Clinical trial NCT03391882: 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)
Official title: An Open-Label, Randomized, Crossover Trial Utilizing a Single-Blinded Rater to Evaluate APL-130277 Compared to Subcutaneous Apomorphine in Levodopa Responsive Subjects With Parkinson's Disease Complicated by Motor Fluctuations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Motor OFF Episodes Associated With Parkinson's Disease
Keywords: Parkinson's Disease
"Off" Episodes
motor fluctuations associated with Parkinson's Disease
Lead sponsor: Sumitomo Pharma America, Inc.
Sponsor class: INDUSTRY
First posted: 2018-01-05
Enrollment: 113
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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)

Detailed description: An Open-Label, Randomized, Crossover Trial utilizing a Single-Blinded Rater to evaluate APL-130277 compared to s.c. Apomorphine in Levodopa Responsive Subjects with Parkinson's Disease Complicated by Motor Fluctuations.

PART A consists of an open label, crossover titration phase where eligible subjects will be randomized to 1 of 2 treatment sequences in a 1:1 ratio to Sublingual APL-130277 followed by subcutaneous apomorphine or subcutaneous apomorphine followed by sublingual APL-130277. Subjects will undergo dose titration with the first study treatment (APL-130277 or sc apomorphine) to tolerance and effect, ie, the tolerable dose that turns the subject from the practically defined "OFF" state to the full "ON" state as determined by both the Investigator and subject. The subject will then be crossed over to the other study treatment (APL-130277 or subcutaneous apomorphine) and similarly titrated to tolerance and effect. These determined doses of APL-130277 and subcutaneous apomorphine will be used during PART B.

PART B consists of an open-label, crossover treatment period where subjects will be randomized to one of the study treatment for 4 weeks, then be crossed over to the other study treatment (APL-130277 or sc apomorphine) for additional 4-weeks of open-label treatment. Subjects return to the clinic for safety and efficacy assessments throughout the treatment period.

This study is designed to test the superiority of sublingually administered APL-130277 against subcutaneously injected apomorphine (APO-go) for the treatment of "OFF" episodes in patients with Parkinson's Disease, as measured by the change from pre-dose to 90 minutes post-dose in MDS UPDRS Part III score in Part B after 4 weeks of dosing in each crossover period.

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

Primary outcomes:
measure: Change From Pre-dose to 90 Mins. Post-dose in Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Score After 4 Weeks of Dosing in Each Crossover Period (Assessed by the Blinded-rater In-clinic at Visit 3 and Visit 6 of PART B).
timeFrame: Pre-dose to 90 minutes post-dose at Week 4 of each treatment period (Visit 3 and 6)
Secondary outcomes:
measure: Durability of Effect, Defined as an Investigator Confirmed Full "ON" Within 30 Minutes Post Dose and at 90 Minutes Post-dose, After 4 Weeks of Dosing in Each Crossover Period (Assessed by the Blinded-rater In-clinic at Visit 3 and Visit 6 of PART B).
timeFrame: Within 30 minutes post-dose and at 90 minutes post-dose at Week 4 of each treatment period (Visit 3 and 6)
measure: Subject Preference for APL Treatment as Measured by the Subject Treatment Preference Questionnaire (TPQ), Planned After the Subject Had Completed Both APL-130277 and sc Apomorphine Treatment Regimens (Assessed In-clinic at Visit 6 of PART B)
timeFrame: After 8 weeks of treatment (Visit 6)
measure: Subject Confirmed Durability of Effect, Defined as Subject Confirmed Full "ON" Within 30 Minutes Post-dose and at 90 Minutes Post-dose, After 4 Weeks of Dosing in Each Crossover Period (Assessed In-clinic at Visit 3 and Visit 6 of PART B).
timeFrame: Week 4
measure: Patient Global Impression of Change (PGI-C): Subject Improvement of "OFF" Episodes, Defined as Very Much Better, Much Better or a Little Better After 4 Weeks of Dosing in Each Crossover Period (Assessed In-clinic at Visit 3 and Visit 6 of PART B).
timeFrame: At Week 4 of each treatment period (Visit 3 and 6, or Early Termination)
Other outcomes:
Locations:
city: Innsbruck
country: Austria
facility: Medical University Innsbruck, Neurolgy Dept
city: Vienna
country: Austria
facility: Wilhelminenspital, Department of Neurology
city: Nimes
country: France
facility: CHU Caremeau, Service de Neurologie
city: Toulouse
country: France
facility: Centre d'Investigation Clinique, CIC 43, CHU Purpan, Hopital Pierre-Paul Riquet, place du Dr. Baylac, Hall D, 2 eme etage -TSA
city: Beelitz-Heilstatten
country: Germany
facility: Klinken Beelitz GmbH Neurologisches Fachkrankenhaus fur Bewegungsstorungen/Parkinson
city: Berlin
country: Germany
facility: Charite-University Medicine Berlin, Department of Neurology, Campus charite Mitte
city: Berlin
country: Germany
facility: St. Joseph Krankenhaus Berlin - Weissensee, Abteilung fur Neurologie
city: Bochum
country: Germany
facility: St. Josef Hospital, Klnikum der Ruhr-Universitat-Bochum, Neurologische Klinik
city: Dresden
country: Germany
facility: Universitatsklinikum Carol Gustav Carus an der TU dDresden, Klinik umd Poliklinik fur Neurologie
city: Haag In Oberbayern
country: Germany
facility: Klinik Haag i.OB
city: Munchen
country: Germany
facility: Klinikum rechts der Isar der Technischen Universitat Munchen
city: Munich
country: Germany
facility: Curiositas ad sanum GmbH
city: Ulm
country: Germany
facility: Universitaets-und Rehabillitatinskliniken Ulm
city: Cassino
country: Italy
facility: San Raffaele Cassino
city: Catania
country: Italy
facility: University Hospital Policlinico-Vittorio Emanuele, Department "G.F. Ingrassia", Section of Neurosciences
city: Napoli
country: Italy
facility: A.O.U. Universita degli Studi della Campania "Luigi Vanvitelli" Dipartamento di Scienze Mediche e Chirurgiche Avanzate
city: Rome
country: Italy
facility: IRCCS San Raffaele Pisana-Clinical Trial Center
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas, Dipartmento di Neurologia 1
city: Salerno
country: Italy
facility: AOU San Giovanni di Dio e Ruggid'Aragona-CEMAND
city: Barakaldo
country: Spain
facility: Hospital Universitario de Cruces, Neurology
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau c/Mas de Casanovas 90
city: Burgos
country: Spain
facility: Hospital Universitario de Burgos
city: Madrid
country: Spain
facility: Hospital Universitario de la Princesa
city: Mostoles
country: Spain
facility: CINAC, Hospital Universitario HB Pueta del Sur
city: Sant Cugat del Valles
country: Spain
facility: Hospital General de Catalunya
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
city: London
country: United Kingdom
facility: 10W, Imperial Memory/PD Research Unit, Imperial College Healthcare NHS Trust
city: Manchester
country: United Kingdom
facility: NHS Forth Valley, Pennine Actue NHS Trust, Fairfield General Hospital
city: Nottingham
country: United Kingdom
facility: Academic Neuroscience Department, C Floor, South Block, Nottingham University Hospitals NHS Trust Queens Medical Centre
city: Plymouth
country: United Kingdom
facility: University Hospitals Plymouth NHS Trust-Derriford Hospital-The Lind Research Center, Level 5, Terence Lewis Building
Study officials:
affiliation: Sumitomo Pharma America, Inc.
name: CNS Medical Director
role: STUDY_DIRECTOR
References: