A Study That Compares the Extent to Which Apomorphine Becomes Available in the Body After Taking Either an Investigational Drug Containing Apomorphine or Apomorphine That is Injected Under the Skin in People With PD Complicated by "OFF" Episodes

A Comparative Bioavailability Study to Evaluate the Single Dose Pharmacokinetic Properties of APL-130277 With Two Different Formulations of Subcutaneous Apomorphine in a Randomized, 3-Period Crossover Design in Subjects With Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes)

A study that compares the extent to which apomorphine becomes available in the body after taking either an investigational drug containing apomorphine or apomorphine that is injected under the skin in people with PD complicated by "OFF" episodes.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease
• Intervention / Treatment: Drug: APL-130277; Drug: APO-go; Drug: Apokyn

Detailed Description

This multi-center study will aim to evaluate the pharmacokinetics (PK) and comparative bioavailability of a single dose of APL-130277 sublingual thin film with subcutaneous (s.c.) APO-go® and s.c. APOKYN® in subjects with Parkinson's disease (PD). The dose of APOKYN® (≤ 5 mg) will be based on the subjects' current prescribed dose. The study is designed as an open-label, randomized, three-way crossover. Subjects will receive all three treatment arms with a minimum 1-day wash-out between each visit (excluding the screening visit) and will be randomly assigned to one of the six sequences

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Boca Raton, Florida, United States, 33486
      • Parkinson's Disease and Movement Disorders Center of Boca Raton
    • Port Charlotte, Florida, United States, 33980
      • Parkinson's Disese Treatment Center of SW Florida
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Quest Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female ≥ 18 years of age.
2. Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria (excluding the "more than one affected relative" criterion).
3. Clinically meaningful response to Levodopa (L-Dopa) with well-defined "OFF" episodes, as determined by the Investigator.
4. Receiving APOKYN® of ≤ 5 mg per dose for at least 4 weeks before the Screening Visit.
5. Receiving stable doses of L-Dopa/carbidopa (immediate or sustained release) administered at least 4 times per day OR Rytary™ administered 3 times per day, for at least 4 weeks before the Screening Visit. Adjunctive PD medication regimens must be maintained at a stable dose for at least 4 weeks prior to the Screening Visit with the exception that MAOB inhibitors must be maintained at a stable level for at least 8 weeks prior to the Screening Visit.
6. No planned medication change(s) or surgical intervention anticipated during the course of study.
7. Patients must experience a well-defined "OFF" episode in the morning if they do not take their morning PD medications on schedule, and must be willing to delay morning doses on the 3 study dosing days
8. Stage III or less on the modified Hoehn and Yahr scale in the "ON" state.
9. Mini-Mental State Examination (MMSE) score > 23.

10. If female and of childbearing potential, must agree to use one of the following methods of birth control:

    • Oral contraceptive;
    • Contraceptive patch;
    • Barrier (diaphragm, sponge or condom) plus spermicidal preparations;
    • Intrauterine contraceptive system;
    • Levonorgestrel implant;
    • Medroxyprogesterone acetate contraceptive injection;
    • Complete abstinence from sexual intercourse;
    • Hormonal vaginal contraceptive ring; or
    • Surgical sterilization or partner sterile (must have documented proof).
11. Male patients must be either surgically sterile, agree to be sexually abstinent or use a barrier method of birth control (e.g., condom) or maintain a monogamous relationship with a person who is not of child-bearing potential from first study drug administration until 30days after final drug administration.
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures to complete the study.
13. Able to understand the consent form, and to provide written informed consent

Exclusion Criteria:

1. Atypical or secondary parkinsonism.
2. Previous treatment with any of the following: continuous subcutaneous (s.c.) apomorphine infusion; or Duodopa/Duopa.
3. Contraindications to APO-go® or APOKYN® or hypersensitivity to apomorphine hydrochloride or any marcrolide antibiotic or any of the ingredients APO-go® or APOKYN® (notably sodium metabisulfite).
4. Female who is pregnant or lactating.
5. Participation in a clinical trial within 30 days prior to the Screening Visit.
6. Receipt of any investigational (ie, unapproved) medication within 30 days prior to the Screening Visit.
7. Any selective 5HT3 antagonists (ie, ondansetron, granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists (excluding quetiapine and clozapine) or dopamine depleting agents within 30 days prior to the Screening Visit.
8. Drug or alcohol dependency in the past 12 months.
9. History of malignant melanoma.
10. Clinically significant medical, surgical, or laboratory abnormality in the opinion of the Investigator.
11. Major psychiatric disorder including, but not limited to, dementia, bipolar disorder, psychosis, or any disorder that, in the opinion of the Investigator, requires ongoing treatment that would make study participation unsafe or make treatment compliance difficult.
12. History of clinically significant hallucinations during the past 6 months.
13. History of clinically significant impulse control disorder(s).
14. Dementia that precludes providing informed consent or would interfere with participation in the study.
15. Current suicidal ideation within one year prior to the Screening Visit as evidenced by answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 5 years.
16. Donation of blood plasma in the 30 days prior to first dosing.
17. Cankers or mouth sores within 30 days prior to the Screening Visit, or other clinically significant oral pathology in the opinion of the Investigator. The Investigator should follow-up with an appropriate specialist on any finding, if indicated, before enrolling a patient into the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: APL-130277, sublingual thin film; APL-130277, sublingual thin film, once daily	Drug: APL-130277; APL-130277 sublingual thin film; Other Names: amomorphine
Active Comparator: Subcutaneous APO-go; Subcutaneous APO-go, once daily	Drug: APO-go; Subcutaneous APO-go; Other Names: amomorphine
Active Comparator: Subcutaneous APOKYN; Subcutaneous APOKYN, once daily	Drug: Apokyn; Subcutaneous APOKYN; Other Names: amomorphine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Plasma Concentration (Cmax)	Dose normalized maximum observed plasma concentration (Cmax)	Day 1
Observed Time of the Maximum Concentration (Tmax)	Time from dosing to Cmax, observed by inspection of individual subject plots of plasma concentration versus time.	Day 1
Area Under the Concentration- Time Curve (AUC Last)	area under the concentration-time curve from time zero to the last measurable plasma concentration-time curve using the linear up log down trapezoidal rule.	Day 1
Area Under the Concentration- Time Curve (AUC Inf)	area under the concentration-time curve from time zero extrapolated to infinity using the linear up log down trapezoidal rule.	Day 1
Mean Residence Time (MRT)	Mean residence time during one dosing interval calculated using the following equation: MRT = AUMCinf/AUC inf. AUMCinf is the area under the first moment (time.plasma concentration vs. time) curve.	Day 1
Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax	Metabolite (apomorphine sulfate) to Parent exposure ratio, Cmax, corrected for molecular weight differences.	Day 1
Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F)	Apparent total clearance of the drug from plasma extravascular administration, calculated as Dose/AUCinf.	Day 1
Apparent Volume of Distribution After Non-intravenous Administration (V/F)	Apparent volume of distribution after extravascular administration, calculated as Dose/(AUCinf * λz).	Day 1
Terminal-phase Half-life (t½)	Terminal phase half-life, as calculated by the following equation: t½ = ln(2)/λz.	Day 1
Terminal-phase Rate Constant ( λz)	Apparent terminal elimination rate constant, determined by log linear regression of the plasma concentration versus time data that was judged to be in the log-linear elimination phase. At least 3 data points in the terminal phase will be used in the determination of the rate constant.	Day 1
Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last	Metabolite (apomorphine sulfate) to Parent exposure ratio, AUClast, corrected for molecular weight differences.	Day 1

Collaborators and Investigators

• Sponsor: Sunovion
• Investigators: Study Chair: CNS Mecdical Director, Sunovion Pharmacetuicals Inc.

Publications and helpful links

General Publications

• Agbo F, Isaacson SH, Gil R, Chiu YY, Brantley SJ, Bhargava P, Navia B. Pharmacokinetics and Comparative Bioavailability of Apomorphine Sublingual Film and Subcutaneous Apomorphine Formulations in Patients with Parkinson's Disease and "OFF" Episodes: Results of a Randomized, Three-Way Crossover, Open-Label Study. Neurol Ther. 2021 Dec;10(2):693-709. doi: 10.1007/s40120-021-00251-6. Epub 2021 May 15.

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2017
• Primary Completion (Actual): March 5, 2019
• Study Completion (Actual): March 5, 2019

Study Registration Dates

• First Submitted: September 11, 2017
• First Submitted That Met QC Criteria: September 21, 2017
• First Posted (Actual): September 25, 2017

Study Record Updates

• Last Update Posted (Actual): August 13, 2020
• Last Update Submitted That Met QC Criteria: August 11, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Parkinson Disease; Off Episodes
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Dopamine Agonists; Dopamine Agents; Emetics; Apomorphine
• Other Study ID Numbers: CTH-203

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No