 1.2 mg Lu AE04621<br>Patients having received a dose of 1.2 mg, independent of which Cohort they belong to. | Drug: 1.2 mg Lu AE04621<br>* 1.2 mg dose group<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability Based on the Safety Variables (Adverse Events, Clinical Safety Laboratory Tests, Vital Signs, Weight, and ECG) | Number of patients with an adverse event | Baseline to day 11 | 
| Area Under the Plasma Concentration-time Curve (AUC(0-24 Hours)) for Lu AE04621 |  | From dosing to up to 24 hours after dosing | 
| Maximum Observed Concentration (Cmax) for Lu AE04621 |  | From dosing to up to 24 hours after dosing | 
| Apparent Elimination Half-life of Lu AE04621 in Plasma (t½) |  | From dosing to up to 24 hours after dosing | 
| Time to Onset of ON Time After Lu AE04621 Administration | ON state is defined as a period of good control of parkinsonian features with relatively good overall function and mobility. Motor fluctuation assessments are patient-reported outcomes, and guidance will be given to the patients on how to complete them. Date and time will be registered when the patient turns to ON and OFF state. OFF state is defined as a period of poor control of parkinsonian features with relatively poor overall function, such as worsening tremor, rigidity, balance or bradykinesia. Data are no presented for the dose groups 0.04, 0.08, and 1.0 mg Lu AE04621 since no patients turned 'ON'. | From dosing to 90 minutes after dosing | 
| Duration of ON Time | ON state is defined as a period of good control of parkinsonian features with relatively good overall function and mobility. Motor fluctuation assessments are patient-reported outcomes, and guidance will be given to the patients on how to complete them. Date and time will be registered when the patient turns to ON and OFF state. OFF state is defined as a period of poor control of parkinsonian features with relatively poor overall function, such as worsening tremor, rigidity, balance or bradykinesia. Outcome measured in minutes. Data are no presented for the dose groups 0.04, 0.08, and 1.0 mg Lu AE04621 since no patients turned 'ON' following administration of Lu AE04621. | From dosing up to 24h post-dose |