Efficacy, Safety and Tolerability Study of APL-130277 for the Acute Treatment of OFF Episodes in Patients With Parkinson's Disease

• Sponsor: Sunovion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02469090
• Collaborator: (none)
• Enrollment: 141
• Locations: 33
• Arms: 2
• Actual Duration (Months): 29.8
• Patients Per Site: 4.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A 12-week, prospective, multi-center, randomized, double-blind, placebo controlled, Phase 3 study in L-Dopa responsive PD patients with motor fluctuations ("OFF" episodes), designed to determine the efficacy, safety and tolerability of APL-130277.

Condition or Disease	Intervention/Treatment	Phase
Parkinson Disease, Off Episodes	Drug: APL-130277; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 141 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Examine the Efficacy, Safety and Tolerability of APL-130277 in Levodopa Responsive Patients With Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes)
• Actual Study Start Date: Jun 18, 2015
• Actual Primary Completion Date: Dec 11, 2017
• Actual Study Completion Date: Dec 11, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: APL-130277 APL-130277 sublingual thin film (10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 35 mg)	Drug: APL-130277; Use to treat up to 5 "OFF" episodes per day; Other Names: Apomorphine Hydrochloride, Sublingual Thin Film
Placebo Comparator: Placebo Matching placebo for APL-130277 sublingual thin film (10 mg, 15 mg, 20 mg, 25 mg, 30 mg and 35 mg)	Drug: Placebo; placebo

Outcome Measures

Primary Outcome Measures

1. Mean Change From Pre-Dose to 30 Minutes Post-Dose in The Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score at Maintenance Visit 4 (MV4) - Week 12 [At t=0 (just prior to dosing) and t=30 minutes at MV4 (Week 12 of the Maintenance Treatment Phase).]

   The Motor Function section (Part III) of the MDS-UPDRS was administered by the Investigator, and 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 least square mean change in the MDS-UPDRS Part III score from pre-dose to 30 minutes post-dose at MV4 is presented. A negative change from pre-dose indicates an improvement.

Secondary Outcome Measures

1. Percentage of Patients With a Patient-related Full 'ON' Response Within 30 Minutes at MV4 - Week 12: Predicted Response Rate [At t=30 minutes at MV4 (Week 12 of the Maintenance Treatment Phase).]

   A full 'ON' response was defined as a period of time where in the judgment of the patient the medication was providing full benefit with regard to mobility, stiffness, slowness and other PD features comparable to or better than that obtained with their standard dose of oral L-dopa and other anti-parkinsonian medications prior to beginning the study. Patients were asked if they attained a full 'ON' state anytime within 30 minutes of dosing. The predicted response rates are presented and were estimated using a generalized linear mixed model.

2. Percentage of Patients With a Patient-related Full 'ON' Response Within 30 Minutes That Had a Duration of Effect of at Least 30 Minutes at MV4 - Week 12: Predicted Response Rate [At MV4 (Week 12 of the Maintenance Treatment Phase).]

   A full 'ON' response was defined as a period of time where in the judgment of the patient the medication was providing full benefit with regard to mobility, stiffness, slowness and other PD features comparable to or better than that obtained with their standard dose of oral L-dopa and other anti-parkinsonian medications prior to beginning the study. The percentage of patients who attained a full 'ON' within 30 minutes of dosing, and whose duration from time when study medication began to have an effect lasted for at least 30 minutes were evaluated. The predicted response rates are presented and were estimated using a generalized linear mixed model.

3. Patient Global Impression of Improvement (PGI-I): Percentage of Patients Who Improved at MV4 - Week 12 [At MV4 (Week 12 of the Maintenance Treatment Phase).]

   During the PGI-I assessment the patient was asked to answer the question "Since starting study medication, how has your illness changed?" with 1 of the following responses: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse and 7 = very much worse. The percentage of patients who improved at MV4 (gave responses 1 - 3) are presented.

4. Clinician Global Impression of Improvement (CGI-I): Percentage of Patients Who Improved at MV4 - Week 12 [At MV4 (Week 12 of the Maintenance Treatment Phase).]

   During the CGI-I assessment the clinician using the question "Compared to his/her condition on baseline, how much has he/she changed?" provided 1 of the following responses: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse and 7 = very much worse. The percentage of patients who improved at MV4 (responses 1 - 3) are presented.

5. Mean Change From Screening Visit to MV4 (Week 12) in MDS-UPDRS Part II: Motor Aspects of Experience of Daily Living [At Screening Visit and at MV4 (Week 12 of the Maintenance Treatment Phase).]

   Part II of the MDS-UPDRS assessed motor experiences of daily living and was self-administered by the patient. The MDS-UPDRS Part II score was calculated as the sum of the individual items of the MDS-UPDRS Part II questionnaire (items 2.1 - 2.13), and was based on 13-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range was from 0 to 52, with a lower score indicating better motor function for daily living and a higher score indicating more severe motor symptoms. The mean change in the MDS-UPDRS Part II score from the screening visit to Week 12 of the Maintenance Treatment Phase is presented. A negative change indicates an improvement.

6. Mean Percentage of Instances Where a Full 'ON' Response Was Achieved at 30 Minutes Post-dose on the Home Dosing Diary Entries During the 2 Days Prior to MV4 - Week 12 [2 days prior to MV4 (Week 12 of the Maintenance Treatment Phase).]

   Patients self-administered their doses of randomized study medication in order to treat up to 5 'OFF' episodes per day and recorded the time of self-administration and the 'ON'/'OFF' status at 30 minutes post-dose in a home dosing diary. A full 'ON' response was defined as a period of time where in the judgment of the patient the medication was providing full benefit with regard to mobility, stiffness, slowness and other PD features comparable to or better than that obtained with their standard dose of oral L-dopa and other anti-parkinsonian medications prior to beginning the study. The percentage of instances in which a full 'ON' response was achieved at 30 minutes out of all recorded episodes was calculated and is presented, and the mean percentage is presented.

7. Mean Change From Screening Visit to MV4 in the Parkinson's Disease Quality of Life Questionnaire (PDQ-39) Summary Index Score [At Screening Visit and at MV4 (Week 12 of the Maintenance Treatment Phase).]

   The PDQ-39 was self-administered by the patient during screening and at each MV. The PDQ-39 assessed the impact of PD on the quality of life in the preceding month using 39-items, each anchored with 5 responses: Never, Occasionally, Sometimes, Often and Always. Items were grouped into 8 scales (Mobility, Activities of daily living, Emotional well-being, Stigma, Social support, Cognitions, Communication and Bodily discomfort) that were scored by expressing summed item scores as a percentage score ranging between 0 and 100. The PDQ-39 summary index score was derived by the sum of the 8 PDQ-39 scale scores divided by 8, yielding a score between 0 and 100. 0 indicates perfect health and 100 indicates worse health as assessed by the measure. A negative change indicates an improvement.

8. Mean Change From Pre-Dose to 15 Minutes Post-Dose in the MDS-UPDRS Part III Score at MV4 - Week 12 [At t=0 (just prior to dosing) and t=15 minutes at MV4 (Week 12 of the Maintenance Treatment Phase).]

   The Motor Function section (Part III) of the MDS-UPDRS was administered by the Investigator, and 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 mean change in the MDS-UPDRS Part III score from pre-dose to 15 minutes post-dose at MV4 is presented. A negative change indicates an improvement.

9. Time From Dosing to When Study Medication Provided an Effect at MV4 - Week 12 [At MV4 (Week 12 of the Maintenance Treatment Phase).]

   The time to effect at MV4 was described using the Kaplan-Meier method, including an estimate of the median time to effect and corresponding 95% confidence interval.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female ≥ 18 years of age.

• Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria.

• Clinically meaningful response to L-Dopa with well-defined early morning "OFF" episodes, as determined by the Investigator.

• Receiving stable doses of L-Dopa/carbidopa (immediate or CR) administered at least 4 times per day OR Rytary™ administered 3 times per day, for at least 4 weeks before the initial Screening Visit

• No planned medication change(s) or surgical intervention anticipated during the course of study.

• Patients 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.

• Stage III or less on the modified Hoehn and Yahr scale in the "ON" state.

• MMSE score > 25.

Exclusion Criteria:

A patient will not be eligible for study entry if any of the following exclusion criteria are met:

• Atypical or secondary parkinsonism.

• Previous treatment with any of the following: a neurosurgical procedure for PD; continuous s.c. apomorphine infusion; or Duodopa/Duopa.

• Treatment with any form of s.c. apomorphine within 7 days prior to the initial Screening Visit (SV1). Patients that stopped s.c. apomorphine for any reason other than systemic safety concerns or lack of efficacy may be considered.

• Contraindications to APOKYN®, or hypersensitivity to apomorphine hydrochloride or any of the ingredients of APOKYN® (notably sodium metabisulfite); Tigan® (trimethobenzamide hydrochloride; patients from US sites only); or domperidone (patients from non-US sites only).

• Participation in a clinical trial within 30 days prior to the initial Screening Visit (SV1).

• Currently taking selective 5HT3 antagonists (i.e., ondansetron, granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists (excluding quetiapine or clozapine) or dopamine depleting agents.

• Drug or alcohol dependency in the past 12 months.

• History of malignant melanoma.

• Clinically significant medical, surgical, or laboratory abnormality in the opinion of the Investigator.

• 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.

• History of clinically significant hallucinations during the past 6 months.

• History of clinically significant impulse control disorder(s).

• Dementia that precludes providing informed consent or would interfere with participation in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama, Birmingham	Birmingham	Alabama	United States	35233
2	Muhammed Ali Parkinson and Movement Disorder CenterBarrow Neurological	Phoenix	Arizona	United States
3	Movement Disorders Center of Arizona	Scottsdale	Arizona	United States	85258
4	Mayo Clinic Arizona	Scottsdale	Arizona	United States	85259
5	The Parkinson's and Movement Disorder Institute	Fountain Valley	California	United States	92708
6	UC Irvine Health Gottschalk Medical Plaza	Irvine	California	United States	92697
7	Keck Medical Center at USC	Los Angeles	California	United States	90033
8	The Research Center of Southern California	Oceanside	California	United States	92056
9	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
10	Parkinsons Disease and Movement Disorders Center	Boca Raton	Florida	United States	33486
11	University of Miami, Miller School of Medicine	Miami	Florida	United States	33136
12	Parkinson's Disease Treatment Center of Southwest Florida	Port Charlotte	Florida	United States	33980
13	USF Parkinson's Disease and Movement Disorder Center	Tampa	Florida	United States	33613
14	Emory University Department of Neurology	Atlanta	Georgia	United States	30329
15	Northwestern University	Chicago	Illinois	United States	60611
16	Rush University Medical Center	Chicago	Illinois	United States	60612
17	Central DuPage Hospital - Neurodegenerative Clinic - Movement Disorders Center	Winfield	Illinois	United States	60190
18	Kansas University Medical Center - Department of Neurology	Kansas City	Kansas	United States	66160
19	University of Kentucky	Lexington	Kentucky	United States	40536
20	Johns Hopkins University	Baltimore	Maryland	United States	21287
21	QUEST Research Institute	Farmington Hills	Michigan	United States	48334
22	Northern Michigan Neurology	Traverse City	Michigan	United States	49684
23	Henry Ford Hospital	West Bloomfield	Michigan	United States	48322
24	Columbia University Medical Center - Neurological Institute, Movement Disorders	New York	New York	United States	10032
25	Raleigh Neurology Associates, P.A.	Raleigh	North Carolina	United States	27607
26	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
27	University of Cincinnati	Cincinnati	Ohio	United States	45219
28	Cleveland Clinic	Cleveland	Ohio	United States	44195
29	The Movement Disorder Clinic of Oklahoma	Tulsa	Oklahoma	United States	74136
30	Jefferson University Hospital Philadelphia	Philadelphia	Pennsylvania	United States	19107
31	University of Virginia, Adult Neurology	Charlottesville	Virginia	United States	22903
32	Evergreen Health	Kirkland	Washington	United States	98034
33	UHN Toronto Western Hospital	Toronto	Ontario	Canada	M5T 2S8

Sponsors and Collaborators

• Sunovion

Investigators

• Study Director: CNS Medical Director, Sunovion

Study Documents (Full-Text)

• Statistical Analysis Plan - Nov 2, 2017
• Study Protocol - May 6, 2015

More Information

Publications

None provided.

• Responsible Party: Sunovion
• ClinicalTrials.gov Identifier: NCT02469090
• Other Study ID Numbers: CTH-300
• First Posted: Jun 11, 2015
• Last Update Posted: Jul 30, 2020
• Last Verified: Jul 1, 2020

• Keywords provided by Sunovion: Parkinson Disease, off episodes
• Additional relevant MeSH terms: Parkinson Disease; Apomorphine

Study Results

Participant Flow

Recruitment Details	Patients with Levodopa (L-dopa) responsive idiopathic Parkinson's Disease (PD) complicated by motor fluctuations ('OFF' episodes) were recruited in 33 study sites in the United States and Canada starting June 2015. Study completed in December 2017. Approval was obtained from the Enrollment Adjudication Committee prior to enrollment of each patient.
Pre-assignment Detail	The study included a Dose Titration Phase in which individual responses to single doses of APL-130277 (10 - 35 milligram [mg]) were evaluated at 5 mg dose increments to determine the starting dose that achieved a full 'ON' within 45 minutes. Patients were randomized at this dose to APL-130277 or placebo in the 12-week Maintenance Treatment Phase.

Arm/Group Title	APL-130277 (Titration)	Placebo (Maintnance)	APL-130277 (Maintenance)
Arm/Group Description	Patients were titrated to identify the efficacious and tolerable dose of APL-130277. On Titration Visit 1 (TV1), patients presented to the clinic in an 'OFF' state and received 10 mg APL-130277. Patients who responded to 10 mg APL-130277 with a full 'ON' response within 45 minutes of dosing, as assessed by the patient and Investigator, completed the Dose Titration Phase. If a complete 'ON' response was not achieved within 45 minutes of dosing, patients restarted their normal PD medication and returned to the clinic within 3 days for the next TV, to receive the next sequential dose of APL-130277 (15 mg at TV2, 20 mg at TV3, 25 mg at TV4, 30 mg at TV5 and 35 mg at TV6). Patients who achieved a full 'ON' response within 45 minutes at a given dose were randomized to the Maintenance Treatment Phase. Any patients who reached 35 mg at TV6 and did not exhibit a full 'ON' response were discontinued.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Period Title: Period 1: Dose Titration Phase
STARTED	141	0	0
COMPLETED	109	0	0
NOT COMPLETED	32	0	0
Period Title: Period 1: Dose Titration Phase
STARTED	0	55	54
COMPLETED	0	46	34
NOT COMPLETED	0	9	20

Baseline Characteristics

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Mainenance)	Total
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Total of all reporting groups
Overall Participants	55	54	109
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	34 61.8%	30 55.6%	64 58.7%
>=65 years	21 38.2%	24 44.4%	45 41.3%
Sex: Female, Male (Count of Participants)
Female	24 43.6%	17 31.5%	41 37.6%
Male	31 56.4%	37 68.5%	68 62.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 5.5%	3 5.6%	6 5.5%
Not Hispanic or Latino	52 94.5%	51 94.4%	103 94.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1.8%	4 7.4%	5 4.6%
Native Hawaiian or Other Pacific Islander	1 1.8%	0 0%	1 0.9%
Black or African American	2 3.6%	0 0%	2 1.8%
White	51 92.7%	50 92.6%	101 92.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	55 100%	53 98.1%	108 99.1%
Canada	0 0%	1 1.9%	1 0.9%
Time Since Diagnosis of PD (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	9.3 (3.84)	8.7 (4.25)	9.0 (4.04)
Time Since Motor Fluctuations Started (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.54 (3.780)	4.69 (3.916)	4.61 (3.831)
Type of 'OFF' episodes experienced (participants) [Number]
Morning akinesia	44 80%	46 85.2%	90 82.6%
Wearing "OFF"	54 98.2%	54 100%	108 99.1%
Delayed "ON"	43 78.2%	29 53.7%	72 66.1%
Dose Failure	23 41.8%	22 40.7%	45 41.3%
Sudden :OFF"	32 58.2%	26 48.1%	58 53.2%
Number of 'OFF' Episodes Typically Experienced Per Day ("OFF" episodes/day) [Mean (Standard Deviation) ]
Mean (Standard Deviation) ["OFF" episodes/day]	3.8 (1.40)	3.9 (1.17)	3.9 (1.29)
Length of 'OFF' Episodes (Minutes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Minutes]	66.1 (30.09)	63.7 (31.91)	64.9 (30.89)
ON' State Modified Hoehn and Yahr Score (participants) [Number]
Hoehn and Yahr Score = 0	0 0%	0 0%	0 0%
Hoehn and Yahr Score = 1	1 1.8%	0 0%	1 0.9%
Hoehn and Yahr Score = 1.5	0 0%	0 0%	0 0%
Hoehn and Yahr Score = 2	38 69.1%	41 75.9%	79 72.5%
Hoehn and Yahr Score = 2.5	4 7.3%	8 14.8%	12 11%
Hoehn and Yahr Score = 3	11 20%	5 9.3%	16 14.7%
Hoehn and Yahr Score = 4	0 0%	0 0%	0 0%
Hoehn and Yahr Score = 5	0 0%	0 0%	0 0%
Missing	1 1.8%	0 0%	1 0.9%
Total Daily L-Dopa Dose (mg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg]	1007.73 (562.323)	1058.70 (563.301)	1032.98 (560.781)

Outcome Measures

1. Primary Outcome

Title	Mean Change From Pre-Dose to 30 Minutes Post-Dose in The Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score at Maintenance Visit 4 (MV4) - Week 12
Description	The Motor Function section (Part III) of the MDS-UPDRS was administered by the Investigator, and 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 least square mean change in the MDS-UPDRS Part III score from pre-dose to 30 minutes post-dose at MV4 is presented. A negative change from pre-dose indicates an improvement.
Time Frame	At t=0 (just prior to dosing) and t=30 minutes at MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The modified Intention-To-Treat (mITT) Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	55	54
Least Squares Mean (Standard Error) [Units on a scale]	-3.5 (1.29)	-11.1 (1.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Maintenance), APL-130277 (Maintenance)
	Comments	Mixed effects model for repeated measures (MMRM) was used to estimate the treatment difference(APL-130277-placebo) Observed change from pre-dose MDS-UPDRS Part III score values after 30 minutes were response values. Treatment group, visit and the interaction between the treatment group and visit were fixed factors. Change from pre-dose in MDS-UPDRS Part III score after 30 minutes at the last TV at which the randomized dose was given up through TV6 was used as a covariate
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	The null-hypothesis to be tested was: H0: APL-130277 is the same as placebo in its effect on the motor function against the 2-sided alternative: H1: Either of the treatment groups is superior to the other in its effect on the motor function.
	Method	LS mean difference
	Comments	To control the family-wise type I error rate, the primary and secondary end points were tested in hierarchical order in the order presented
Method of Estimation	Estimation Parameter	LS mean differnce
	Estimated Value	-7.6
	Confidence Interval	(2-Sided) 95%; -11.5 to -3.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.96
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Patients With a Patient-related Full 'ON' Response Within 30 Minutes at MV4 - Week 12: Predicted Response Rate
Description	A full 'ON' response was defined as a period of time where in the judgment of the patient the medication was providing full benefit with regard to mobility, stiffness, slowness and other PD features comparable to or better than that obtained with their standard dose of oral L-dopa and other anti-parkinsonian medications prior to beginning the study. Patients were asked if they attained a full 'ON' state anytime within 30 minutes of dosing. The predicted response rates are presented and were estimated using a generalized linear mixed model.
Time Frame	At t=30 minutes at MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	55	54
Number [number of participants]	16 29.1%	35 64.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Maintenance), APL-130277 (Maintenance)
	Comments	This was analyzed using a generalized linear mixed model (with logit link function) for binomial data. The model included the observed outcomes as the response values, with treatment group, visit, and the interaction between treatment group and visit as fixed factors and the "ON/OFF" assessment at the last open-label titration visit at which the randomized dose was given as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0426
	Comments
	Method	Adjusted Odds Ratio
	Comments
Method of Estimation	Estimation Parameter	Adjusted odds ratio
	Estimated Value	2.81
	Confidence Interval	(2-Sided) 95%; 1.036 to 7.644
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Patients With a Patient-related Full 'ON' Response Within 30 Minutes That Had a Duration of Effect of at Least 30 Minutes at MV4 - Week 12: Predicted Response Rate
Description	A full 'ON' response was defined as a period of time where in the judgment of the patient the medication was providing full benefit with regard to mobility, stiffness, slowness and other PD features comparable to or better than that obtained with their standard dose of oral L-dopa and other anti-parkinsonian medications prior to beginning the study. The percentage of patients who attained a full 'ON' within 30 minutes of dosing, and whose duration from time when study medication began to have an effect lasted for at least 30 minutes were evaluated. The predicted response rates are presented and were estimated using a generalized linear mixed model.
Time Frame	At MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	55	54
Number [number of participants]	14 25.5%	31 57.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Maintenance), APL-130277 (Maintenance)
	Comments	This was analyzed using a generalized linear mixed model (with logit link function) for binomial data. The model included the observed outcomes as the response values, with treatment group, visit, and the interaction between treatment group and visit as fixed factors and the "ON/OFF" assessment at the last open-label titration visit at which the randomized dose was given as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0501
	Comments	The hierarchical testing stopped at this endpoint due to non-significant result. P-values for endpoints after this endpoint have not been presented and the confidence interval presented are unadjusted for multiplicity.
	Method	Adjusted odds ratio
	Comments
Method of Estimation	Estimation Parameter	Adjusted odds ratio
	Estimated Value	2.80
	Confidence Interval	(2-Sided) 95%; 1.00 to 7.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Patient Global Impression of Improvement (PGI-I): Percentage of Patients Who Improved at MV4 - Week 12
Description	During the PGI-I assessment the patient was asked to answer the question "Since starting study medication, how has your illness changed?" with 1 of the following responses: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse and 7 = very much worse. The percentage of patients who improved at MV4 (gave responses 1 - 3) are presented.
Time Frame	At MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	55	54
Number [percentage of participants]	20.0 36.4%	37.0 68.5%

5. Secondary Outcome

Title	Clinician Global Impression of Improvement (CGI-I): Percentage of Patients Who Improved at MV4 - Week 12
Description	During the CGI-I assessment the clinician using the question "Compared to his/her condition on baseline, how much has he/she changed?" provided 1 of the following responses: 1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse and 7 = very much worse. The percentage of patients who improved at MV4 (responses 1 - 3) are presented.
Time Frame	At MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	55	54
Number [percentage of participants]	20.0 36.4%	40.7 75.4%

6. Secondary Outcome

Title	Mean Change From Screening Visit to MV4 (Week 12) in MDS-UPDRS Part II: Motor Aspects of Experience of Daily Living
Description	Part II of the MDS-UPDRS assessed motor experiences of daily living and was self-administered by the patient. The MDS-UPDRS Part II score was calculated as the sum of the individual items of the MDS-UPDRS Part II questionnaire (items 2.1 - 2.13), and was based on 13-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range was from 0 to 52, with a lower score indicating better motor function for daily living and a higher score indicating more severe motor symptoms. The mean change in the MDS-UPDRS Part II score from the screening visit to Week 12 of the Maintenance Treatment Phase is presented. A negative change indicates an improvement.
Time Frame	At Screening Visit and at MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	44	33
Least Squares Mean (95% Confidence Interval) [units on a scale]	2.095	0.995

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Maintenance), APL-130277 (Maintenance)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-1.100
	Confidence Interval	(2-Sided) 95%; -3.159 to 0.959
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Mean Percentage of Instances Where a Full 'ON' Response Was Achieved at 30 Minutes Post-dose on the Home Dosing Diary Entries During the 2 Days Prior to MV4 - Week 12
Description	Patients self-administered their doses of randomized study medication in order to treat up to 5 'OFF' episodes per day and recorded the time of self-administration and the 'ON'/'OFF' status at 30 minutes post-dose in a home dosing diary. A full 'ON' response was defined as a period of time where in the judgment of the patient the medication was providing full benefit with regard to mobility, stiffness, slowness and other PD features comparable to or better than that obtained with their standard dose of oral L-dopa and other anti-parkinsonian medications prior to beginning the study. The percentage of instances in which a full 'ON' response was achieved at 30 minutes out of all recorded episodes was calculated and is presented, and the mean percentage is presented.
Time Frame	2 days prior to MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	55	54
Least Squares Mean (95% Confidence Interval) [percentage of instnces]	31.10	78.70

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Maintenance), APL-130277 (Maintenance)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	47.60
	Confidence Interval	(2-Sided) 95%; 28.84 to 66.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Mean Change From Screening Visit to MV4 in the Parkinson's Disease Quality of Life Questionnaire (PDQ-39) Summary Index Score
Description	The PDQ-39 was self-administered by the patient during screening and at each MV. The PDQ-39 assessed the impact of PD on the quality of life in the preceding month using 39-items, each anchored with 5 responses: Never, Occasionally, Sometimes, Often and Always. Items were grouped into 8 scales (Mobility, Activities of daily living, Emotional well-being, Stigma, Social support, Cognitions, Communication and Bodily discomfort) that were scored by expressing summed item scores as a percentage score ranging between 0 and 100. The PDQ-39 summary index score was derived by the sum of the 8 PDQ-39 scale scores divided by 8, yielding a score between 0 and 100. 0 indicates perfect health and 100 indicates worse health as assessed by the measure. A negative change indicates an improvement.
Time Frame	At Screening Visit and at MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	55	54
Least Squares Mean (95% Confidence Interval) [units on a scale]	-1.671	0.309

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Maintenance), APL-130277 (Maintenance)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.979
	Confidence Interval	(2-Sided) 95%; -2.162 to 6.120
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Mean Change From Pre-Dose to 15 Minutes Post-Dose in the MDS-UPDRS Part III Score at MV4 - Week 12
Description	The Motor Function section (Part III) of the MDS-UPDRS was administered by the Investigator, and 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 mean change in the MDS-UPDRS Part III score from pre-dose to 15 minutes post-dose at MV4 is presented. A negative change indicates an improvement.
Time Frame	At t=0 (just prior to dosing) and t=15 minutes at MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	55	54
Least Squares Mean (95% Confidence Interval) [units on a scale]	-3.0	-6.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Maintenance), APL-130277 (Maintenance)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -6.7 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Time From Dosing to When Study Medication Provided an Effect at MV4 - Week 12
Description	The time to effect at MV4 was described using the Kaplan-Meier method, including an estimate of the median time to effect and corresponding 95% confidence interval.
Time Frame	At MV4 (Week 12 of the Maintenance Treatment Phase).

Outcome Measure Data

Analysis Population Description

The mITT Population consisted of all patients who were randomized and received at least 1 post-randomization dose of study medication (APL-130277 or placebo). Patients were grouped according to the randomized treatment group. Only patients with data available for analysis at the time point are presented.

Arm/Group Title	Placebo (Maintenance)	APL-130277 (Maintenance)
Arm/Group Description	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.	Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
Measure Participants	55	54
Median (95% Confidence Interval) [Minutes]	NA	21.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (Maintenance), APL-130277 (Maintenance)
	Comments	Median Time to effect for APL-130277 versus placebo patients
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard ratio
	Estimated Value	3.4
	Confidence Interval	(2-Sided) 95%; 1.99 to 5.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Dose Titration Phase (21 days): all AEs that started on/after the first dose of APL-130277 but before the first dose of study medication during the Maintenance Treatment Phase. Maintenance Treatment Phase (12 weeks): all AEs that started on/after the first dose of study medication during the Maintenance Treatment Phase.
Adverse Event Reporting Description	All AEs were collected for each patient. Patients were queried in a non-leading manner, without specific prompting. Treatment emergent AEs are presented for the Dose Titration Phase (APl-130277 [titration]) and for the Maintenance Treatment Phase (APL-130277 [maintenance] and Placebo [maintenance]).
Arm/Group Title	APL-130277 (Titration)		Placebo (Maintenance)		APL-130277 (Maintenance)
Arm/Group Description	Patients were titrated to identify the efficacious and tolerable dose of APL-130277. On Titration Visit 1 (TV1), patients presented to the clinic in an 'OFF' state and received 10 mg APL-130277. Patients who responded to 10 mg APL-130277 with a full 'ON' response within 45 minutes of dosing, as assessed by the patient and Investigator, completed the Dose Titration Phase. If a complete 'ON' response was not achieved within 45 minutes of dosing, patients restarted their normal PD medication and returned to the clinic within 3 days for the next TV, to receive the next sequential dose of APL-130277 (15 mg at TV2, 20 mg at TV3, 25 mg at TV4, 30 mg at TV5 and 35 mg at TV6). Patients who achieved a full 'ON' response within 45 minutes at a given dose were randomized to the Maintenance Treatment Phase. Any patients who reached 35 mg at TV6 and did not exhibit a full 'ON' response were discontinued.		Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive placebo in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the matching placebo for the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.		Patients who completed the Dose Titration Phase and were randomized in a blinded manner (1:1 ratio) to receive APL-130277 in the 12-week double-blind Maintenance Treatment Phase. Patients self-administered the strength of treatment determined during the Dose Titration Phase in up to 5 'OFF' episodes per day for 12 weeks in the at-home portion of the study. Patients returned to the clinic in 4-week intervals for safety and efficacy assessments. Patients completed a dosing diary at home for 2 days prior to the scheduled visit.
All Cause Mortality
	APL-130277 (Titration)		Placebo (Maintenance)		APL-130277 (Maintenance)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/141 (0%)		0/55 (0%)		1/54 (1.9%)
Serious Adverse Events
	APL-130277 (Titration)		Placebo (Maintenance)		APL-130277 (Maintenance)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/141 (0.7%)		1/55 (1.8%)		2/54 (3.7%)
Cardiac disorders
Cardiac arrest	0/141 (0%)	0	0/55 (0%)	0	1/54 (1.9%)	1
Cardiac failure congestive	0/141 (0%)	0	0/55 (0%)	0	1/54 (1.9%)	1
Infections and infestations
Staphylococcal infection	1/141 (0.7%)	1	0/55 (0%)	0	0/54 (0%)	0
Metabolism and nutrition disorders
Hypokalaemia	0/141 (0%)	0	0/55 (0%)	0	1/54 (1.9%)	1
Nervous system disorders
Encephalopathy	0/141 (0%)	0	1/55 (1.8%)	1	0/54 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/141 (0%)	0	1/55 (1.8%)	1	0/54 (0%)	0
Other (Not Including Serious) Adverse Events
	APL-130277 (Titration)		Placebo (Maintenance)		APL-130277 (Maintenance)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/141 (42.6%)		12/55 (21.8%)		39/54 (72.2%)
Gastrointestinal disorders
Nausea	29/141 (20.6%)	40	2/55 (3.6%)	2	15/54 (27.8%)	18
Oral mucosalerythema	6/141 (4.3%)	13	2/55 (3.6%)	2	4/54 (7.4%)	4
Vomiting	6/141 (4.3%)	6	0/55 (0%)	0	4/54 (7.4%)	5
Dry mouth	2/141 (1.4%)	4	0/55 (0%)	0	3/54 (5.6%)	3
Diarrhoea	2/141 (1.4%)	2	1/55 (1.8%)	1	2/54 (3.7%)	2
Glossodynia	0/141 (0%)	0	0/55 (0%)	0	2/54 (3.7%)	2
Lip oedema	0/141 (0%)	0	0/55 (0%)	0	2/54 (3.7%)	2
Lip swelling	1/141 (0.7%)	1	0/55 (0%)	0	2/54 (3.7%)	2
Lip ulceration	2/141 (1.4%)	2	0/55 (0%)	0	2/54 (3.7%)	2
General disorders
Chills	8/141 (5.7%)	11	0/55 (0%)	0	2/54 (3.7%)	3
Fatigue	4/141 (2.8%)	4	0/55 (0%)	0	4/54 (7.4%)	5
Infections and infestations
Bronchitis	0/141 (0%)	0	1/55 (1.8%)	2	2/54 (3.7%)	2
Tooth infection	0/141 (0%)	0	2/55 (3.6%)	2	0/54 (0%)	0
Injury, poisoning and procedural complications
Fall	6/141 (4.3%)	6	1/55 (1.8%)	1	3/54 (5.6%)	3
Laceration	1/141 (0.7%)	1	0/55 (0%)	0	3/54 (5.6%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma	2/141 (1.4%)	2	0/55 (0%)	0	2/54 (3.7%)	4
Nervous system disorders
Somnolence	16/141 (11.3%)	28	1/55 (1.8%)	1	7/54 (13%)	11
Dizziness	16/141 (11.3%)	21	0/55 (0%)	0	5/54 (9.3%)	6
Headache	11/141 (7.8%)	16	0/55 (0%)	0	3/54 (5.6%)	3
Ageusia	0/141 (0%)	0	0/55 (0%)	0	2/54 (3.7%)	2
Psychiatric disorders
Anxiety	4/141 (2.8%)	5	1/55 (1.8%)	1	2/54 (3.7%)	2
Respiratory, thoracic and mediastinal disorders
Oropharyngeal swelling	0/141 (0%)	0	0/55 (0%)	0	2/54 (3.7%)	2
Yawning	17/141 (12.1%)	27	1/55 (1.8%)	1	2/54 (3.7%)	3
Rhinorrhoea	9/141 (6.4%)	16	0/55 (0%)	0	4/54 (7.4%)	5
Throat irritation	1/141 (0.7%)	1	0/55 (0%)	0	2/54 (3.7%)	2
Skin and subcutaneous tissue disorders
Hyperhidrosis	6/141 (4.3%)	9	2/55 (3.6%)	2	3/54 (5.6%)	3
Vascular disorders
Flushing	4/141 (2.8%)	7	0/55 (0%)	0	2/54 (3.7%)	2

Limitations/Caveats

[Not Specified]

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 multi-center publication; provided however if a multi-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.