Staccato Apomorphine Multi-dose PK and PD in Patients With Parkinson's Disease

Study Overview
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Brief Summary
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This study will be conducted in subjects with established Parkinson's disease in 2 parts. Part A will examine the tolerability, safety, and pharmacokinetics of AZ-009 dose escalation ; and Part B will assess the tolerability, safety, pharmacokinetics, and pharmacodynamics of AZ-009 compared with placebo in a crossover design

Detailed Description
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This study will be conducted in subjects with established Parkinson's disease in 2 parts. Part A will examine the tolerability, safety, and pharmacokinetics of daily doses of AZ-009 for 5 days followed by 3 doses on each of days 6 and 7 in dose escalation through 3 cohorts Part B will assess the tolerability, safety, pharmacokinetics, and pharmacodynamics of AZ-009 compared with placebo in subjects with established Parkinson's disease experiencing regular OFF episodes

Official Title
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A Placebo-Controlled, Double-Blind, Multiple Ascending Dose Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamic Profile of AZ-009 in Subjects With Established Parkinson's Disease

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: 009-A1
* Drug: 009-A2
* Drug: 009-A3
* Drug: 009-A0
* Drug: 009-B1 (active --> placebo) crossover
* Drug: 009-B2 (placebo --> active) crossover


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult males and females between 30 and 85 years of age, inclusive at the time of signing the informed consent document with a clinical diagnosis of Parkinson's Disease Body weight ≥ 50 kg and BMI within the range of 18 to 32 kg/m2. Willing and able to be confined at the clinical research center for the study period and adhere to overall study visit schedule, procedures and other protocol requirements. Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures being conducted. Exclusion Criteria: Any significant medical condition, psychiatric illness or history of depression that could, in the investigator's opinion, compromise the subject's safety or interfere with the completion of this protocol. History of clinically significant central nervous system, cardiac, pulmonary, metabolic, renal, hepatic, or gastrointestinal conditions including gastric bypass or other weight loss

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 85 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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study will be conducted in subjects with established Parkinson's disease in 2 parts. Part A will examine the tolerability, safety, and pharmacokinetics of AZ-009 dose escalation ; and Part B will assess the tolerability, safety, pharmacokinetics, and pharmacodynamics of AZ-009 compared with placebo in a crossover design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A-1a<br>Part A, Arm 1 (active), Dose 1 (009-A1) | Drug: 009-A1<br>* Inhaled apomorphine via Staccato aerosol, Dose 1 (low dose) each day for first 5 days, then 3 doses Dose 1 (low dose) q 2 hr on Day 6<br>|
| Experimental: A-2a<br>Part A, Arm 2 (active), Dose 2 (009-A2) | Drug: 009-A2<br>* Inhaled apomorphine via Staccato aerosol, Dose 2 (middle dose) each day for first 5 days, then 3 doses Dose 2 (middle dose) q 2 hr on Day 6<br>|
| Experimental: A-3a<br>Part A, Arm 3 (active), Dose 3 (009-A3) | Drug: 009-A3<br>* Inhaled apomorphine via Staccato aerosol, Dose 3 (high dose) each day for first 5 days, then 3 doses Dose 3 (high dose) q 2 hr on Day 6<br>|
| Placebo Comparator: A-0p<br>Part A, placebo comparator in all 3 arms, placebo dose (009-A0) | Drug: 009-A0<br>* Inhaled placebo via Staccato aerosol, Dose 0 (placebo) each day for first 5 days, then 3 doses Dose 0 (placebo) q 2 hr on Day 6<br>|
| Experimental: B-1 (009-B3 -> 009-B0)<br>Crossover (active to placebo) | Drug: 009-B1 (active --> placebo) crossover<br>* Up to 2 doses (Dose 3) ; minimum of 2 hrs between doses, on Day 1, followed by Up to 2 doses (placebo) ; minimum of 2 hrs between doses, on Day 2<br>|
| Experimental: B-1 (009-B0 -> 009-B3)<br>Crossover (placebo to active) | Drug: 009-B2 (placebo --> active) crossover<br>* Up to 2 doses (placebo) ; minimum of 2 hrs between doses, on Day 1, followed by Up to 2 doses (Dose 3) ; minimum of 2 hrs between doses, on Day 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A - Dose Proportionality of multi-dose inhaled apomorphine by Power Analysis of AUC | Dose proportionality of inhaled Staccato apomorphine AUC across all 3 doses during Days 1-5 and multiple daily dosing (all 3 doses q 2 hr per day) on Day 6 using a power model [regression of log(AUC) versus log(dose)] in subjects with established Parkinson's disease | 6 days | 
| B1 - Effect on MDS-UPDRS in Parkinson's disease OFF periods | Explore in a crossover design on consecutive days the pharmacodynamics of AZ-009 compared with placebo on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III in subjects with established Parkinson's disease experiencing regular OFF episodes. | 2 days | 
| B2 - Effect on Physician Disease State Assessment in Parkinson's disease OFF periods | Explore in a crossover design on consecutive days the pharmacodynamics of AZ-009 compared with placebo on the Physician Disease State Assessment in subjects with established Parkinson's disease experiencing regular OFF episodes. | 2 days | 
| B3 - Effect on Patient Assessment of ON/OFF in Parkinson's disease OFF periods | Explore in a crossover design on consecutive days the pharmacodynamics of AZ-009 compared with placebo on Patient Assessment of ON/OFF in subjects with established Parkinson's disease experiencing regular OFF episodes. | 2 days |