A Study to Examine APL-130277 in Patients With Parkinson's Disease

• Sponsor: Sunovion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02228590
• Collaborator: (none)
• Enrollment: 20
• Locations: 4
• Arm: 1
• Actual Duration (Months): 2.8
• Patients Per Site: 5
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the efficacy, tolerability and safety of single treatments of APL-130277 in 16 patients with Parkinson's Disease (PD)

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: APL-130277	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study to Examine the Safety, Tolerability and Efficacy of APL-130277 in Patients With Parkinson's Disease
• Actual Study Start Date: Aug 31, 2014
• Actual Primary Completion Date: Nov 24, 2014
• Actual Study Completion Date: Nov 24, 2014

Arms and Interventions

Arm	Intervention/Treatment
Other: APL-130277 open label baseline comparison	Drug: APL-130277; Apomorphine Hydrochloride, Sublingual Thin Film; Other Names: Apomorphine Hydrochloride, Sublingual Thin Film

Outcome Measures

Primary Outcome Measures

1. The Percentage of Patients With Resolution of an 'OFF' Episode to an 'ON' State Following Administration of APL-130277 [At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.]

   Clinical confirmation of an 'OFF' state was assessed prior to dosing and confirmation of 'OFF' or 'ON' was assessed after dosing at Visits 3 - 5 by the Investigator. The first full 'ON' dose was defined as the earliest dose in which a patient achieved a full 'ON' state as assessed by the Investigator. The percentage of patients who achieved their first full 'ON' is presented for each timepoint, regardless of the dose received, and for the study overall (i.e. all post-dose timepoints).

2. Time to 'ON' State From Time of Dosing of APL-130277 [At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.]

   Clinical confirmation of 'OFF' or 'ON' was assessed after dosing at Visits 3 - 5 by the Investigator. The time to the full 'ON' state from the time of dosing in minutes was calculated from timings noted by the Investigator and recorded in the electronic case report form (eCRF). The mean time taken for a patient to reach their first full 'ON' state following administration of APL-130277 is presented for patients who turned 'ON' for the study overall.

3. Duration of 'ON' Response From Time of Dosing of APL-130277 [At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.]

   Clinical confirmation of 'OFF' or 'ON' was assessed after dosing at Visits 3 - 5 by the Investigator. The duration of the 'ON' response was defined as the length of time in which a patient was confirmed 'ON' within a dose, and was calculated from the time noted by the Investigator and recorded in the eCRF. The mean duration of the first full 'ON' response following administration of APL-130277 is presented for patients who turned 'ON' for the study overall.

4. Percentage of Patients Who Completed the Trial and Experienced an 'ON' Episode [At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.]

   Clinical confirmation of 'OFF' or 'ON' was assessed after dosing at Visits 3 - 5 by the Investigator. For the overall study, the percentage of patients who completed the trial, and who experienced an 'ON' episode is presented.

5. Pharmacokinetic (PK) Evaluation: Maximum Observed Plasma Concentration (Cmax) [Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.]

   The mean Cmax values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, with a lower limit of quantification of 0.020 nanograms per millilitre (ng/mL).

6. PK Evaluation: Time of Maximum Observed Plasma Concentration (Tmax) [Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.]

   The median Tmax values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated LC-MS/MS assay, with a lower limit of quantification of 0.020 ng/mL.

7. PK Evaluation: Time to Last Analytically Quantifiable Concentration (Tlast) [Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.]

   The mean Tlast values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated LC-MS/MS assay, with a lower limit of quantification of 0.020 ng/mL.

8. PK Evaluation: Area Under the Plasma Concentration Time Curve, From Time 0 to 90 Minutes (AUC0-90) [Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.]

   The mean AUC0-90 values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated LC-MS/MS assay, with a lower limit of quantification of 0.020 ng/mL.

9. PK Evaluation: Area Under the Plasma Concentration Time Curve, From Time 0 to the Last Measurable Non-zero Concentration (AUClast) [Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.]

   The mean AUClast values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated LC-MS/MS assay, with a lower limit of quantification of 0.020 ng/mL. The AUClast was calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method).

Secondary Outcome Measures

1. Percentage Change in MDS-UPDRS Section III Score From Pre-dose Assessment [At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.]

   The Motor Function section (Section III) of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) included 33 scores based on 18-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range was from 0 to 132, with a lower score indicating better motor function and a higher score indicating more severe motor symptoms. The percent change in the MDS-UPDRS Section III score from pre-dose to the first full ON dose or last dose for non-responders is presented. A negative change from baseline indicates an improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female ≥18 years of age.

2. Clinical diagnosis of Idiopathic PD

3. Receiving stable doses of L-dopa +/- other adjunctive PD therapy for at least 4 weeks before study participation.

4. At least one OFF episode per day and a total daily OFF time of > 2 hours duration.

5. Experience predictable OFF episodes in the morning on awakening prior to receiving morning dose of levodopa.

6. Stage I to III on the Hoehn and Yahr scale in the "ON" state.

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

8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures to complete the study.

9. Able to understand the consent form, and to provide written informed consent.

Exclusion Criteria:

1. Atypical or secondary parkinsonism

2. Changes in L-dopa or other PD drug dosing regimens 4 weeks before the screening visit.

3. Past treatment with any form of apomorphine within 30 days of Dosing Day 1 (patients who stopped apomorphine for reasons other than lack of efficacy OR tolerability issues may be considered for the trial).

4. Female who is pregnant or lactating.

5. Contraindications to APOKYN or hypersensitive to apomorphine hydrochloride or any of the ingredients of APOKYN (notably sodium metabisulfite), or Tigan®.

6. Participation in any other clinical trial within 14 days of the screening visit.

7. Receipt of any investigational (i.e., unapproved) medication within 30 days of the screening visit.

8. Currently taking, or likely to need to take at any time during the course of the study

9. Currently taking dopamine antagonists or depleting drugs excluding anticholinergics and/or antihistamines with anticholinergic effects.

10. Drug or alcohol dependency in the past 6 months.

11. Clinically significant orthostatic hypotension.

12. Malignant melanoma or a history of previously treated malignant melanoma within 5 years.

13. Clinically significant medical surgical or laboratory abnormality in the judgment of the investigator.

14. Psychiatric disorder, including but not limited to dementia or any disorder that, in the opinion of the Investigator requires ongoing treatment that would make study participation unsafe or make treatment compliance difficult.

15. Dementia that precludes providing informed consent.

16. Potential for lack of compliance and follow-up in the judgment of the investigator.

17. Any other condition, current therapy, or prior therapy (within 30 days of the screening visit), which, in the opinion of the Investigator, would make the subject unsuitable for the study.

18. Previous neurosurgery for PD.

19. Donation of blood or plasma in the 30 days prior to dosing.

20. Presence of cankers or mouth sores.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Sun Health Research Institute	Sun City	Arizona	United States	85351
2	Rocky Mountain Movement Disorders Center	Englewood	Colorado	United States	80113
3	Parkinson's Disease and Movement Disorders Center of Boca Raton	Boca Raton	Florida	United States	33486
4	University of South Florida Parkinson's Disease and Movement Disorders Center	Tampa	Florida	United States	33613

Sponsors and Collaborators

• Sunovion

Investigators

• Study Director: CNS Medical Director, Sunovion

Study Documents (Full-Text)

• Study Protocol - Sep 10, 2014
• Statistical Analysis Plan - Jun 2, 2015

More Information

Publications

None provided.

• Responsible Party: Sunovion
• ClinicalTrials.gov Identifier: NCT02228590
• Other Study ID Numbers: CTH-105
• First Posted: Aug 29, 2014
• Last Update Posted: Jul 30, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Sunovion: Parkinson's Disease
• Additional relevant MeSH terms: Parkinson Disease; Apomorphine

Study Results

Participant Flow

Recruitment Details	Patients with moderate to advanced Idiopathic Parkinson's Disease (PD) were recruited to this study in 4 study sites in the United States from August 2014. The study was completed in November 2014.
Pre-assignment Detail	23 patients were screened, 20 were assigned to treatment and 1 withdrew consent prior to treatment. 19 received APL-130277 APL-130277 sublingual film for the acute intermittent treatement of OFF episodes in PD patients . Doses studied were 10, 15, 20, 25 and 30 milligrams (mg).

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Period Title: Overall Study
STARTED	20
COMPLETED	19
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Overall Participants	19
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	12 63.2%
>=65 years	7 36.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.5 (8.71)
Sex: Female, Male (Count of Participants)
Female	5 26.3%
Male	14 73.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 15.8%
Not Hispanic or Latino	16 84.2%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	19 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	19 100%

Outcome Measures

1. Primary Outcome

Title	The Percentage of Patients With Resolution of an 'OFF' Episode to an 'ON' State Following Administration of APL-130277
Description	Clinical confirmation of an 'OFF' state was assessed prior to dosing and confirmation of 'OFF' or 'ON' was assessed after dosing at Visits 3 - 5 by the Investigator. The first full 'ON' dose was defined as the earliest dose in which a patient achieved a full 'ON' state as assessed by the Investigator. The percentage of patients who achieved their first full 'ON' is presented for each timepoint, regardless of the dose received, and for the study overall (i.e. all post-dose timepoints).
Time Frame	At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

The modified Intent-to-Treat (mITT) Population consisted of all patients who received at least 1 dose of study medication.

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Measure Participants	19
Overall	78.9 415.3%
15 minutes post-dose	31.6 166.3%
30 minutes post-dose	78.9 415.3%
45 minutes post-dose	68.4 360%
60 minutes post-dose	68.4 360%
90 minutes post-dose	47.4 249.5%

2. Primary Outcome

Title	Time to 'ON' State From Time of Dosing of APL-130277
Description	Clinical confirmation of 'OFF' or 'ON' was assessed after dosing at Visits 3 - 5 by the Investigator. The time to the full 'ON' state from the time of dosing in minutes was calculated from timings noted by the Investigator and recorded in the electronic case report form (eCRF). The mean time taken for a patient to reach their first full 'ON' state following administration of APL-130277 is presented for patients who turned 'ON' for the study overall.
Time Frame	At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who received at least 1 dose of study medication, and data is presented for patients who turned 'ON'.

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Measure Participants	19
Mean (Standard Deviation) [minutes]	24.0 (7.61)

3. Primary Outcome

Title	Duration of 'ON' Response From Time of Dosing of APL-130277
Description	Clinical confirmation of 'OFF' or 'ON' was assessed after dosing at Visits 3 - 5 by the Investigator. The duration of the 'ON' response was defined as the length of time in which a patient was confirmed 'ON' within a dose, and was calculated from the time noted by the Investigator and recorded in the eCRF. The mean duration of the first full 'ON' response following administration of APL-130277 is presented for patients who turned 'ON' for the study overall.
Time Frame	At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who received at least 1 dose of study medication, and data is presented for patients who turned 'ON'.

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Measure Participants	19
Mean (Standard Deviation) [minutes]	50.0 (19.36)

4. Primary Outcome

Title	Percentage of Patients Who Completed the Trial and Experienced an 'ON' Episode
Description	Clinical confirmation of 'OFF' or 'ON' was assessed after dosing at Visits 3 - 5 by the Investigator. For the overall study, the percentage of patients who completed the trial, and who experienced an 'ON' episode is presented.
Time Frame	At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who received at least 1 dose of study medication.

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Measure Participants	19
Number [percentage of participants]	78.9 415.3%

5. Primary Outcome

Title	Pharmacokinetic (PK) Evaluation: Maximum Observed Plasma Concentration (Cmax)
Description	The mean Cmax values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay, with a lower limit of quantification of 0.020 nanograms per millilitre (ng/mL).
Time Frame	Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

Blood draws for APL-130277 PK analyses were collected at select sites only. The PK Population consisted of all patients who had sufficient concentration-time data to derive noncompartmental PK parameters.

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Measure Participants	8
10 mg APL-130277 Dose 1 Day 1	2.01 (0.914)
15 mg APL-130277 Dose 2 Day 1	2.52 (1.04)
10 mg APL-130277 Dose 1 Day 2	4.18 (NA)
20 mg APL-130277 Dose 1 Day 2	3.82 (1.81)
25 mg APL-130277 Dose 2 Day 2	4.84 (NA)
20 mg APL-130277 Dose 1 Day 3	2.82 (1.38)
25 mg APL-130277 Dose 1 Day 3	12.3 (NA)
30 mg APL-130277 Dose 1 Day 3	4.22 (NA)
25 mg APL-130277 Dose 2 Day 3	4.84 (2.99)

6. Primary Outcome

Title	PK Evaluation: Time of Maximum Observed Plasma Concentration (Tmax)
Description	The median Tmax values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated LC-MS/MS assay, with a lower limit of quantification of 0.020 ng/mL.
Time Frame	Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

Blood draws for APL-130277 PK analyses were collected at select sites only. The PK Population consisted of all patients who had sufficient concentration-time data to derive noncompartmental PK parameters.

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Measure Participants	8
10 mg APL-130277 Dose 1 Day 1	60.0
15 mg APL-130277 Dose 2 Day 1	35.0
20 mg APL-130277 Dose 1 Day 2	47.0
20 mg APL-130277 Dose 1 Day 3	56.5
25 mg APL-130277 Dose 2 Day 3	45.0

7. Primary Outcome

Title	PK Evaluation: Time to Last Analytically Quantifiable Concentration (Tlast)
Description	The mean Tlast values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated LC-MS/MS assay, with a lower limit of quantification of 0.020 ng/mL.
Time Frame	Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

Blood draws for APL-130277 PK analyses were collected at select sites only. The PK Population consisted of all patients who had sufficient concentration-time data to derive noncompartmental PK parameters.

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Measure Participants	8
10 mg APL-130277 Dose 1 Day 1	89.4 (8.63)
15 mg APL-130277 Dose 2 Day 1	90.8 (2.04)
10 mg APL-130277 Dose 1 Day 2	95.0 (NA)
20 mg APL-130277 Dose 1 Day 2	88.9 (15.1)
25 mg APL-130277 Dose 2 Day 2	94.0 (NA)
20 mg APL-130277 Dose 1 Day 3	95.2 (6.40)
25 mg APL-130277 Dose 1 Day 3	102 (NA)
30 mg APL-130277 Dose 1 Day 3	92.0 (NA)
25 mg APL-130277 Dose 2 Day 3	75.7 (24.8)

8. Primary Outcome

Title	PK Evaluation: Area Under the Plasma Concentration Time Curve, From Time 0 to 90 Minutes (AUC0-90)
Description	The mean AUC0-90 values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated LC-MS/MS assay, with a lower limit of quantification of 0.020 ng/mL.
Time Frame	Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

Blood draws for APL-130277 PK analyses were collected at select sites only. The PK Population consisted of all patients who had sufficient concentration-time data to derive noncompartmental PK parameters.

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Measure Participants	8
10 mg APL-130277 Dose 1 Day 1	132 (42.8)
15 mg APL-130277 Dose 2 Day 1	149 (57.2)
10 mg APL-130277 Dose 1 Day 2	269 (NA)
20 mg APL-130277 Dose 1 Day 2	216 (127)
25 mg APL-130277 Dose 2 Day 2	266 (NA)
20 mg APL-130277 Dose 1 Day 3	170 (77.2)
25 mg APl-130277 Dose 1 Day 3	507 (NA)
30 mg APL-130277 Dose 1 Day 3	197 (NA)
25 mg APL-130277 Dose 2 Day 3	367 (NA)

9. Primary Outcome

Title	PK Evaluation: Area Under the Plasma Concentration Time Curve, From Time 0 to the Last Measurable Non-zero Concentration (AUClast)
Description	The mean AUClast values are presented for each dosage administered at Visits 3, 4, and 5 for which data was available. Plasma concentrations of the active substance of APL-130277, apomorphine, were analysed using a validated LC-MS/MS assay, with a lower limit of quantification of 0.020 ng/mL. The AUClast was calculated by a combination of linear and logarithmic trapezoidal methods (linear up/log down method).
Time Frame	Just prior to dosing and at 10, 20, 30, 45, 60 and 90 minutes after each dose at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

Blood draws for APL-130277 PK analyses were collected at select sites only. The PK Population consisted of all patients who had sufficient concentration-time data to derive noncompartmental PK parameters.

Arm/Group Title	APL-130277
Arm/Group Description	At each dosing visit patients were assessed in a 'OFF' state by withholding their PD medication the night before, a dose of APL-130277 was administered. If the patient did not convert to a full 'ON' state within 3 hours and did not experience orthostatic hypotension, the next higher dose of APL-130277 was administered. If the patient did not turn ON with the next higher dose, levodopa was administered and completed their visit. Possible administered doses of APL-130277 were 10, 15, 20, 25 and 30 mg. Dosing Day 1: The starting dose was 10 mg APL-130277, and if no response 15 mg was administered. Dosing Day 2: Either the dose which elicited a response (i.e. an 'ON' state) at Day 1 was administered or the next higher dose (20 mg) was given. If no response occurred at 20 mg APL-130277, 25 mg was administered. Dosing Day 3: Either the dose which elicited a response at Day 2 was administered or the next higher dose (30 mg). If no response occurred at 30 mg the patient was discontinued.
Measure Participants	8
10 mg APL-130277 Dose 1 Day 1	121 (52.2)
15 mg APL-130277 Dose 2 Day 1	151 (58.4)
10 mg APL-130277 Dose 1 Day 2	279 (NA)
20 mg APL-130277 Dose 1 Day 2	203 (122)
25 mg APL-130277 Dose 2 Day 2	277 (NA)
20 mg APL-130277 Dose 1 Day 3	179 (69.2)
25 mg APl-130277 Dose 1 Day 3	566 (NA)
30 mg APl-130277 Dose 1 Day 3	206 (NA)
25 mg APL-130277 Dose 2 Day 3	268 (193)

10. Secondary Outcome

Title	Percentage Change in MDS-UPDRS Section III Score From Pre-dose Assessment
Description	The Motor Function section (Section III) of the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) included 33 scores based on 18-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range was from 0 to 132, with a lower score indicating better motor function and a higher score indicating more severe motor symptoms. The percent change in the MDS-UPDRS Section III score from pre-dose to the first full ON dose or last dose for non-responders is presented. A negative change from baseline indicates an improvement.
Time Frame	At 15, 30, 45, 60 and 90 minutes after dosing at Visits 3 - 5.

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who received at least 1 dose of study medication.

Arm/Group Title	APL-130277
Arm/Group Description	At each of 3 dosing visits patients were assessed in a practically defined 'OFF' state after withholding their usual PD medications the night before and APL-130277 sublingual film was administered initially at 10 mg. If the patient did not convert to a full 'ON' state within 3 hours from initial dosing and did not experience orthostatic
Measure Participants	19
Change from Pre-Dose to 15 min Post-Dose	-27.9 (20.72)
Change from Pre-Dose to 30 min Post-Dose	-34.4 (19.04)
Change from Pre-Dose to 45 min Post-Dose	-35.6 (20.03)
Change from Pre-Dose to 60 min Post-Dose	-32.4 (23.20)
Change from Pre-Dose to 90 min Post-Dose	-23.8 (26.14)

Adverse Events

Time Frame	Treatment-emergent adverse events (AEs) were collected over a timeframe of approximately 3 months, with an onset at the time of or following the start of treatment with study medication and prior to 7 days after the end of treatment, or AEs which started prior to treatment but worsened at the time of or following the start of treatment.
Adverse Event Reporting Description	Adverse events are presented for the Safety Population which consisted of all patients who were enrolled into the study and received at least 1 dose of study medication.
Arm/Group Title	APL-130277
Arm/Group Description	At each of 3 dosing visits patients were assessed in a practically defined 'OFF' state after withholding their usual PD medications the night before and APL-130277 sublingual film was administered initially at 10 mg. If the patient did not convert to a full 'ON' state within 3 hours from initial dosing and did not experience orthostatic
All Cause Mortality
	APL-130277
	Affected / at Risk (%)	# Events
Total	0/19 (0%)
Serious Adverse Events
	APL-130277
	Affected / at Risk (%)	# Events
Total	1/19 (5.3%)
Gastrointestinal disorders
Dysphagia	1/19 (5.3%)	1
Other (Not Including Serious) Adverse Events
	APL-130277
	Affected / at Risk (%)	# Events
Total	13/19 (68.4%)
Gastrointestinal disorders
nausea	4/19 (21.1%)	8
vomiting	1/19 (5.3%)	1
General disorders
chest discomfort	1/19 (5.3%)	1
chest pain	1/19 (5.3%)	1
fatigue	1/19 (5.3%)	1
Musculoskeletal and connective tissue disorders
muscle spasms	1/19 (5.3%)	1
muscuar weakness	1/19 (5.3%)	1
musculoskeletal stiffness	1/19 (5.3%)	1
neck pain	1/19 (5.3%)	1
Nervous system disorders
balance disorder	1/19 (5.3%)	1
dizziness	7/19 (36.8%)	8
headache	2/19 (10.5%)	3
paraesthesia	1/19 (5.3%)	1
somnolence	6/19 (31.6%)	8
tremor	1/19 (5.3%)	2
Psychiatric disorders
apathy	1/19 (5.3%)	1
nervousness	1/19 (5.3%)	1
Respiratory, thoracic and mediastinal disorders
yawning	3/19 (15.8%)	4
upper-airway cough syndrome	1/19 (5.3%)	1
Skin and subcutaneous tissue disorders
hyperhidrosis	2/19 (10.5%)	2
Vascular disorders
hot flush	1/19 (5.3%)	1
orthostatic hypotension	1/19 (5.3%)	1
peripheral coldness	1/19 (5.3%)	2

Limitations/Caveats

Due to the 90-minute sampling estimate λz values or calculate AUCinf, AUCext, or half-life as stated in the protocol was not possible.No PK parameters were calculated for subjects with fewer than 4 quantifiable concentrations following BLQ imputation

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In the event the Study is part of a multi-center study, the first publication of the results of the Study shall be made in conjunction with the results of other participating study sites as a mult-center publication; provided however, if a mult-center publication is not forthcoming within twenty-four (24) months following completion of the Study at all sites, institution and Investigator shall be free to publish.