Trial Outcomes & Findings for A Cardiac Safety Study of an Investigational Drug to See How if Affects the Heart in People With Parkinson's Disease Complicated by Motor Fluctuations "OFF" Episodes (NCT NCT03187301)

Last Updated: 2020-08-10

Results Overview

For the primary central tendency analysis, the changes from baseline (ΔQTcF) were compared between APL-130277 and placebo (ΔΔQTcF). Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 minutes (mins) and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. These average values were used in all change from baseline calculations.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

48 participants

Primary outcome timeframe

Baseline to 15, 30, 45, 60 mins and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits.

Results posted on

2020-08-10

Participant Flow

Patients with Parkinson's disease (PD) complicated by motor fluctuations ('OFF' episodes) were recruited in 13 study sites in Italy and the United States, starting April 2017. The study was completed in December 2017. Approval was obtained from the Enrollment Adjudication Committee and Sponsor prior to enrollment of each patient.

Dose Titration Phase: individual responses to single doses of APL 130277 were evaluated at 5 mg increments up to 40 mg and then 10 mg increments up to 60 mg until a full 'ON' was achieved. If tolerated, patients were titrated to a supratherapeutic dose (up to 60 mg) which was 1 or 2 levels above the initial dose producing an 'ON' response.

Participant milestones

Participant milestones
Measure	APL-130277, Then Placebo, Then Moxifloxacin Sequence 1: Participants first received APL-130277. After a 3-day washout period, they then received Placebo. After a 3-day washout period, they then received Moxifloxacin.	Placebo, Then Moxifloxacin, Then APL-130277 Sequence 2: Participants first received Placebo. After a 3-day washout period, they then received Moxifloxacin. After a 3-day washout period, they then received APL-130277.	Moxifloxacin, Then APL-130277, Then Placebo Sequence 3: Participants first received Moxifloxacin. After a 3-day washout period, they then received APL-130277. After a 3-day washout period, they then received Placebo.	Moxifloxacin, Then Placebo, Then APL-130277 Sequence 4: Participants first received Moxifloxacin. After a 3-day washout period, they then received Placebo. After a 3-day washout period, they then received APL-130277.	APL-130277, Then Moxifloxacin, Then Placebo Sequence 5: Participants first received APL-130277. After a 3-day washout period, they then received Moxifloxacin. After a 3-day washout period, they then received Placebo.	Placebo, Then APL-130277, Then Moxifloxacin Sequence 6: Participants first received Placebo. After a 3-day washout period, they then received APL-130277. After a 3-day washout period, they then received Moxifloxacin.	Sequence Not Assigned Sequence Not Assigned: Participants not randomized to a treatment sequence.
Titration Period STARTED	7	7	7	6	7	7	7
Titration Period COMPLETED	7	7	7	6	7	7	0
Titration Period NOT COMPLETED	0	0	0	0	0	0	7
Pre-Intervention STARTED	7	7	7	6	7	7	0
Pre-Intervention COMPLETED	6	7	7	6	7	7	0
Pre-Intervention NOT COMPLETED	1	0	0	0	0	0	0
First Intervention STARTED	6	7	7	6	7	7	0
First Intervention COMPLETED	6	7	7	6	7	7	0
First Intervention NOT COMPLETED	0	0	0	0	0	0	0
First Washout STARTED	6	7	7	6	7	7	0
First Washout COMPLETED	6	7	7	6	7	7	0
First Washout NOT COMPLETED	0	0	0	0	0	0	0
Second Intervention STARTED	6	7	7	6	7	7	0
Second Intervention COMPLETED	6	7	7	6	7	7	0
Second Intervention NOT COMPLETED	0	0	0	0	0	0	0
Second Washout STARTED	6	7	7	6	7	7	0
Second Washout COMPLETED	6	7	7	6	7	7	0
Second Washout NOT COMPLETED	0	0	0	0	0	0	0
Third Intervention STARTED	6	7	7	6	7	7	0
Third Intervention COMPLETED	6	7	7	6	7	7	0
Third Intervention NOT COMPLETED	0	0	0	0	0	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	APL-130277, Then Placebo, Then Moxifloxacin Sequence 1: Participants first received APL-130277. After a 3-day washout period, they then received Placebo. After a 3-day washout period, they then received Moxifloxacin.	Sequence Not Assigned Sequence Not Assigned: Participants not randomized to a treatment sequence.
Titration Period Adverse Event	0	5
Titration Period Withdrawal by Subject	0	1
Titration Period Exclusion Criteria Met	0	1
Pre-Intervention Withdrawal by Subject	1	0

Baseline Characteristics

A Cardiac Safety Study of an Investigational Drug to See How if Affects the Heart in People With Parkinson's Disease Complicated by Motor Fluctuations "OFF" Episodes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Overall (Cross-Over) n=40 Participants Patients who successfully completed the Dose Titration Phase of the study were randomized to 1 of 6 treatment sequences in the single-dose Randomized Crossover Assessment Phase. Following confirmation by both the Investigator and the patient that the patient was in the 'OFF' state, the patient was dosed according to the patient's random treatment assignment with 1. APL-130277 at the dose determined in the Dose Titration Phase; OR 2. Matched placebo APL-130277; OR 3. A single 400 mg dose of moxifloxacin. Patients were randomized in equal numbers to 6 possible sequences of the above 3 study treatments determined by a 3-way balanced crossover design. There was a 3-day washout period between treatment period dosing visits. Dosing of APL-130277 and placebo was double-blinded, and dosing of moxifloxacin was open-label.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	25 Participants n=5 Participants
Age, Categorical >=65 years	15 Participants n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants
Sex: Female, Male Male	26 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	14 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	26 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants
Race (NIH/OMB) White	37 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	24 participants n=5 Participants
Region of Enrollment Italy	16 participants n=5 Participants
Time Since Diagnosis of PD	8.30 years STANDARD_DEVIATION 4.322 • n=5 Participants
Presence of a Rest Tremor at the Time of Diagnosis yes	27 participants n=5 Participants
Presence of a Rest Tremor at the Time of Diagnosis no	13 participants n=5 Participants
Time Since Initiationof L-dopa Treatment	6.20 years STANDARD_DEVIATION 4.502 • n=5 Participants
Time Since Motor Fluctuations Started	5.05 years STANDARD_DEVIATION 3.811 • n=5 Participants
Type of "OFF" Episode Experienced Morning akinesia	6 participants n=5 Participants
Type of "OFF" Episode Experienced Wearing-off	31 participants n=5 Participants
Type of "OFF" Episode Experienced Sudden-off	1 participants n=5 Participants
Type of "OFF" Episode Experienced Dose failure	1 participants n=5 Participants
Type of "OFF" Episode Experienced Delayed "ON"	0 participants n=5 Participants
Type of "OFF" Episode Experienced Other	1 participants n=5 Participants
Number of "OFF" Episodes/Day zero	1 "OFF" Episodes/day n=5 Participants
Number of "OFF" Episodes/Day one	0 "OFF" Episodes/day n=5 Participants
Number of "OFF" Episodes/Day two	3 "OFF" Episodes/day n=5 Participants
Number of "OFF" Episodes/Day three	14 "OFF" Episodes/day n=5 Participants
Number of "OFF" Episodes/Day four	12 "OFF" Episodes/day n=5 Participants
Number of "OFF" Episodes/Day five	9 "OFF" Episodes/day n=5 Participants
Number of "OFF" Episodes/Day six	1 "OFF" Episodes/day n=5 Participants
Typical Length of "OFF" Episode	1.30 hours STANDARD_DEVIATION 0.915 • n=5 Participants
Total Daily L-Dopa Dose	620.5 mg STANDARD_DEVIATION 273.05 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline to 15, 30, 45, 60 mins and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits.

Population: The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase. Please Note: The pre-specified primary comparison was between APL-130277 and Placebo.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=40 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=40 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) 15 mins post-dose	0.2 msec Standard Error 1.98	-3.7 msec Standard Error 1.97	—	—	—	—
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) 30 mins post-dose	0.3 msec Standard Error 1.98	-2.7 msec Standard Error 1.97	—	—	—	—
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) 45 mins post-dose	0.0 msec Standard Error 1.98	-3.7 msec Standard Error 1.97	—	—	—	—
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) 60 mins post-dose	2.7 msec Standard Error 1.98	-3.5 msec Standard Error 1.97	—	—	—	—
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) 2 hours post-dose	1.8 msec Standard Error 1.98	-3.0 msec Standard Error 1.97	—	—	—	—
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) 3 hours post-dose	0.1 msec Standard Error 1.98	-1.6 msec Standard Error 1.98	—	—	—	—
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) 4 hours post-dose	-0.9 msec Standard Error 1.98	-0.2 msec Standard Error 1.98	—	—	—	—

PRIMARY outcome

Timeframe: Baseline to 60 mins and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits.

For the assay sensitivity analysis in support of the primary central tendency analysis, the changes from baseline (ΔQTcF) were compared between moxifloxacin (positive control) and placebo (ΔΔQTcF). Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 60 mins and 2, 3 and 4 hours post-dose for each of the 3 treatment period dosing visits in the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. These average values were used in all change from baseline calculations.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=40 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=40 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) 60 mins post-dose	6.5 msec Standard Error 1.98	-3.5 msec Standard Error 1.97	—	—	—	—
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) 2 hours post-dose	9.3 msec Standard Error 1.99	-3.0 msec Standard Error 1.97	—	—	—	—
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) 3 hours post-dose	9.3 msec Standard Error 1.98	-1.6 msec Standard Error 1.98	—	—	—	—
Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) 4 hours post-dose	8.8 msec Standard Error 1.98	-0.2 msec Standard Error 1.98	—	—	—	—

SECONDARY outcome

Timeframe: Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.

Population: The PK population included all patients with at least one PK evaluation. Only patients with data available for analysis are presented.

The maximum observed plasma concentration (Cmax) for apomorphine and apomorphine sulfate (metabolite) was determined in patients treated with APL-130277. Pharmacokinetic (PK) parameters were derived using a non-compartmental analysis method. Bioanalysis of apomorphine and apomorphine-sulfate plasma concentration were measured using a validated liquid chromatography-tandem mass spectrometry (LC/MS-MS) method. The calibration range was 0.0200 nanograms per milliliter (ng/mL) to 20.0 ng/mL apomorphine and 10.0 to 1000 ng/mL apomorphine sulfate (metabolite). PK assessments were performed at each period of the Randomized Crossover Assessment Phase (at P1V1, P2V2 and P3V3) and results are presented for each of the APL-130277 doses administered (as determined for each patient during the Dose Titration Phase).

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=14 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=4 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset n=15 Participants Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset n=2 Participants Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset n=3 Participants Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset n=1 Participants Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 Apomorphine	5.14 ng/mL Standard Deviation 3.28	6.57 ng/mL Standard Deviation 1.22	4.23 ng/mL Standard Deviation 2.81	4.16 ng/mL Standard Deviation 2.54	9.29 ng/mL Standard Deviation 9.97	4.61 ng/mL Standard Deviation NA only 1 subject analyzed- cmax was determined for one patient so calculation of standard deviation was not applicable
Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 Apomorphine sulfate	220 ng/mL Standard Deviation 77.4	319 ng/mL Standard Deviation 97.9	377 ng/mL Standard Deviation 82.0	446 ng/mL Standard Deviation 46.7	458 ng/mL Standard Deviation 12.7	1420 ng/mL Standard Deviation NA only 1 subject analyzed- cmax was determined for one patient so calculation of standard deviation was not applicable

SECONDARY outcome

Timeframe: Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.

Population: The PK population included all patients with at least one PK evaluation. Only patients with data available for analysis are presented.

The time of maximum observed plasma concentration (Tmax) for apomorphine and apomorphine sulfate (metabolite) was determined in patients treated with APL-130277. PK parameters were derived using a non-compartmental analysis method. Bioanalysis of apomorphine and apomorphine-sulfate plasma concentration were measured using a validated LC/MS-MS method. The calibration range was 0.0200 ng/mL to 20.0 ng/mL apomorphine and 10.0 to 1000 ng/mL apomorphine sulfate. PK assessments were performed at each period of the Randomized Crossover Assessment Phase (at P1V1, P2V2 and P3V3) and results are presented for each of the APL-130277 doses administered (as determined for each patient during the Dose Titration Phase).

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=14 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=4 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset n=15 Participants Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset n=2 Participants Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset n=3 Participants Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset n=1 Participants Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 Apomorphine	0.75 hours Interval 0.5 to 1.02	0.75 hours Interval 0.5 to 0.75	1.00 hours Interval 0.5 to 2.07	1.50 hours Interval 1.0 to 2.0	0.58 hours Interval 0.5 to 0.88	0.78 hours Tmax was determined for one patient so calculation of standard deviation was not applicable
Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 Apomorphne sulfate	2.00 hours Interval 1.0 to 4.0	1.52 hours Interval 0.75 to 2.17	2.00 hours Interval 0.5 to 2.07	1.50 hours Interval 1.0 to 2.0	2.13 hours Interval 1.0 to 4.08	0.52 hours Tmax was determined for one patient so calculation of standard deviation was not applicable

SECONDARY outcome

Timeframe: Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.

Population: The PK population included all patients with at least one PK evaluation. Only patients with data available for analysis are presented.

The area under the concentration-time curve from time of dosing to the last measurable point (AUClast) for apomorphine and apomorphine sulfate (metabolite) was determined in patients treated with APL-130277. PK parameters were derived using a non-compartmental analysis method. Bioanalysis of apomorphine and apomorphine-sulfate plasma concentration were measured using a validated LC/MS-MS method. The calibration range was 0.0200 ng/mL to 20.0 ng/mL apomorphine and 10.0 to 1000 ng/mL apomorphine sulfate. PK assessments were performed at each period of the Randomized Crossover Assessment Phase (at P1V1, P2V2 and P3V3) and results are presented for each of the APL-130277 doses administered (as determined for each patient during the Dose Titration Phase).

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=14 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=4 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset n=15 Participants Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset n=2 Participants Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset n=3 Participants Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset n=1 Participants Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 Apomorphine	7.70 h*ng/mL Standard Deviation 4.15	9.39 h*ng/mL Standard Deviation 3.31	7.55 h*ng/mL Standard Deviation 3.81	7.84 h*ng/mL Standard Deviation 0.975	12.1 h*ng/mL Standard Deviation 6.63	10.9 h*ng/mL Standard Deviation NA AUClast was determined for one patient so calculation of standard deviation was not applicable.
AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 Apomorphine sulfate	558 h*ng/mL Standard Deviation 161	734 h*ng/mL Standard Deviation 155	861 h*ng/mL Standard Deviation 147	870 h*ng/mL Standard Deviation 108	979 h*ng/mL Standard Deviation 127	1980 h*ng/mL Standard Deviation NA AUClast was determined for one patient so calculation of standard deviation was not applicable.

SECONDARY outcome

Timeframe: From first dose of study medication up to last study visit for Randomized Crossover Assessment Phase, approximately up to 2 weeks

Population: The Crossover Phase Safety Population consisted of all patients who were randomized and received at least one post-randomization dose of study medication (APL-130277, moxifloxacin or placebo) during the Randomized Crossover Assessment Phase.

AE definition: any untoward medical occurrence in a clinical trial participant. Serious AE definition: an AE that is fatal, life threatening, requires in-patient hospitalization or prolongation of existing hospitalization, results in permanent (persistent) disability/incapacity, is a congenital anomaly/birth defect or is an important medical event. Severity of AEs were classified as: mild: causes no limitation of usual activities, moderate: causes some limitation of usual activities; or severe: prevents or severely limits usual activities. The investigator assessed AEs for relatedness to study medication. TEAEs were defined as all AEs that started on or after the first dose of study medication (APL-130277, moxifloxacin or placebo). Results are presented for TEAEs during the Randomized Crossover Assessment Phase.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=40 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=40 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset n=40 Participants Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Number of Patients With Treatment-Emergent Adverse Events (TEAEs) Any TEAE	13 participants	6 participants	4 participants	—	—	—
Number of Patients With Treatment-Emergent Adverse Events (TEAEs) Drug-related TEAE	12 participants	2 participants	0 participants	—	—	—
Number of Patients With Treatment-Emergent Adverse Events (TEAEs) Severe TEAE	1 participants	0 participants	0 participants	—	—	—
Number of Patients With Treatment-Emergent Adverse Events (TEAEs) Serious TEAE	0 participants	0 participants	0 participants	—	—	—
Number of Patients With Treatment-Emergent Adverse Events (TEAEs) TEAE leading to death	0 participants	0 participants	0 participants	—	—	—

SECONDARY outcome

Timeframe: Baseline and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.

QTcB was defined as QT interval corrected with Bazett's method. QT was defined as time between start of Q wave and end of T wave. QTcB was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=40 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=40 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset n=40 Participants Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase 15 mins post-dose	2.7 msec Standard Error 2.24	-1.7 msec Standard Error 2.22	-2.5 msec Standard Error 2.23	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase 30 mins post-dose	1.9 msec Standard Error 2.24	-0.7 msec Standard Error 2.22	1.4 msec Standard Error 2.23	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase 45 mins post-dose	0.1 msec Standard Error 2.24	-3.2 msec Standard Error 2.22	7.8 msec Standard Error 2.23	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase 60 mins post-dose	-0.1 msec Standard Error 2.24	-3.3 msec Standard Error 2.22	8.4 msec Standard Error 2.23	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase 2 hours post-dose	4.7 msec Standard Error 2.24	-0.4 msec Standard Error 2.22	11.1 msec Standard Error 2.25	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase 3 hours post-dose	7.2 msec Standard Error 2.24	2.7 msec Standard Error 2.24	12.8 msec Standard Error 2.23	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase 4 hours post-dose	8.1 msec Standard Error 2.24	5.5 msec Standard Error 2.24	12.1 msec Standard Error 2.23	—	—	—

SECONDARY outcome

Timeframe: Baseline (pre-dose) and at 30, 60 and 90 minutes after dosing during the Dose Titration Phase.

Population: The Efficacy Population included all patients who had efficacy assessments at the lowest dose level resulting in a full 'ON' and at a higher dose level during the Dose Titration 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 squares mean change in the MDS-UPDRS Part III score from pre-dose to 30, 60 and 90 minutes post-dose during the Dose Titration Phase at the highest tolerated APL-130277 dose level (indicated as Day 2) and the lowest APL-130277 dose resulting in a full 'ON' (indicated as Day 1) are presented.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=35 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase 30 mins post-dose (day 1)	-21.1 units on a scale Standard Error 1.79	—	—	—	—	—
Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase 30 mins post-dose (day 2)	-26.7 units on a scale Standard Error 1.78	—	—	—	—	—
Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase 60 mins post-dose (day 1)	-26.3 units on a scale Standard Error 1.46	—	—	—	—	—
Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase 60 mins post-dose (day 2)	-31.3 units on a scale Standard Error 1.72	—	—	—	—	—
Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase 90 mins post-dose (day 1)	-25.2 units on a scale Standard Error 1.43	—	—	—	—	—
Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase 90 mins post-dose (day 2)	-28.9 units on a scale Standard Error 1.68	—	—	—	—	—

SECONDARY outcome

Timeframe: Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.

Population: The Efficacy Population included all patients who had efficacy assessments at the lowest dose level resulting in a full 'ON' and at a higher dose level during the Dose Titration Phase.

The time to 'ON' was calculated as minutes from the time when the patient received APL-130277 until the time the patient turned fully 'ON', as assessed by the Investigator. Data was censored at 90 minutes. The median time to a full 'ON' response during the Dose Titration Phase following the highest tolerated APL-130277 dose level (indicated as Day 2) and the lowest APL-130277 dose resulting in a full 'ON' (indicated as Day 1) are presented. The median time to 'ON' on Day 1 and Day 2 was calculated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=35 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Median Time to 'ON' During the Dose Titration Phase Day 1	30 minutes Interval 22.0 to 45.0	—	—	—	—	—
Median Time to 'ON' During the Dose Titration Phase Day 2	30 minutes Interval 22.0 to 60.0	—	—	—	—	—

SECONDARY outcome

Timeframe: Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.

Population: The Efficacy Population included all patients who had efficacy assessments at the lowest dose level resulting in a full 'ON' and at a higher dose level during the Dose Titration Phase.

The duration of 'ON' was calculated as minutes from the time when the patient turned fully 'ON' until the time when the patient turned 'OFF', as assessed by the Investigator. If the patient did not turn fully 'ON' within 90 minutes the duration of 'ON' was defined as zero minutes. If the patient turned fully 'ON' and did not turn 'OFF' by 90 minutes, the data was censored at 90 minutes minus the time when the patient turned fully 'ON'. The median duration of a full 'ON' response during the Dose Titration Phase following the highest tolerated APL-130277 dose level (indicated as Day 2) and the lowest APL-130277 dose resulting in a full 'ON' (indicated as Day 1) are presented. The median duration of 'ON' on Day 1 and Day 2 was calculated using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=35 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Median Duration of 'ON' During the Dose Titration Phase Day 1	NA minutess The median duration and inter-quartile range could not be estimated because approximately 90% of patients were censored (i.e. still 'ON' at last observation) on both days	—	—	—	—	—
Median Duration of 'ON' During the Dose Titration Phase Day 2	NA minutess The median duration and inter-quartile range could not be estimated because approximately 90% of patients were censored (i.e. still 'ON' at last observation) on both days	—	—	—	—	—

SECONDARY outcome

Timeframe: Baseline and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.

Heart rate was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=40 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=40 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset n=40 Participants Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase 4 hours post-dose	9.5 Beats per minute Standard Error 1.31	6.2 Beats per minute Standard Error 1.31	2.9 Beats per minute Standard Error 1.31	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase 15 mins post-dose	2.5 Beats per minute Standard Error 1.31	2.1 Beats per minute Standard Error 1.30	0.1 Beats per minute Standard Error 1.31	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase 30 mins post-dose	1.5 Beats per minute Standard Error 1.31	2.1 Beats per minute Standard Error 1.30	0.5 Beats per minute Standard Error 1.31	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase 45 mins post-dose	0.1 Beats per minute Standard Error 1.31	0.8 Beats per minute Standard Error 1.30	3.6 Beats per minute Standard Error 1.31	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase 60 mins post-dose	-3.0 Beats per minute Standard Error 1.31	0.1 Beats per minute Standard Error 1.30	1.8 Beats per minute Standard Error 1.31	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase 2 hours post-dose	3.3 Beats per minute Standard Error 1.31	2.8 Beats per minute Standard Error 1.30	1.5 Beats per minute Standard Error 1.32	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase 3 hours post-dose	7.6 Beats per minute Standard Error 1.31	4.6 Beats per minute Standard Error 1.31	3.3 Beats per minute Standard Error 1.31	—	—	—

SECONDARY outcome

Timeframe: Baseline (pre-dose P1V1) and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.

PR interval was defined as time from the onset of the P wave to the start of the QRS complex. PR interval was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=40 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=40 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset n=40 Participants Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase 15 mins post-dose	0.4 msec Standard Error 1.72	-1.9 msec Standard Error 1.71	-1.1 msec Standard Error 1.72	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase 30 mins post-dose	-1.6 msec Standard Error 1.73	-0.2 msec Standard Error 1.71	-0.2 msec Standard Error 1.72	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase 45 mins post-dose	1.2 msec Standard Error 1.72	0.1 msec Standard Error 1.71	-1.1 msec Standard Error 1.72	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase 60 mins post-dose	2.5 msec Standard Error 1.72	-0.3 msec Standard Error 1.71	1.5 msec Standard Error 1.72	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase 2 hours post-dose	-0.2 msec Standard Error 1.72	-1.7 msec Standard Error 1.71	-0.1 msec Standard Error 1.73	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase 3 hours post-dose	-1.5 msec Standard Error 1.73	-2.2 msec Standard Error 1.72	1.6 msec Standard Error 1.72	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase 4 hours post-dose	-3.7 msec Standard Error 1.73	-3.1 msec Standard Error 1.72	0.8 msec Standard Error 1.72	—	—	—

SECONDARY outcome

Timeframe: Baseline and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.

QRS interval was defined as the time of QRS complex (Q, R, and S waves). QRS interval was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=40 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=40 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset n=40 Participants Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase 15 mins post-dose	-0.7 msec Standard Error 0.94	-1.2 msec Standard Error 0.93	-0.7 msec Standard Error 0.94	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase 30 mins post-dose	-0.4 msec Standard Error 0.94	-0.9 msec Standard Error 0.93	-0.1 msec Standard Error 0.94	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase 45 mins post-dose	-1.2 msec Standard Error 0.94	-0.1 msec Standard Error 0.93	-0.9 msec Standard Error 0.94	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase 60 mins post-dose	-0.8 msec Standard Error 0.94	-1.4 msec Standard Error 0.93	-0.4 msec Standard Error 0.94	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase 2 hours post-dose	1.1 msec Standard Error 0.94	-1.3 msec Standard Error 0.93	-1.1 msec Standard Error 0.95	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase 3 hours post-dose	-0.2 msec Standard Error 0.94	-0.9 msec Standard Error 0.94	-1.0 msec Standard Error 0.94	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase 4 hours post-dose	0.5 msec Standard Error 0.94	-0.6 msec Standard Error 0.94	0.4 msec Standard Error 0.94	—	—	—

SECONDARY outcome

Timeframe: Baseline and at 15, 30, 45, 60 minutes and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.

Uncorrected QT interval was defined as time between start of Q wave and end of T wave. QT interval was determined during continuous 12-lead ECG (Holter) monitoring at each of the 3 treatment period dosing visits at pre-specified timepoints post-dose. Baseline was defined as the mean of the 9 ECGs (3 sets of triplicate ECGs) recorded at baseline (pre-dose P1V1). In case any of the 9 ECGs were missing, the baseline was defined as the mean of the available baseline values. The post-dose ECGs were evaluated at 15, 30, 45 and 60 mins and 2, 3 and 4 hours post-dose at each of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase. For each of the time points, an average value was calculated based on the 3 (or all available) ECGs. Results are presented for the mean change from baseline at each pre-specified post-dose timepoint.

Outcome measures

Outcome measures
Measure	APL-130277 (Cross-over) n=40 Participants Patients who received a single dose of APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Placebo (Cross-over) n=40 Participants Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	20 mg AP:-130277 PK Subset n=40 Participants Patients who received a single dose of 20 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	25 mg APL-130277 PK Subset Patients who received a single dose of 25 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	35 mg APL-130277 PK Subset Patients who received a single dose of 35 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	50 mg AP:-130277 PK Subset Patients who received a single dose of 50 mg APL-130277 (as determined in the Dose Titration Phase) in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase 15 mins post-dose	-3.9 msec Standard Error 3.05	-7.1 msec Standard Error 3.02	-2.7 msec Standard Error 3.04	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase 30 mins post-dose	-2.2 msec Standard Error 3.05	-6.1 msec Standard Error 3.02	-0.7 msec Standard Error 3.04	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase 45 mins post-dose	0.3 msec Standard Error 3.05	-4.2 msec Standard Error 3.02	-2.2 msec Standard Error 3.04	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase 60 mins post-dose	8.3 msec Standard Error 3.05	-3.5 msec Standard Error 3.02	3.5 msec Standard Error 3.04	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase 2 hours post-dose	-2.6 msec Standard Error 3.05	-7.6 msec Standard Error 3.02	6.2 msec Standard Error 3.07	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase 3 hours post-dose	-12.0 msec Standard Error 3.05	-8.9 msec Standard Error 3.04	3.0 msec Standard Error 3.04	—	—	—
ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase 4 hours post-dose	-16.4 msec Standard Error 3.05	-10.1 msec Standard Error 3.05	2.8 msec Standard Error 3.04	—	—	—

Adverse Events

APL-130277 (Titration)

Serious events: 0 serious events

Other events: 41 other events

Deaths: 0 deaths

APL-130277 (Cross-over)

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Placebo (Crossover)

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Moxifloxacin (Crossover)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

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