Clinical trial NCT02542696: Open-Label Phase 3 Study to Examine the Long-Term Safety, Tolerability and Efficacy of APL-130277 for the Acute Treatment of "OFF" Episodes in Patients With Parkinson's Disease
Official title: An Open-Label, Phase 3 Study Examining the Long-Term Safety, Tolerability and Efficacy of APL-130277 in Levodopa Responsive Patients With Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Parkinson Disease
Lead sponsor: Sumitomo Pharma America, Inc.
Sponsor class: INDUSTRY
First posted: 2015-09-07
Enrollment: 496
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: An Open-Label Phase 3 Study to Examine the Long-Term Safety, Tolerability and Efficacy of APL-130277 for the Acute Treatment of "OFF" Episodes in Patients With Parkinson's Disease


Eligibility criteria: De Novo Subjects 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 L-Dopa as determined by the Investigator.
4. Receiving stable doses of L-Dopa/carbidopa (immediate or CR) 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 must be maintained at a stable dose for at least 4 weeks prior to the initial Screening Visit (SV1) with the exception that MAO-B inhibitors must be maintained at a stable level for at least 8 weeks prior to the initial Screening Visit (SV1).
5. No planned medication change(s) or surgical intervention anticipated during the course of study.
6. Subject must experience at least one well defined "OFF" episode per day with a total daily "OFF" time duration of ≥ 2 hours during the waking day, based on patient self-assessment.
7. Subject and/or caregiver must be trained in performing home dosing diary assessments of the motor state and must be able to recognize "ON" and "OFF" states.
8. Stage III or less on the modified Hoehn and Yahr scale in the "ON" state.
9. MMSE score \> 25.
10. If female and of childbearing potential, must agree to be sexually abstinent or use one of the following highly effective methods of birth control:

    * Hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, and implants);
    * Intrauterine contraceptive system;
    * Surgical sterilization or partner sterile (must have documented proof); AND

    One of the following effective methods of birth control:
    * Male/female condom;
    * Cervical cap with spermicide;
    * Diaphragm with spermicide;
    * Contraceptive sponge.
11. Male subjects must be either surgically sterile, agree to be sexually inactive or use a double-barrier method of birth control (eg, condom and diaphragm with spermicide, condom with cervical cap and spermicide) from first study drug administration until 90 days after final drug administration.
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures.
13. Able to understand the consent form, and to provide written informed consent.

De Novo Subjects Exclusion Criteria -

1. Atypical or secondary parkinsonism.
2. Previous treatment with any of the following: a neurosurgical procedure for PD; continuous s.c. apomorphine infusion; Duodopa/Duopa; or APL-130277.
3. Treatment with any form of s.c. apomorphine within 7 days prior to the second Screening Visit (SV2). Patients that stopped s.c. apomorphine for any reason other than systemic safety concerns or lack of efficacy may be considered.
4. Contraindications to APOKYN®, or hypersensitivity to apomorphine hydrochloride or any of the ingredients of APOKYN® (notably sodium metabisulfite).
5. Female who is pregnant or lactating.
6. Participation in a clinical trial within 30 days prior to the initial Screening Visit (SV1).
7. Receipt of any investigational (ie, unapproved) medication within 30 days prior to the initial Screening Visit (SV1).
8. Currently taking selective 5HT3 antagonists (ie, ondansetron, granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists (excluding quetiapine or clozapine) or dopamine depleting agents.
9. Drug or alcohol dependency in the past 12 months.
10. Subject has a history of malignancy within 5 years prior to the Screening visit, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Pituitary tumors of any duration are excluded.
11. Clinically significant medical, surgical, or laboratory abnormality in the opinion of the Investigator.
12. 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.
13. History of clinically significant hallucinations during the past 6 months.
14. History of clinically significant impulse control disorder(s).
15. Dementia that precludes providing informed consent or would interfere with participation in the study.
16. Current suicidal ideation within one year prior to the second Screening Visit (SV2) as evidenced by answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the C-SSRS or attempted suicide within the last 5 years.
17. Donation of blood or plasma in the 30 days prior to first dosing.
18. Presence of canker or mouth sores in the 30 days prior to the initial Screening Visit (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 patient into the study.

Rollover Subjects Inclusion Criteria

1. Completion of any of the following studies: CTH-201, CTH-203, CTH-300, or CTH 302; and, in the opinion of the Investigator, would benefit from continued treatment with APL 130277.
2. No major changes in concomitant PD medications since completion of any of the following studies: CTH-201, CTH-203, CTH-300, or CTH 302. Any change in PD medications since the previous study should be discussed with the Medical Monitor to determine subject eligibility in the current study.
3. If female and of childbearing potential, must agree to be sexually abstinent or use one of the following highly effective methods of birth control:

   * Hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, and implants);
   * Intrauterine contraceptive system;
   * Surgical sterilization or partner sterile (must have documented proof); AND

   One of the following effective methods of birth control:
   * Male/female condom;
   * Cervical cap with spermicide;
   * Diaphragm with spermicide;
   * Contraceptive sponge.
4. Male subjects must be either surgically sterile, agree to be sexually inactive or use a double-barrier method of birth control (eg, condom and diaphragm with spermicide, condom with cervical cap and spermicide) from first study drug administration until 90 days after final drug administration.
5. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures.
6. Able to understand the consent form, and to provide written informed consent.

Rollover Subjects Exclusion Criteria

1. Female who is pregnant or lactating.
2. Presence of any major psychiatric disorder including, but not limited to, dementia, bipolar disorder, psychosis (including clinically significant hallucinations during the past 6 months) or any disorder that, in the opinion of the Investigator, requires ongoing treatment that would make study participation unsafe or make treatment compliance difficult.
3. Presence of any clinically significant medical (including but not limited to CNS, cardiovascular, hepatic, pulmonary, metabolic, or renal events), surgical, or laboratory abnormality that would make study participation unsafe or make treatment compliance difficult. Clinical significance to be determined by the Investigator.
4. Receipt of any investigational (ie, unapproved) medication or participation in any clinical trial of an investigational product since completing a previous study using APL 130277.
5. Development of canker or mouth sores within 14 days of completing a previous study using APL-130277. For other clinically significant oral pathology, the Investigator should follow-up with an appropriate specialist on any finding, if indicated, before enrolling such a subject into the study. Clinical significance to be determined by the Investigator. The eligibility of subjects who have experienced AEs related to the oral cavity during the previous study using APL-130277, should be reviewed with the medical monitor and approval obtained.
6. Current suicidal ideation within one year of the screening visit, as evidenced by answering "yes" to Question 4 or 5 on the suicidal ideation portion of the C SSRS at Screening or attempted suicide within 5 years.

CTH-301 Completer Subjects Inclusion Criteria

1. Completion of the CTH-301 study under protocol version 3.00, and in the opinion of the Investigator, would benefit from continued treatment with APL 130277.
2. If female and of childbearing potential, must agree to be sexually abstinent or use one of the following highly effective methods of birth control:

   * Hormonal contraceptives (eg, combined oral contraceptives, patch, vaginal ring, injectables, and implants);
   * Intrauterine contraceptive system;
   * Surgical sterilization or partner sterile (must have documented proof); AND

   One of the following effective methods of birth control:
   * Male/female condom;
   * Cervical cap with spermicide;
   * Diaphragm with spermicide;
   * Contraceptive sponge.
3. Male subjects must be either surgically sterile, agree to be sexually inactive or use a double-barrier method of birth control (eg, condom and diaphragm with spermicide, condom with cervical cap and spermicide) from first study drug administration until 90 days after final drug administration.
4. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures.
5. Able to understand the consent form, and to provide written informed consent.

CTH-301 Completer Subjects Exclusion Criteria

1. Female who is pregnant or lactating.
2. Presence of any major psychiatric disorder including, but not limited to, dementia, bipolar disorder, psychosis (including clinically significant hallucinations during the past 6 months) or any disorder that, in the opinion of the Investigator, requires ongoing treatment that would make study participation in unsafe or make treatment compliance difficult.
3. Presence of any clinically significant medical (including but not limited to CNS, cardiovascular, hepatic, pulmonary, metabolic, or renal events), surgical, or laboratory abnormality that would make study participation unsafe or make treatment compliance difficult. Clinical significance to be determined by the Investigator.
4. Receipt of any investigational (ie, unapproved) medication or participation in any clinical trial since completing the CTH 301 study.
5. Development of canker or mouth sores since completing the CTH 301 study. For other clinically significant oral pathology, the Investigator should follow-up with an appropriate specialist on any finding, if indicated, before enrolling such a patient into the study. Clinical significance to be determined by the Investigator.
6. Current suicidal ideation as evidenced by answering "yes" to Question 4 or 5 on the suicidal ideation portion of the C-SSRS at the Screening Visit Phase 2 (SVP2).

Primary outcomes:
measure: Evaluation of Safety and Tolerability Data Collected, Based on Number of Participants With Adverse Events in the LTS Phase
timeFrame: up to approximately 3 years
Secondary outcomes:
measure: The Percentage of Instances Where a Full "ON" Response Was Achieved Within 30 Minutes After Self-administration of Study Medication at Week 24 Visit (LTS V4) of the LTS Phase Based on the Home Dosing Diary Entries.
timeFrame: Week 24
measure: The Percentage of Instances Where a Full "ON" Response Was Achieved Within 30 Minutes After Self-administration of Study Medication at Week 36 Visit (LTS V5) of the LTS Phase Based on the Home Dosing Diary Entries.
timeFrame: Week 36
measure: The Percentage of Instances Where a Full "ON" Response Was Achieved Within 30 Minutes After Self-administration of Study Medication at Week 48 Visit (LTS V6) of the LTS Phase Based on the Home Dosing Diary Entries.
timeFrame: Week 48
measure: Percentage of Subjects With a Subject-rated Full "ON" Response Within 30 Minutes at Week 24 Visit (LTS V4) of the LTS Phase.
timeFrame: Week 24
measure: Percentage of Subjects With a Subject-rated Full "ON" Response Within 30 Minutes at Week 36 Visit (LTS V5) of the LTS Phase.
timeFrame: Week 36
measure: Percentage of Subjects With a Subject-rated Full "ON" Response Within 30 Minutes at Week 48 Visit (LTS V6) of the LTS Phase.
timeFrame: Week 48
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 15 Minutes After Dosing at Week 24 Visit (LTS V4) of the LTS Phase.
timeFrame: Week 24, 15 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 30 Minutes After Dosing at Week 24 Visit (LTS V4) of the LTS Phase.
timeFrame: Week 24, 30 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 60 Minutes After Dosing at Week 24 Visit (LTS V4) of the LTS Phase.
timeFrame: Week 24, 60 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 90 Minutes After Dosing at Week 24 Visit (LTS V4) of the LTS Phase.
timeFrame: Week 24, 90 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 15 Minutes After Dosing at Week 36 Visit (LTS V5) of the LTS Phase.
timeFrame: Week 36, 15 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 30 Minutes After Dosing at Week 36 Visit (LTS V5) of the LTS Phase.
timeFrame: Week 36, 30 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 60 Minutes After Dosing at Week 36 Visit (LTS V5) of the LTS Phase.
timeFrame: Week 36, 60 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 90 Minutes After Dosing at Week 36 Visit (LTS V5) of the LTS Phase.
timeFrame: Week 36, 90 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 15 Minutes After Dosing at Week 48 Visit (LTS V6) of the LTS Phase.
timeFrame: Week 48, 15 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 30 Minutes After Dosing at Week 48 Visit (LTS V6) of the LTS Phase.
timeFrame: Week 48, 30 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 60 Minutes After Dosing at Week 48 Visit (LTS V6) of the LTS Phase.
timeFrame: Week 48, 60 mins after dosing
measure: Mean Change From Pre-dose in MDS-UPDRS Part III Motor Examination (MDS UPDRS MOTOR) Score at 90 Minutes After Dosing at Week 48 Visit (LTS V6) of the LTS Phase.
timeFrame: Week 48, 90 mins after dosing
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Muhammed Ali Parkinson and Movement Disorder Center/Barrow Neurological Institute
state: Arizona
city: Scottsdale
country: United States
facility: Movement Disorders Center of Arizona
state: Arizona
city: Little Rock
country: United States
facility: Clinical Trials, Inc.
state: Arkansas
city: Fountain Valley
country: United States
facility: The Parkinson's and Movement Disorder Institute
state: California
city: Irvine
country: United States
facility: UC Irvine Health Gottschalk Medical Plaza
state: California
city: Los Angeles
country: United States
facility: Keck Medical Center at USC
state: California
city: Aurora
country: United States
facility: University of Colorado School of Medicine
state: Colorado
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Boca Raton
country: United States
facility: Parkinsons Disease and Movement Disorders Center
state: Florida
city: Miami
country: United States
facility: University of Miami, Miller School of Medicine
state: Florida
city: Port Charlotte
country: United States
facility: Parkinson's Disease Treatment Center of Southwest Florida
state: Florida
city: Saint Petersburg
country: United States
facility: Suncoast Neuroscience Associates Inc.
state: Florida
city: Tampa
country: United States
facility: USF Parkinson's Disease and Movement Disorder Center
state: Florida
city: Atlanta
country: United States
facility: Emory University Department of Neurology
state: Georgia
city: Augusta
country: United States
facility: GRU Movement Disorders
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Glenview
country: United States
facility: NorthShore Neurological Institute B043D
state: Illinois
city: Winfield
country: United States
facility: Central DuPage Hospital - Neurodegenerative Clinic - Movement Disorders Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Dept. of Neurology
state: Iowa
city: Kansas City
country: United States
facility: Kansas University Medical Center-Department of Neurology
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: East Lansing
country: United States
facility: Michigan State University - Dept. of Neurology
state: Michigan
city: Farmington Hills
country: United States
facility: QUEST Research Institute
state: Michigan
city: West Bloomfield
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Golden Valley
country: United States
facility: Park Nicolet Institute - Stuthers Parkinson's Center
state: Minnesota
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center, Department of Neurology
state: New York
city: New York
country: United States
facility: Bendheim Parkinson's and Movement Disorder Center (Mount Sinai Medical Center)
state: New York
city: New York
country: United States
facility: Columbia University Medical Center - Neurological Institute, Movement Disorders
state: New York
city: Durham
country: United States
facility: Duke University - Movement Disorders Clinic
state: North Carolina
city: Raleigh
country: United States
facility: Raleigh Neurology Associates, P.A.
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Health
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center
state: Ohio
city: Toledo
country: United States
facility: UT Gardner-McMaster Parkinson's Center
state: Ohio
city: Tulsa
country: United States
facility: The Movement Disorder Clinic of Oklahoma
state: Oklahoma
city: Philadelphia
country: United States
facility: Jefferson University Hospital Philadelphia
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: Houston Methodist Neurological Institute
state: Texas
city: Tyler
country: United States
facility: East Texas Medical Center
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Adult Neurology
state: Virginia
city: Virginia Beach
country: United States
facility: Sentara Neuroscience Institute
state: Virginia
city: Kirkland
country: United States
facility: Evergreen Health
state: Washington
city: Seattle
country: United States
facility: Swedish Neuroscience Research
state: Washington
city: Innsbruck
country: Austria
facility: Medical University Innsbruck Neurology Department
city: Wien
country: Austria
facility: Wilhelminenspital Department of Neurology
city: Toronto
country: Canada
facility: UHN Toronto Western Hospital
state: Ontario
city: Toulouse
country: France
facility: Centre d'Investigation Clinique, CIC 1436, CHU Purpan
city: Bochum
country: Germany
facility: St. Josef-Hospital, Klinikum der Ruhr-Universitaet-Bochum, Neurologische Klinik
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm Neurologisches Studienzentrum im RKU
city: Ancona
country: Italy
facility: Ospedali Riuniti di Ancona
city: Cassino
country: Italy
facility: Centro Ricerche San Raffaele
city: Chieti
country: Italy
facility: Aging Research Center, Ce.S.I. University Foundation, Chieti-Pescara Behavioural Neurology & Movement Disorders Unit
city: Rome
country: Italy
facility: IRCCS San Raffaele Pisana - Clinical Trial Center
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Sant Cugat del Vallés
country: Spain
facility: Hospital Universitari General de Catalunya
city: London
country: United Kingdom
facility: Kings College, The Maurice Wohl Neuroscience Institute
state: Greater London
city: Salford
country: United Kingdom
facility: Manchester University
state: Greater Manchester
city: Newcastle-upon-Tyne
country: United Kingdom
facility: Newcastle University
state: Northumberland
city: Larbert
country: United Kingdom
facility: Forth Valley Royal Hospital
state: Stirlingshire
city: Bury
country: United Kingdom
facility: Fairfield General Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter NHS Foundation Trust
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospitals NHS Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare Trust NHS
city: Plymouth
country: United Kingdom
facility: Plymouth University
Study officials:
affiliation: Sumitomo Pharma America, Inc.
name: CNS Medical Director
role: STUDY_DIRECTOR
References: