Trial Outcomes & Findings for Efficacy, Safety and Tolerability Study of APL-130277 for the Acute Treatment of OFF Episodes in Patients With Parkinson's Disease (NCT NCT02469090)

Last Updated: 2020-07-30

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

141 participants

Primary outcome timeframe

At t=0 (just prior to dosing) and t=30 minutes at MV4 (Week 12 of the Maintenance Treatment Phase).

Results posted on

2020-07-30

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	APL-130277 (Titration) 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.	Placebo (Maintnance) 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.	APL-130277 (Maintenance) 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 1: Dose Titration Phase STARTED	141	0	0
Period 1: Dose Titration Phase COMPLETED	109	0	0
Period 1: Dose Titration Phase NOT COMPLETED	32	0	0
Period 2: Maintenance Treatment Phase STARTED	0	55	54
Period 2: Maintenance Treatment Phase COMPLETED	0	46	34
Period 2: Maintenance Treatment Phase NOT COMPLETED	0	9	20

Reasons for withdrawal

Reasons for withdrawal
Measure	APL-130277 (Titration) 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.	Placebo (Maintnance) 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.	APL-130277 (Maintenance) 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 1: Dose Titration Phase Adverse Event	12	0	0
Period 1: Dose Titration Phase Withdrawal by Subject	8	0	0
Period 1: Dose Titration Phase Lost to Follow-up	1	0	0
Period 1: Dose Titration Phase Lack of Efficacy	11	0	0
Period 2: Maintenance Treatment Phase Adverse Event	0	5	15
Period 2: Maintenance Treatment Phase Withdrawal by Subject	0	3	4
Period 2: Maintenance Treatment Phase Lack of Efficacy	0	1	0
Period 2: Maintenance Treatment Phase Death	0	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Mainenance) n=54 Participants 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 n=109 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Age, Categorical Between 18 and 65 years	34 Participants n=99 Participants	30 Participants n=107 Participants	64 Participants n=206 Participants
Age, Categorical >=65 years	21 Participants n=99 Participants	24 Participants n=107 Participants	45 Participants n=206 Participants
Sex: Female, Male Female	24 Participants n=99 Participants	17 Participants n=107 Participants	41 Participants n=206 Participants
Sex: Female, Male Male	31 Participants n=99 Participants	37 Participants n=107 Participants	68 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=99 Participants	3 Participants n=107 Participants	6 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	52 Participants n=99 Participants	51 Participants n=107 Participants	103 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	1 Participants n=99 Participants	4 Participants n=107 Participants	5 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) Black or African American	2 Participants n=99 Participants	0 Participants n=107 Participants	2 Participants n=206 Participants
Race (NIH/OMB) White	51 Participants n=99 Participants	50 Participants n=107 Participants	101 Participants n=206 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Region of Enrollment United States	55 Participants n=99 Participants	53 Participants n=107 Participants	108 Participants n=206 Participants
Region of Enrollment Canada	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Time Since Diagnosis of PD	9.3 years STANDARD_DEVIATION 3.84 • n=99 Participants	8.7 years STANDARD_DEVIATION 4.25 • n=107 Participants	9.0 years STANDARD_DEVIATION 4.04 • n=206 Participants
Time Since Motor Fluctuations Started	4.54 years STANDARD_DEVIATION 3.780 • n=99 Participants	4.69 years STANDARD_DEVIATION 3.916 • n=107 Participants	4.61 years STANDARD_DEVIATION 3.831 • n=206 Participants
Type of 'OFF' episodes experienced Morning akinesia	44 participants n=99 Participants	46 participants n=107 Participants	90 participants n=206 Participants
Type of 'OFF' episodes experienced Wearing "OFF"	54 participants n=99 Participants	54 participants n=107 Participants	108 participants n=206 Participants
Type of 'OFF' episodes experienced Delayed "ON"	43 participants n=99 Participants	29 participants n=107 Participants	72 participants n=206 Participants
Type of 'OFF' episodes experienced Dose Failure	23 participants n=99 Participants	22 participants n=107 Participants	45 participants n=206 Participants
Type of 'OFF' episodes experienced Sudden :OFF"	32 participants n=99 Participants	26 participants n=107 Participants	58 participants n=206 Participants
Number of 'OFF' Episodes Typically Experienced Per Day	3.8 "OFF" episodes/day STANDARD_DEVIATION 1.40 • n=99 Participants	3.9 "OFF" episodes/day STANDARD_DEVIATION 1.17 • n=107 Participants	3.9 "OFF" episodes/day STANDARD_DEVIATION 1.29 • n=206 Participants
Length of 'OFF' Episodes	66.1 Minutes STANDARD_DEVIATION 30.09 • n=99 Participants	63.7 Minutes STANDARD_DEVIATION 31.91 • n=107 Participants	64.9 Minutes STANDARD_DEVIATION 30.89 • n=206 Participants
ON' State Modified Hoehn and Yahr Score Hoehn and Yahr Score = 0	0 participants n=99 Participants	0 participants n=107 Participants	0 participants n=206 Participants
ON' State Modified Hoehn and Yahr Score Hoehn and Yahr Score = 1	1 participants n=99 Participants	0 participants n=107 Participants	1 participants n=206 Participants
ON' State Modified Hoehn and Yahr Score Hoehn and Yahr Score = 1.5	0 participants n=99 Participants	0 participants n=107 Participants	0 participants n=206 Participants
ON' State Modified Hoehn and Yahr Score Hoehn and Yahr Score = 2	38 participants n=99 Participants	41 participants n=107 Participants	79 participants n=206 Participants
ON' State Modified Hoehn and Yahr Score Hoehn and Yahr Score = 2.5	4 participants n=99 Participants	8 participants n=107 Participants	12 participants n=206 Participants
ON' State Modified Hoehn and Yahr Score Hoehn and Yahr Score = 3	11 participants n=99 Participants	5 participants n=107 Participants	16 participants n=206 Participants
ON' State Modified Hoehn and Yahr Score Hoehn and Yahr Score = 4	0 participants n=99 Participants	0 participants n=107 Participants	0 participants n=206 Participants
ON' State Modified Hoehn and Yahr Score Hoehn and Yahr Score = 5	0 participants n=99 Participants	0 participants n=107 Participants	0 participants n=206 Participants
ON' State Modified Hoehn and Yahr Score Missing	1 participants n=99 Participants	0 participants n=107 Participants	1 participants n=206 Participants
Total Daily L-Dopa Dose	1007.73 mg STANDARD_DEVIATION 562.323 • n=99 Participants	1058.70 mg STANDARD_DEVIATION 563.301 • n=107 Participants	1032.98 mg STANDARD_DEVIATION 560.781 • n=206 Participants

PRIMARY outcome

Timeframe: At t=0 (just prior to dosing) and t=30 minutes at MV4 (Week 12 of the Maintenance Treatment Phase).

Population: 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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Maintenance) n=54 Participants 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.
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	-3.5 Units on a scale Standard Error 1.29	-11.1 Units on a scale Standard Error 1.46

SECONDARY outcome

Timeframe: At t=30 minutes at MV4 (Week 12 of the Maintenance Treatment Phase).

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Maintenance) n=54 Participants 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.
Percentage of Patients With a Patient-related Full 'ON' Response Within 30 Minutes at MV4 - Week 12: Predicted Response Rate	16 number of participants	35 number of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Maintenance) n=54 Participants 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.
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	14 number of participants	31 number of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Maintenance) n=54 Participants 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.
Patient Global Impression of Improvement (PGI-I): Percentage of Patients Who Improved at MV4 - Week 12	20.0 percentage of participants	37.0 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Maintenance) n=54 Participants 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.
Clinician Global Impression of Improvement (CGI-I): Percentage of Patients Who Improved at MV4 - Week 12	20.0 percentage of participants	40.7 percentage of participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=44 Participants 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.	APL-130277 (Maintenance) n=33 Participants 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.
Mean Change From Screening Visit to MV4 (Week 12) in MDS-UPDRS Part II: Motor Aspects of Experience of Daily Living	2.095 units on a scale Interval 0.749 to 3.44	0.995 units on a scale Interval -0.559 to 2.549

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Maintenance) n=54 Participants 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.
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	31.10 percentage of instnces Interval 19.25 to 42.95	78.70 percentage of instnces Interval 64.16 to 93.24

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Maintenance) n=54 Participants 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.
Mean Change From Screening Visit to MV4 in the Parkinson's Disease Quality of Life Questionnaire (PDQ-39) Summary Index Score	-1.671 units on a scale Interval -4.442 to 1.101	0.309 units on a scale Interval -2.748 to 3.366

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Maintenance) n=54 Participants 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.
Mean Change From Pre-Dose to 15 Minutes Post-Dose in the MDS-UPDRS Part III Score at MV4 - Week 12	-3.0 units on a scale Interval -5.1 to -0.8	-6.4 units on a scale Interval -8.8 to -4.0

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Placebo (Maintenance) n=55 Participants 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.	APL-130277 (Maintenance) n=54 Participants 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.
Time From Dosing to When Study Medication Provided an Effect at MV4 - Week 12	NA Minutes Interval 42.73 to Less than 40% of placebo patients were observed to have the event.	21.2 Minutes Interval 15.0 to 27.0

Adverse Events

APL-130277 (Titration)

Serious events: 1 serious events

Other events: 60 other events

Deaths: 0 deaths

Placebo (Maintenance)

Serious events: 1 serious events

Other events: 12 other events

Deaths: 0 deaths

APL-130277 (Maintenance)

Serious events: 2 serious events

Other events: 39 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	APL-130277 (Titration) n=141 participants at risk 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.	Placebo (Maintenance) n=55 participants at risk 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.	APL-130277 (Maintenance) n=54 participants at risk 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.
Infections and infestations Staphylococcal infection	0.71% 1/141 • Number of events 1 • 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. 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 \[maintenance\]).	0.00% 0/55 • 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. 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 \[maintenance\]).	0.00% 0/54 • 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. 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 \[maintenance\]).
Cardiac disorders Cardiac arrest	0.00% 0/141 • 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. 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 \[maintenance\]).	0.00% 0/55 • 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. 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 \[maintenance\]).	1.9% 1/54 • Number of events 1 • 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. 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 \[maintenance\]).
Cardiac disorders Cardiac failure congestive	0.00% 0/141 • 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. 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 \[maintenance\]).	0.00% 0/55 • 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. 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 \[maintenance\]).	1.9% 1/54 • Number of events 1 • 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. 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 \[maintenance\]).
Metabolism and nutrition disorders Hypokalaemia	0.00% 0/141 • 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. 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 \[maintenance\]).	0.00% 0/55 • 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. 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 \[maintenance\]).	1.9% 1/54 • Number of events 1 • 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. 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 \[maintenance\]).
Nervous system disorders Encephalopathy	0.00% 0/141 • 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. 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 \[maintenance\]).	1.8% 1/55 • Number of events 1 • 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. 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 \[maintenance\]).	0.00% 0/54 • 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. 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 \[maintenance\]).
Renal and urinary disorders Acute kidney injury	0.00% 0/141 • 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. 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 \[maintenance\]).	1.8% 1/55 • Number of events 1 • 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. 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 \[maintenance\]).	0.00% 0/54 • 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. 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 \[maintenance\]).

Other adverse events

Additional Information

CNS Medical Director

Sunovion Pharmaceuticals Inc.

Phone: 1-866-503-6351

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER