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

• Sponsor: Sunovion (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03187301
• Collaborator: (none)
• Enrollment: 48
• Locations: 15
• Arms: 3
• Actual Duration (Months): 4.6
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

A cardiac safety study of an investigational drug to see how it affects the heart in people with Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes)

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease; Off Episodes of Parkinson Disease	Drug: APL-130277; Drug: Placebo; Drug: Moxifloxacin	Phase 2

Detailed Description

This multi-center, Phase 2, Randomized, Double-Blind, Placebo Controlled, 3-Period Crossover, Positive Control study designed to evaluate the QT interval prolongation potential of 10 mg to 60 mg doses of APL-130277 compared to placebo and the positive control, 400mg moxifloxacin in subjects with Parkinson's Disease (PD) who experience motor fluctuations ("OFF" episodes) The patient is titrated to the highest tolerated dose from 10mg to 60mg, and then is randomized to one of six crossover sequences. Each sequence includes treatment with the following:

1. Treatment A: APL-130277 at the dose determined in the Dose Titration Phase,

2. Treatment B: Matched placebo,

3. Treatment C: A single 400 mg dose of moxifloxacin

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double blind period
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-Blind, Placebo Controlled, 3-Period Crossover, Positive Control, QT-Evaluation Study of APL-130277 in Subjects With Parkinson's Disease Complicated by Motor Fluctuations ("OFF" Episodes)
• Actual Study Start Date: Aug 3, 2017
• Actual Primary Completion Date: Dec 21, 2017
• Actual Study Completion Date: Dec 21, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: APL-130277 APL-130277 at the dose determined in the dose titration phase	Drug: APL-130277; APL-130277 single dose
Placebo Comparator: Placebo Placebo	Drug: Placebo; Placebo single dose
Active Comparator: moxifloxacin moxifloxacin at a single 400mg dose	Drug: Moxifloxacin; moxifloxacin 400mg single dose

Outcome Measures

Primary Outcome Measures

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

   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.

2. 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) [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.

Secondary Outcome Measures

1. Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 [Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.]

   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).

2. Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 [Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.]

   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).

3. AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 [Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.]

   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).

4. Number of Patients With Treatment-Emergent Adverse Events (TEAEs) [From first dose of study medication up to last study visit for Randomized Crossover Assessment Phase, approximately up to 2 weeks]

   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.

5. ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase [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.

6. 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 [Baseline (pre-dose) and at 30, 60 and 90 minutes after dosing 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.

7. Median Time to 'ON' During the Dose Titration Phase [Time of dosing up to 90 minutes post-dose 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.

8. Median Duration of 'ON' During the Dose Titration Phase [Time of dosing up to 90 minutes post-dose 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.

9. ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase [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.

10. ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase [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.

11. ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase [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.

12. ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase [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.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• 1. Male or female ≥ 18 years of age. 2) Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria (excluding the "more than one affected relative" criterion).

1. Clinically meaningful response to Levodopa (L-Dopa). Subjects with or without well defined "OFF" episodes, as determined by the Investigator will be allowed.

2. Receiving stable doses of L-Dopa/carbidopa (immediate or sustained release) administered at least 3 times per day OR Rytary™ administered 3 times per day, for at least 4 weeks before the initial Screening Visit (SV1). Subjects receiving L-Dopa/carbidopa 3 times a day must also be on stable treatment with adjunctive PD medication regimens. These regimens bust me maintained at a stable dose for at least 4 weeks prior to the initial Screening Visit (SV1) with the exception that MAO-B inhibitors must be maintained at a stable level for at least 8 weeks prior to the initial Screening Visit (SV1).

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

4. the subject must be able to have a drug withdrawal induced "OFF" episode.

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

6. Mini-Mental State Examination (MMSE) score > 21.

7. If female and of childbearing potential, must agree to use one of the following methods of birth control throughout the study and until at least 30 days after final drug administration:

• Oral contraceptive

• Contraceptive patch

• Barrier (diaphragm, sponge or condom) plus spermicidal preparations

• Intrauterine contraceptive system

• Levonorgestrel implant

• Medroxyprogesterone acetate contraceptive injection

• Complete abstinence from sexual intercourse;

• Hormonal vaginal contraceptive ring; or

• Surgical sterilization or partner sterile (must have documented proof).

10)Male subjects must be either surgically sterile, agree to be sexually abstinent or use a barrier method of birth control (e.g., condom) from first study drug administration until at least 30 days after final drug administration

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

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

13)Must be approved as a satisfactory candidate by the Enrollment Authorization Committee (EAC) and the Sponsor.

Exclusion Criteria:

1. Atypical or secondary parkinsonism

2. Nausea associated with the use of dopamine agonists that requires treatment with an antiemetic.

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

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

5. Contraindications to moxifloxacin or APOKYN®, or hypersensitivity to apomorphine hydrochloride or any macrolide antibiotic or any of the ingredients of APOKYN® (notably sodium metabisulfite).

6. Female who is pregnant or lactating.

7. Participation in a clinical trial within 30 days prior to the initial Screening Visit (SV1), with the exception of clinical studies related to APL-13077.

8. Receipt of any investigational (i.e., unapproved) medication within 30 days prior to the initial Screening Visit (SV1), with the exception of APL-13077.

9. Any selective 5HT3 antagonists (i.e., ondansetron, granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists (including Tigan [trimethobenzamide] and domperidone, but excluding quetiapine or clozapine) or dopamine depleting agents within 30 days prior to initial Screening Visit (SV1).

10. Drug or alcohol dependency in the past 12 months.

11. Subject has a history of malignancy within 5 years prior to SV1, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer. Pituitary tumors of any duration are excluded.

12. Documented abnormalities with ECGs including, arrhythmias, clinically meaningful interval irregularities, structural heart abnormalities ,myocardial infarction, presence or history of a pacemaker, or any abnormality of the ECG that in the opinion of the Investigator, would interfere with the ability to measure the QT interval, or correct the QT interval for heart rate.

13. Male subjects with a screening corrected QT interval using Fridericia's formula (QTcF) of ≥ 450 ms; female subjects with a screening QT interval ≥ 470 ms. Eligibility will be based on the core laboratory ECG interpretation report.

14. HR at screening < 45 bpm or > 100 bpm.

15. QRS duration at screening >120 ms

16. PR interval at screening >200 ms.

17. Subjects with a history of cataplexy, unexplained syncope or seizures.

18. Family history of sudden cardiac death.

19. Heart failure (NYHA Class II or greater) and/or a myocardial infarction.

20. Current use of any concomitant mediations that prolong the QT/QTc interval. Refer to https://crediblemeds.org for listing.

21. History of additional risk factors for TdP (i.e., heart failure, hypokalemia, family history of Long QT Syndrome).

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

23. Subject has a positive screening laboratory test result for human immunodeficiency virus (HIV).

24. Subject has a positive screening laboratory test result for hepatitis B surface antigen or hepatitis C antibodies and has liver function test results at screening above the ULN for the reference laboratory.

25. Major psychiatric disorder including, but not limited to, dementia, bipolar disorder, psychosis (including Parkinson's disease psychosis), or any disorder that, in the opinion of the Investigator, requires ongoing treatment that would make study participation unsafe or make treatment compliance difficult.

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

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

28. Current suicidal ideation within one year prior to the second Screening Visit (SV2) as evidenced by answering "yes" to Questions 4 or 5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating Scale (C-SSRS) or attempted suicide within the last 5 years.

29. Donation of blood plasma in the 30 days prior to first dosing.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Movement Disorders Center of Arizona	Scottsdale	Arizona	United States	85258
2	Clinical Trials, Inc.	Little Rock	Arkansas	United States	72205
3	The Parkinson's and Movement Disorder Institute	Fountain Valley	California	United States	92708
4	Parkinson's Disease and Movement Disorders Center of Boca Raton	Boca Raton	Florida	United States	33486
5	MD Clinical	Hallandale Beach	Florida	United States	33009
6	Bioclinica Reserach	Orlando	Florida	United States	32806
7	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
8	The NeuroMedical Center, PC	Baton Rouge	Louisiana	United States	70810
9	QUEST Research Institute	Farmington Hills	Michigan	United States	48334
10	Central Texas Neurology Consultants	Round Rock	Texas	United States	78681
11	Casa di Cura villa Margherita (Neurologia)	Arcugnano		Italy	36057
12	Centro Ricerche San Raffaele	Cassino		Italy	03043
13	Agine Research Center, University Foundahon Chica-Pescara, Behavioral Neurology and Movement Disorders Unit	Chieti		Italy
14	Neurologia, Policlinico Tor Vergata	Rome		Italy	00133
15	IRCCS San Raffaele Pisana,Clinical Trial Center	Rome		Italy	00163

Sponsors and Collaborators

• Sunovion

Investigators

• Study Chair: CNS Medical Director, Sunovion Pharmacetuicals Inc.

Study Documents (Full-Text)

• Study Protocol - Aug 28, 2017
• Statistical Analysis Plan - Dec 21, 2017

More Information

Publications

None provided.

• Responsible Party: Sunovion
• ClinicalTrials.gov Identifier: NCT03187301
• Other Study ID Numbers: CTH-201; 2016-001762-29
• First Posted: Jun 14, 2017
• Last Update Posted: Aug 10, 2020
• Last Verified: Jul 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Sunovion: Parkinson's Disease; Off episodes
• Additional relevant MeSH terms: Parkinson Disease; Moxifloxacin; Apomorphine

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	APL-130277, Then Placebo, Then Moxifloxacin	Placebo, Then Moxifloxacin, Then APL-130277	Moxifloxacin, Then APL-130277, Then Placebo	Moxifloxacin, Then Placebo, Then APL-130277	APL-130277, Then Moxifloxacin, Then Placebo	Placebo, Then APL-130277, Then Moxifloxacin	Sequence Not Assigned
Arm/Group Description	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 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.	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.	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.	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.	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: Participants not randomized to a treatment sequence.
Period Title: Titration Period
STARTED	7	7	7	6	7	7	7
COMPLETED	7	7	7	6	7	7	0
NOT COMPLETED	0	0	0	0	0	0	7
Period Title: Titration Period
STARTED	7	7	7	6	7	7	0
COMPLETED	6	7	7	6	7	7	0
NOT COMPLETED	1	0	0	0	0	0	0
Period Title: Titration Period
STARTED	6	7	7	6	7	7	0
COMPLETED	6	7	7	6	7	7	0
NOT COMPLETED	0	0	0	0	0	0	0
Period Title: Titration Period
STARTED	6	7	7	6	7	7	0
COMPLETED	6	7	7	6	7	7	0
NOT COMPLETED	0	0	0	0	0	0	0
Period Title: Titration Period
STARTED	6	7	7	6	7	7	0
COMPLETED	6	7	7	6	7	7	0
NOT COMPLETED	0	0	0	0	0	0	0
Period Title: Titration Period
STARTED	6	7	7	6	7	7	0
COMPLETED	6	7	7	6	7	7	0
NOT COMPLETED	0	0	0	0	0	0	0
Period Title: Titration Period
STARTED	6	7	7	6	7	7	0
COMPLETED	6	7	7	6	7	7	0
NOT COMPLETED	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Overall (Cross-Over)
Arm/Group Description	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 APL-130277 at the dose determined in the Dose Titration Phase; OR Matched placebo APL-130277; OR 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.
Overall Participants	40
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 62.5%
>=65 years	15 37.5%
Sex: Female, Male (Count of Participants)
Female	14 35%
Male	26 65%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 35%
Not Hispanic or Latino	26 65%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 7.5%
White	37 92.5%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	24 60%
Italy	16 40%
Time Since Diagnosis of PD (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.30 (4.322)
Presence of a Rest Tremor at the Time of Diagnosis (participants) [Number]
yes	27 67.5%
no	13 32.5%
Time Since Initiationof L-dopa Treatment (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	6.20 (4.502)
Time Since Motor Fluctuations Started (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	5.05 (3.811)
Type of "OFF" Episode Experienced (participants) [Number]
Morning akinesia	6 15%
Wearing-off	31 77.5%
Sudden-off	1 2.5%
Dose failure	1 2.5%
Delayed "ON"	0 0%
Other	1 2.5%
Number of "OFF" Episodes/Day ("OFF" Episodes/day) [Number]
zero	1
one	0
two	3
three	14
four	12
five	9
six	1
Typical Length of "OFF" Episode (hours) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [hours]	1.30 (0.915)
Total Daily L-Dopa Dose (mg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg]	620.5 (273.05)

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Cross-over)	Placebo (Cross-over)
Arm/Group Description	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.	Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.
Measure Participants	40	40
15 mins post-dose	0.2 (1.98)	-3.7 (1.97)
30 mins post-dose	0.3 (1.98)	-2.7 (1.97)
45 mins post-dose	0.0 (1.98)	-3.7 (1.97)
60 mins post-dose	2.7 (1.98)	-3.5 (1.97)
2 hours post-dose	1.8 (1.98)	-3.0 (1.97)
3 hours post-dose	0.1 (1.98)	-1.6 (1.98)
4 hours post-dose	-0.9 (1.98)	-0.2 (1.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	15 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The mixed model for repeated measurements (MMRM) included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% confidence intervals (CIs) for APL-130277 versus placebo fell below 10 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	4.0
	Confidence Interval	(2-Sided) 90%; 0.5 to 7.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.11
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	30 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean difference
	Estimated Value	3.0
	Confidence Interval	(2-Sided) 90%; -0.5 to 6.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.11
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	45 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	3.7
	Confidence Interval	(2-Sided) 90%; 0.2 to 7.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.11
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	60 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	6.2
	Confidence Interval	(2-Sided) 90%; 2.7 to 9.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.11
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	2 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	4.8
	Confidence Interval	(2-Sided) 90%; 1.3 to 8.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.11
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	3 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 90%; -1.7 to 5.3
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.12
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	4 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	For each post-dose time point, change from baseline (ΔQTcF) was compared between APL-130277 and placebo (ΔΔQTcF). The hypothesis of no clinical difference was accepted, if all upper limits of the two-sided 90% CIs for APL-130277 versus placebo fell below 10 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Sqaure (LS) Mean Difference
	Estimated Value	-0.7
	Confidence Interval	() 90%; -4.2 to 2.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.12
	Estimation Comments

2. Secondary Outcome

Title	Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277
Description	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).
Time Frame	Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	10 mg APL-130277 PK Subset	15mg AP:-130277 PK Subset	20 mg AP:-130277 PK Subset	25 mg APL-130277 PK Subset	35 mg APL-130277 PK Subset	50 mg AP:-130277 PK Subset
Arm/Group Description	Patients who received a single dose of 10 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.	Patients who received a single dose of 15 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.	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.	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.	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.	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.
Measure Participants	14	4	15	2	3	1
Apomorphine	5.14 (3.28)	6.57 (1.22)	4.23 (2.81)	4.16 (2.54)	9.29 (9.97)	4.61 (NA)
Apomorphine sulfate	220 (77.4)	319 (97.9)	377 (82.0)	446 (46.7)	458 (12.7)	1420 (NA)

3. Secondary Outcome

Title	Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277
Description	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).
Time Frame	Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	10 mg APL-130277 PK Subset	15 mg APL-130277 PK Subset	20 mg APL-130277 PK Subset	25 mg APL-130277 PK Subset	35 mg APL-130277 PK Subset	50 mg APL-130277 PK Subset
Arm/Group Description	Patients who received a single dose of 10 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.	Patients who received a single dose of 15 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.	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.	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.	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.	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.
Measure Participants	14	4	15	2	3	1
Apomorphine	0.75	0.75	1.00	1.50	0.58	0.78
Apomorphne sulfate	2.00	1.52	2.00	1.50	2.13	0.52

4. Secondary Outcome

Title	AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277
Description	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).
Time Frame	Blood samples for PK assessments were taken prior to dosing and at 0.5, 0.75, 1, 2, and 4 hours post-dose.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	10 mg APL-130277 PK Subset	15 mg APL-130277 PK Subset	20 mg APL-130277 PK Subset	25 mg APL-130277 PK Subset	35 mg APL-130277 PK Subset	50 mg APL-130277 PK Subset
Arm/Group Description	Patients who received a single dose of 10 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.	Patients who received a single dose of 15 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.	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.	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.	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.	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.
Measure Participants	14	4	15	2	3	1
Apomorphine	7.70 (4.15)	9.39 (3.31)	7.55 (3.81)	7.84 (0.975)	12.1 (6.63)	10.9 (NA)
Apomorphine sulfate	558 (161)	734 (155)	861 (147)	870 (108)	979 (127)	1980 (NA)

5. Secondary Outcome

Title	Number of Patients With Treatment-Emergent Adverse Events (TEAEs)
Description	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.
Time Frame	From first dose of study medication up to last study visit for Randomized Crossover Assessment Phase, approximately up to 2 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Cross-over)	Placebo (Crossover)	Moxifloxacin (Crossover)
Arm/Group Description	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.	Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	Patients who received a single dose of 400 mg moxifloxacin in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Measure Participants	40	40	40
Any TEAE	13 32.5%	6 NaN	4 NaN
Drug-related TEAE	12 30%	2 NaN	0 NaN
Severe TEAE	1 2.5%	0 NaN	0 NaN
Serious TEAE	0 0%	0 NaN	0 NaN
TEAE leading to death	0 0%	0 NaN	0 NaN

6. Secondary Outcome

Title	ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Cross-over)	Placebo (Crossover)	Moxifloxacin (Crossover)
Arm/Group Description	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.	Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	Patients who received a single dose of 400 mg moxifloxacin in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Measure Participants	40	40	40
15 mins post-dose	2.7 (2.24)	-1.7 (2.22)	-2.5 (2.23)
30 mins post-dose	1.9 (2.24)	-0.7 (2.22)	1.4 (2.23)
45 mins post-dose	0.1 (2.24)	-3.2 (2.22)	7.8 (2.23)
60 mins post-dose	-0.1 (2.24)	-3.3 (2.22)	8.4 (2.23)
2 hours post-dose	4.7 (2.24)	-0.4 (2.22)	11.1 (2.25)
3 hours post-dose	7.2 (2.24)	2.7 (2.24)	12.8 (2.23)
4 hours post-dose	8.1 (2.24)	5.5 (2.24)	12.1 (2.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	15 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	4.4
	Confidence Interval	(2-Sided) 90%; 0.3 to 8.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.54
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	30 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 90%; -1.6 to 6.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.54
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	45 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	3.2
	Confidence Interval	(2-Sided) 90%; -0.9 to 7.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.54
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	60 mins post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	3.3
	Confidence Interval	(2-Sided) 90%; -0.9 to 7.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.54
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	2 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	5.0
	Confidence Interval	(2-Sided) 90%; 0.8 to 9.2
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.54
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	3 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	4.6
	Confidence Interval	(2-Sided) 90%; 0.4 to 8.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.55
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	4 hours post-dose: time-matched, baseline-corrected comparison between APL-130277 and placebo using the ΔΔQTcB approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcB as a covariate. The patient nested within sequence was included as a random effect
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Differeence
	Estimated Value	2.6
	Confidence Interval	(2-Sided) 90%; -1.6 to 6.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.56
	Estimation Comments

7. Secondary Outcome

Title	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
Description	The Motor Function section (Part III) of the MDS-UPDRS was administered by the Investigator, and included 33 scores based on 18-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range was from 0 to 132, with a lower score indicating better motor function and a higher score indicating more severe motor symptoms. The least 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.
Time Frame	Baseline (pre-dose) and at 30, 60 and 90 minutes after dosing during the Dose Titration Phase.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Titration)
Arm/Group Description	Patients were titrated to an effective and tolerable dose of APL-130277. Patients were dosed with increasing doses of APL 130277 starting with 10 mg at TV 1 up to a maximum of 60 mg. Patients who did not achieve a complete and full 'ON' response with the 10 mg APL 130277 dose at TV1 restarted their normal PD medications and were asked to return to the clinic the next business day for TV2, to assess the next highest dose. The evaluation continued sequentially with 15 mg (TV2), 20 mg (TV3), 25 mg (TV4), 30 mg (TV5), 35 mg (TV6), 40 mg (TV7), 50 mg (TV8), and 60 mg (TV9) doses of APL-130277 until a full 'ON' state 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. If the patient was unable to tolerate 1 or either of the 2 additional dose levels after reaching a full "ON" state patients were randomized to the previous tolerable dose.
Measure Participants	35
30 mins post-dose (day 1)	-21.1 (1.79)
30 mins post-dose (day 2)	-26.7 (1.78)
60 mins post-dose (day 1)	-26.3 (1.46)
60 mins post-dose (day 2)	-31.3 (1.72)
90 mins post-dose (day 1)	-25.2 (1.43)
90 mins post-dose (day 2)	-28.9 (1.68)

8. Secondary Outcome

Title	Median Time to 'ON' During the Dose Titration Phase
Description	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.
Time Frame	Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Titration)
Arm/Group Description	Patients were titrated to an effective and tolerable dose of APL-130277. Patients were dosed with increasing doses of APL 130277 starting with 10 mg at TV 1 up to a maximum of 60 mg. Patients who did not achieve a complete and full 'ON' response with the 10 mg APL 130277 dose at TV1 restarted their normal PD medications and were asked to return to the clinic the next business day for TV2, to assess the next highest dose. The evaluation continued sequentially with 15 mg (TV2), 20 mg (TV3), 25 mg (TV4), 30 mg (TV5), 35 mg (TV6), 40 mg (TV7), 50 mg (TV8), and 60 mg (TV9) doses of APL-130277 until a full 'ON' state 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. If the patient was unable to tolerate 1 or either of the 2 additional dose levels after reaching a full "ON" state patients were randomized to the previous tolerable dose.
Measure Participants	35
Day 1	30
Day 2	30

9. Secondary Outcome

Title	Median Duration of 'ON' During the Dose Titration Phase
Description	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.
Time Frame	Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Titration)
Arm/Group Description	Patients were titrated to an effective and tolerable dose of APL-130277. Patients were dosed with increasing doses of APL 130277 starting with 10 mg at TV 1 up to a maximum of 60 mg. Patients who did not achieve a complete and full 'ON' response with the 10 mg APL 130277 dose at TV1 restarted their normal PD medications and were asked to return to the clinic the next business day for TV2, to assess the next highest dose. The evaluation continued sequentially with 15 mg (TV2), 20 mg (TV3), 25 mg (TV4), 30 mg (TV5), 35 mg (TV6), 40 mg (TV7), 50 mg (TV8), and 60 mg (TV9) doses of APL-130277 until a full 'ON' state 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. If the patient was unable to tolerate 1 or either of the 2 additional dose levels after reaching a full "ON" state patients were randomized to the previous tolerable dose.
Measure Participants	35
Day 1	NA
Day 2	NA

10. Primary Outcome

Title	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)
Description	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.
Time Frame	Baseline to 60 mins and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Moxifloxacin (Crossover)	Placebo (Cross-over)
Arm/Group Description	Patients who received a single dose of 400 mg moxifloxacin in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.
Measure Participants	40	40
60 mins post-dose	6.5 (1.98)	-3.5 (1.97)
2 hours post-dose	9.3 (1.99)	-3.0 (1.97)
3 hours post-dose	9.3 (1.98)	-1.6 (1.98)
4 hours post-dose	8.8 (1.98)	-0.2 (1.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	60 mins post-dose: time-matched, baseline-corrected comparison between moxifloxacin and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	The hypothesis of assay sensitivity(difference in QTcF time between moxifloxacin and placebo)was evaluated by observing if any of the 4 post-dose evaluation time points had a one-sided(Bonferroni-corrected)95% lower confidence limit which was equal to, or exceeded, 5 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	10.0
	Confidence Interval	(2-Sided) 90%; 5.3 to 14.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.11
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	2 hours post-dose: time-matched, baseline-corrected comparison between moxifloxacin and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	The hypothesis of assay sensitivity(difference in QTcF time between moxifloxacin and placebo)was evaluated by observing if any of the 4 post-dose evaluation time points had a one-sided(Bonferroni-corrected)95% lower confidence limit which was equal to, or exceeded, 5 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	12.3
	Confidence Interval	(2-Sided) 90%; 7.5 to 17.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.12
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	3 hours post-dose: time-matched, baseline-corrected comparison between moxifloxacin and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	The hypothesis of assay sensitivity(difference in QTcF time between moxifloxacin and placebo)was evaluated by observing if any of the 4 post-dose evaluation time points had a one-sided(Bonferroni-corrected)95% lower confidence limit which was equal to, or exceeded, 5 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	10.9
	Confidence Interval	(2-Sided) 90%; 6.1 to 15.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.12
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	APL-130277 (Cross-over), Placebo (Cross-over)
	Comments	4 hours post-dose: time-matched, baseline-corrected comparison between moxifloxacin and placebo using the ΔΔQTcF approach. The MMRM included region, gender, planned sequence, period, treatment, time, and interaction between treatment and time as fixed factors, and baseline QTcF as a covariate. The patient nested within sequence was included as a random effect.
	Type of Statistical Test	Non-Inferiority
	Comments	The hypothesis of assay sensitivity(difference in QTcF time between moxifloxacin and placebo)was evaluated by observing if any of the 4 post-dose evaluation time points had a one-sided(Bonferroni-corrected)95% lower confidence limit which was equal to, or exceeded, 5 msec.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean Difference
	Estimated Value	9.0
	Confidence Interval	(2-Sided) 90%; 4.2 to 13.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.12
	Estimation Comments

11. Secondary Outcome

Title	ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Cross-over)	Placebo (Cross-over)	Moxifloxacin (Crossover)
Arm/Group Description	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.	Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Patients who received a single dose of 400 mg moxifloxacin in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Measure Participants	40	40	40
15 mins post-dose	2.5 (1.31)	2.1 (1.30)	0.1 (1.31)
30 mins post-dose	1.5 (1.31)	2.1 (1.30)	0.5 (1.31)
45 mins post-dose	0.1 (1.31)	0.8 (1.30)	3.6 (1.31)
60 mins post-dose	-3.0 (1.31)	0.1 (1.30)	1.8 (1.31)
2 hours post-dose	3.3 (1.31)	2.8 (1.30)	1.5 (1.32)
3 hours post-dose	7.6 (1.31)	4.6 (1.31)	3.3 (1.31)
4 hours post-dose	9.5 (1.31)	6.2 (1.31)	2.9 (1.31)

12. Secondary Outcome

Title	ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Cross-over)	Placebo (Cross-over)	Moxifloxacin (Crossover)
Arm/Group Description	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.	Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Patients who received a single dose of 400 mg moxifloxacin in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Measure Participants	40	40	40
15 mins post-dose	0.4 (1.72)	-1.9 (1.71)	-1.1 (1.72)
30 mins post-dose	-1.6 (1.73)	-0.2 (1.71)	-0.2 (1.72)
45 mins post-dose	1.2 (1.72)	0.1 (1.71)	-1.1 (1.72)
60 mins post-dose	2.5 (1.72)	-0.3 (1.71)	1.5 (1.72)
2 hours post-dose	-0.2 (1.72)	-1.7 (1.71)	-0.1 (1.73)
3 hours post-dose	-1.5 (1.73)	-2.2 (1.72)	1.6 (1.72)
4 hours post-dose	-3.7 (1.73)	-3.1 (1.72)	0.8 (1.72)

13. Secondary Outcome

Title	ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Cross-over)	Placebo (Cross-over)	Moxifloxacin (Crossover)
Arm/Group Description	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.	Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Patients who received a single dose of 400 mg moxifloxacin in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Measure Participants	40	40	40
15 mins post-dose	-0.7 (0.94)	-1.2 (0.93)	-0.7 (0.94)
30 mins post-dose	-0.4 (0.94)	-0.9 (0.93)	-0.1 (0.94)
45 mins post-dose	-1.2 (0.94)	-0.1 (0.93)	-0.9 (0.94)
60 mins post-dose	-0.8 (0.94)	-1.4 (0.93)	-0.4 (0.94)
2 hours post-dose	1.1 (0.94)	-1.3 (0.93)	-1.1 (0.95)
3 hours post-dose	-0.2 (0.94)	-0.9 (0.94)	-1.0 (0.94)
4 hours post-dose	0.5 (0.94)	-0.6 (0.94)	0.4 (0.94)

14. Secondary Outcome

Title	ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase
Description	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.
Time Frame	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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	APL-130277 (Cross-over)	Placebo (Cross-over)	Moxifloxacin (Crossover)
Arm/Group Description	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.	Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Assessment Crossover Phase.	Patients who received a single dose of 400 mg moxifloxacin in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
Measure Participants	40	40	40
15 mins post-dose	-3.9 (3.05)	-7.1 (3.02)	-2.7 (3.04)
30 mins post-dose	-2.2 (3.05)	-6.1 (3.02)	-0.7 (3.04)
45 mins post-dose	0.3 (3.05)	-4.2 (3.02)	-2.2 (3.04)
60 mins post-dose	8.3 (3.05)	-3.5 (3.02)	3.5 (3.04)
2 hours post-dose	-2.6 (3.05)	-7.6 (3.02)	6.2 (3.07)
3 hours post-dose	-12.0 (3.05)	-8.9 (3.04)	3.0 (3.04)
4 hours post-dose	-16.4 (3.05)	-10.1 (3.05)	2.8 (3.04)

Adverse Events

Time Frame	Dose Titration Phase (up to 28 days): all AEs that started on/after the first dose of APL-130277 but before the first dose of study medication during the Randomized Crossover Assessment Phase. Randomized Crossover Assessment Phase (up to 18 days): all AEs that started on/after the first dose of study medication during the Crossover Phase up to end of study.
Adverse Event Reporting Description	All AEs were collected for each patient. Patients were queried in a non-leading manner, without specific prompting. TEAEs are presented for the Dose Titration Phase (APl-130277 [titration]) and for the Randomized Crossover Assessment Phase (APL-130277 [crossover], Placebo [crossover] and Moxifloxacin [crossover]).
Arm/Group Title	APL-130277 (Titration)		APL-130277 (Cross-over)		Placebo (Crossover)		Moxifloxacin (Crossover)
Arm/Group Description	Patients were titrated to an effective and tolerable dose of APL-130277. Patients were dosed with increasing doses of APL 130277 starting with 10 mg at TV 1 up to a maximum of 60 mg. Patients who did not achieve a complete and full 'ON' response with the 10 mg APL 130277 dose at TV1 restarted their normal PD medications and were asked to return to the clinic the next business day for TV2, to assess the next highest dose. The evaluation continued sequentially with 15 mg (TV2), 20 mg (TV3), 25 mg (TV4), 30 mg (TV5), 35 mg (TV6), 40 mg (TV7), 50 mg (TV8), and 60 mg (TV9) doses of APL-130277 until a full 'ON' state 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. If the patient was unable to tolerate 1 or either of the 2 additional dose levels after reaching a full "ON" state patients were randomized to the previous tolerable dose.		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 APL-130277 at the dose determined in the Dose Titration Phase; OR Matched placebo APL-130277; OR 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.		Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.		Patients who received a single dose of 400 mg moxifloxacin in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.
All Cause Mortality
	APL-130277 (Titration)		APL-130277 (Cross-over)		Placebo (Crossover)		Moxifloxacin (Crossover)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/48 (0%)		0/40 (0%)		0/40 (0%)		0/40 (0%)
Serious Adverse Events
	APL-130277 (Titration)		APL-130277 (Cross-over)		Placebo (Crossover)		Moxifloxacin (Crossover)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/48 (0%)		0/40 (0%)		0/40 (0%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	APL-130277 (Titration)		APL-130277 (Cross-over)		Placebo (Crossover)		Moxifloxacin (Crossover)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/48 (85.4%)		13/40 (32.5%)		6/40 (15%)		4/40 (10%)
Cardiac disorders
Bundle branch block left	0/48 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Nodal arrhythmia	0/48 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Bundle branch block right	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Ear and labyrinth disorders
Vertigo	2/48 (4.2%)	2	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Eye disorders
blepharospasm	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Gastrointestinal disorders
Nausea	27/48 (56.3%)	35	4/40 (10%)	4	0/40 (0%)	0	0/40 (0%)	0
Vomiting	9/48 (18.8%)	9	2/40 (5%)	2	0/40 (0%)	0	0/40 (0%)	0
Diarrhoea	0/48 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Eructation	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Gastrooesophageal reflux disease	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Glossodynia	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
General disorders
Chills	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Malaise	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Infections and infestations
Infected cyst	0/48 (0%)	0	0/40 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0
Urinary tract infection	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Injury, poisoning and procedural complications
Contusion	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Fall	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Investigations
Blood pressure systolic decreased	2/48 (4.2%)	2	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Electrocardiogram QT prolonged	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Weight descreased	0/48 (0%)	0	0/40 (0%)	0	0/40 (0%)	0	1/40 (2.5%)	1
Musculoskeletal and connective tissue disorders
Neck pain	0/48 (0%)	0	0/40 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0
Nervous system disorders
Somnolence	12/48 (25%)	20	6/40 (15%)	6	2/40 (5%)	2	1/40 (2.5%)	1
Dizziness	8/48 (16.7%)	8	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Dyskinesia	2/48 (4.2%)	2	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Headache	3/48 (6.3%)	3	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Tremor	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Sinus headache	0/48 (0%)	0	0/40 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0
Psychiatric disorders
Agitation	0/48 (0%)	0	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Reproductive system and breast disorders
Spontaneous penile erection	1/48 (2.1%)	2	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Respiratory, thoracic and mediastinal disorders
Yawning	2/48 (4.2%)	3	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Skin and subcutaneous tissue disorders
Hyperhidrosis	7/48 (14.6%)	7	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Vascular disorders
Hypotension	4/48 (8.3%)	5	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Hypertension	0/48 (0%)	0	0/40 (0%)	0	2/40 (5%)	2	0/40 (0%)	0
Hot Flush	1/48 (2.1%)	1	1/40 (2.5%)	1	0/40 (0%)	0	0/40 (0%)	0
Orthostatic hypertension	1/48 (2.1%)	1	0/40 (0%)	0	0/40 (0%)	0	0/40 (0%)	0
Orthostatic hypotension	2/48 (4.2%)	5	1/40 (2.5%)	2	0/40 (0%)	0	2/40 (5%)	3

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

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