A Study of an Investigational Drug to See How it Affects the People With Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes) Compared to an Approved Drug Used to Treat People With Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes)
Condition: Motor OFF Episodes Associated With Parkinson's Disease
MeSH terms: Parkinson Disease
Intervention: APL-130277; subcutaneous apomorphine
Intervention description: APL-130277: Part A- determine the dose; Part B- 28-day repeat dosing at the dose determined in Part A; subcutaneous apomorphine Part A- determine the dose; Part B- 28-day repeat dosing at the dose determined in Part A
Intervention MeSH terms: Apomorphine
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Masking description: Open label: APL-130277 and Subcutaneous Apomorphine
Single-Blinded Rater for MDS-UPDRS Part III Motor Examination assessment in Part B.
Enrollment: 113.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Parkinson's Disease; "Off" Episodes; motor fluctuations associated with Parkinson's Disease

Summary:

      A study of an investigational drug to see how it affects the people with Parkinson's Disease
      complicated by motor fluctuations ("OFF" Episodes) compared to an approved drug used to treat
      people with Parkinson's Disease complicated by motor fluctuations ("OFF" Episodes)
    

Eligibility criteria:

        Inclusion Criteria:

          1. The subject (and caregiver, if applicable) must be fully informed of and understand
             the objectives, procedures, and possible benefits and risks of the study, and give
             written informed consent prior to performing any study related activities.

          2. Male or female ≥ 18 years of age.

          3. Clinical diagnosis of Idiopathic Parkinson's disease (PD), consistent with UK Brain
             Bank Criteria (excluding the "more than one affected relative" criterion).

          4. Clinically meaningful response to levodopa (L-Dopa), as determined by the
             Investigator.

          5. Subjects at screening must demonstrate an adequate L-Dopa response on the Movement
             Disorder Society Unified Parkinson's Disease Rating Scale (MDS UPDRS) Part III in the
             "ON" state compared to the MDS UPDRS Part III in the "OFF" state and on the Hoehn and
             Yahr, as determined during the review by Enrollment Adjudication Committee (EAC),
             Sponsor, and Medical Monitor.

          6. Receiving stable doses of L Dopa/carbidopa and/or L Dopa/benserazide and/or L
             Dopa/carbidopa/entacapone (immediate or chronic release) administered at least 4 times
             per day OR Rytary™ administered at least 3 times per day for at least 4 weeks before
             the initial screening Visit (SV1). Adjunctive PD medication regimens are permitted but
             must be maintained at a stable dose for at least 4 weeks prior to SV1 with the
             exception of monoamine oxidase B (MAO B) inhibitors, which must be maintained at a
             stable level for at least 8 weeks prior to SV1.

          7. No planned medication change(s) or surgical intervention anticipated during the course
             of study.

          8. Subjects must experience at least one well defined "OFF" episode per day and have a
             total daily "OFF" time duration of > 2 hours during the waking day, based on judgment
             of physician and subject self assessment.

          9. Subject must have predictable morning "OFF" periods, based on judgment of physician
             and subject self assessment.

         10. Subject, and where appropriate caregiver, must be trained in completing the home
             dosing diaries and able to recognize "ON" and "OFF" states.

         11. Stage III or less on the modified Hoehn and Yahr scale in the "ON" state.

         12. Mini-Mental State Examination (MMSE) score > 25.

         13. Female subject of childbearing potential and male subject with female partner of
             childbearing potential must agree to either remain abstinent or use adequate and
             reliable contraception throughout the study and for at least 7 days after the last
             dose of study drug has been taken. Note: Continued use of adequate and reliable
             contraception is recommended through 30 days after study completion.

         14. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
             and other study related procedures to complete the study.

         15. Must be approved as a satisfactory candidate by the Enrollment Adjudication Committee
             (EAC), Medical Monitor, and Sponsor.

        Exclusion Criteria:

          1. Atypical or secondary parkinsonism.

          2. Major focal brain disorders including malignancy or stroke.

          3. Prior treatment with any of the following: a neurosurgical procedure for PD;
             continuous subcutaneous (subcutaneous) apomorphine infusion; subcutaneous
             (subcutaneous) apomorphine injection; Duodopa/Duopa; or APL-130277.

          4. Contraindications to domperidone, subcutaneous apomorphine, or hypersensitivity to
             apomorphine hydrochloride or any of the ingredients of subcutaneous apomorphine
             (notably sodium metabisulfite).

          5. Female who is pregnant or lactating.

          6. Participation in an interventional clinical study and/or receipt of any
             investigational (ie, unapproved) medication within 30 days prior to SV1.

          7. Currently taking selective 5HT3 antagonists (ie, ondansetron, granisetron, dolasetron,
             palonosetron, alosetron), dopamine antagonists (excluding quetiapine or clozapine) or
             dopamine depleting agents. Subjects receiving anti depressants must be on a stable
             daily dose for at least 8 weeks prior to SV1.

          8. The subject has a current diagnosis or history of substance abuse (excluding nicotine
             and caffeine) or alcohol abuse (in the opinion of the investigator) < 6 months prior
             to SV1.

          9. The recreational use of cannabinoids and hallucinogenic are excluded, as well any use
             of a sublingual formulation of any drug.

         10. Subject has a history of malignancy within 5 years prior to SV1, except for adequately
             treated basal cell or squamous cell skin cancer or in situ cervical cancer.

         11. Subject has a clinically significant abnormality on screening evaluation including
             physical examination, vital signs, electrocardiogram (ECG), or laboratory tests that
             the Investigator considers to be inappropriate to allow participation in the study.

         12. Subject has screening laboratory test results of: blood urea nitrogen (BUN) value ≥
             1.5 times the upper limit of normal (ULN) for the reference range; serum creatinine >
             1.5 times the ULN for the reference range; or alanine aminotransferase (ALT) or
             aspartate aminotransferase (AST) value ≥ 2 times the ULN for the reference laboratory.

         13. Subject has random (non-fasting) screening glucose of ≥ 200 mg/dL (11.1 mmol/L) or
             HbA1c > 7.0%.

         14. Subjects with type 1 diabetes, or insulin dependent diabetics are excluded. Subjects
             with type 2 diabetes are eligible for study inclusion if the following conditions are
             met:

               -  Subject's screening glucose is < 200 mg/dL (11.1 mmol/L). Note: Subjects with
                  random (non fasting) blood glucose at screening ≥ 200 mg/dL (11.1 mmol/L) must be
                  retested in a fasted state; and

               -  Subject's hemoglobin A1c (HbA1c) ≤ 7.0%; and

               -  If the subject is currently being treated with oral anti-diabetic medication(s),
                  the dose must have been stable for at least 4 weeks prior to SV1. Such medication
                  may be adjusted or discontinued during the study, as clinically indicated.

         15. The subject's screening ECG results of corrected QT interval using Fridericia's
             formula (QTcF) ≥ 450 msec for male subjects or ≥ 470 msec for female subjects.
             Eligibility will be based on the core laboratory ECG interpretation report.

         16. Subject has a positive screening laboratory test result for human immunodeficiency
             virus (HIV).

         17. Subject has a positive screening laboratory test result for hepatitis B surface
             antigen or hepatitis C antibodies and has liver function test results at screening
             above the ULN for the reference laboratory.

         18. Subject has any other medical disorder that, in the opinion of the Investigator, could
             interfere with the subject's participation in the study.

         19. Subject has major psychiatric disorder(s), including but not limited to: bipolar
             disorder, psychosis (eg, Parkinson's Disease Psychosis), major depressive episode, or
             any disorder that, in the opinion of the Investigator, would require treatment that
             could make study participation unsafe or make treatment compliance difficult.

         20. History of clinically significant impulse control disorder(s).

         21. History of symptomatic orthostatic hypotension requiring medication.

         22. History of severe dyskinesia based on a score of 4 on the MDS-UPDRS Part IV.

         23. Dementia that precludes providing informed consent or would interfere with
             participation in the study.

         24. Current/recent suicidal ideation as evidenced by answering "yes" to "Suicidal
             Ideation" item 4 (active suicidal ideation with some intent to act, without specific
             plan) or item 5 (active suicidal ideation with specific plan and intent) on the C-SSRS
             assessment at screening (using the "screening /Baseline Version" scale, in the past 12
             months) or attempted suicide within the last 5 years.

         25. Presence of canker or mouth sores in the 30 days prior to SV1, 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 subject into the study