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

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)

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02542696

Enrollment

496

Registered

2015-09-07

Start date

2015-08-31

Completion date

2022-11-08

Last updated

2023-11-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Parkinson Disease

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

Interventions

DRUGAPL-130277

Used to treat up to 5 OFF episodes per day

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion 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

Design outcomes

Primary

Measure	Time frame	Description
Evaluation of Safety and Tolerability Data Collected, Based on Number of Participants With Adverse Events in the LTS Phase	up to approximately 3 years	Number of Participants (%) with Adverse Events in the LTS Phase

Secondary

Measure	Time frame	Description
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.	Week 36	—
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.	Week 48	—
Percentage of Subjects With a Subject-rated Full ON Response Within 30 Minutes at Week 24 Visit (LTS V4) of the LTS Phase.	Week 24	—
Percentage of Subjects With a Subject-rated Full ON Response Within 30 Minutes at Week 36 Visit (LTS V5) of the LTS Phase.	Week 36	—
Percentage of Subjects With a Subject-rated Full ON Response Within 30 Minutes at Week 48 Visit (LTS V6) of the LTS Phase.	Week 48	—
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.	Week 24, 15 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 24, 30 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 24, 60 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 24	The percentage of instances where a full ON response was achieved
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.	Week 36, 15 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 36, 30 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 36, 60 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 36, 90 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 48, 15 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 48, 30 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 48, 60 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 48, 90 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).
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.	Week 24, 90 mins after dosing	The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).

Countries

Austria, Canada, France, Germany, Italy, Spain, United Kingdom, United States

Participant flow

Participants by arm

Arm	Count
APL-130277 APL-130277 sublingual thin film (10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 35 mg)	496
Total	496

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	167
Overall Study	Death	8
Overall Study	DECREASED OFF TIME	1
Overall Study	DID NOT MEET CRITERIA FOR CONTINUATION	1
Overall Study	ELIGIBILITY CRITERIA NOT MET	8
Overall Study	Lack of Efficacy	26
Overall Study	Lost to Follow-up	6
Overall Study	MEDICAL HISTORY	1
Overall Study	PATIENT WITHDRAWN DURING TITRATION AS COULD NOT TITRATE DRUG TO GET RESPONSE OF ON FROM PATIENT	1
Overall Study	PROGRESSION OF PARKINSON'S DISEASE	5
Overall Study	Protocol Violation	5
Overall Study	SITE UNABLE TO COMPLY WITH PROTOCOL	2
Overall Study	SPONSOR DECISION	3
Overall Study	STUDY TERMINATED BY SPONSOR	36
Overall Study	SUBJECT DECISION	2
Overall Study	Withdrawal by Subject	104

Baseline characteristics

Characteristic	APL-130277
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	257 Participants
Age, Categorical Between 18 and 65 years	239 Participants
Age, Continuous	64.4 Years STANDARD_DEVIATION 8.72
Age, Customized <65 years	239 Participants
Age, Customized >=65 years and <75 years	197 Participants
Age, Customized >=75 years	60 Participants
Baseline BMI (kg/m^2)	27.654 kg/m^2 STANDARD_DEVIATION 5.5287
Baseline Height (cm)	172.01 cm STANDARD_DEVIATION 9.754
Baseline MDS-UPDRS Part III Score	43.0 Score STANDARD_DEVIATION 14.85
Baseline MDS-UPDRS Part II Score	14.6 Score STANDARD_DEVIATION 7.15
Baseline MDS-UPDRS Part I Score	11.0 Score STANDARD_DEVIATION 5.42
Baseline Weight (kg)	82.14 kg STANDARD_DEVIATION 18.74
Country Aut	4 Participants
Country Can	7 Participants
Country Deu	23 Participants
Country Esp	11 Participants
Country Gbr	41 Participants
Country Ita	19 Participants
Country United States	391 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	39 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	457 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Mini-Mental State Examination Total Score 26	30 Participants
Mini-Mental State Examination Total Score <26	3 Participants
Mini-Mental State Examination Total Score 27	38 Participants
Mini-Mental State Examination Total Score 28	53 Participants
Mini-Mental State Examination Total Score 29	114 Participants
Mini-Mental State Examination Total Score 30	183 Participants
Mini-Mental State Examination Total Score Missing	75 Participants
ON State Modified Hoehn and Yahr Score 0	2 Participants
ON State Modified Hoehn and Yahr Score 1	12 Participants
ON State Modified Hoehn and Yahr Score 1.5	9 Participants
ON State Modified Hoehn and Yahr Score 2	243 Participants
ON State Modified Hoehn and Yahr Score 2.5	53 Participants
ON State Modified Hoehn and Yahr Score 3	42 Participants
ON State Modified Hoehn and Yahr Score 4	1 Participants
ON State Modified Hoehn and Yahr Score Missing	134 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants
Race (NIH/OMB) Asian	4 Participants
Race (NIH/OMB) Black or African American	10 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants
Race (NIH/OMB) White	478 Participants
Screening MDS-UPDRS Part III Score	42.0 Score STANDARD_DEVIATION 14.55
Sex: Female, Male Female	163 Participants
Sex: Female, Male Male	333 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	8 / 496
other Total, other adverse events	319 / 496
serious Total, serious adverse events	64 / 496

Outcome results

Primary

Evaluation of Safety and Tolerability Data Collected, Based on Number of Participants With Adverse Events in the LTS Phase

Number of Participants (%) with Adverse Events in the LTS Phase

Time frame: up to approximately 3 years

Population: Based on Long Term Safety Full Analysis Set

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
APL-130277	Evaluation of Safety and Tolerability Data Collected, Based on Number of Participants With Adverse Events in the LTS Phase	365 Participants

Secondary

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.

The summary score used here is Part III motor examination score. Higher MDS-UPDRS scores reflect worse motor function. MDS-UPDRS III is a total of 18 questions with 33 individual items, each item ranges from 0-4 (0=normal, 1=slight, 2=mild, 3= moderate, and 4=severe). The MDS-UPDRS III motor score is the summation of all these 33 individual item scores, and hence ranges from 0-132. Score drops over time imply improvement in motor function (higher values represent a worse outcome).

Time frame: Week 24, 15 mins after dosing