A Cardiac Safety Study of an Investigational Drug to See... | NCT03187301

ID	Type	Description	Link
2016-001762-29	EudraCT Number

Label	Type	Description	Intervention Names
APL-130277	Experimental	APL-130277 at the dose determined in the dose titration phase	Drug: APL-130277
Placebo	Placebo Comparator	Placebo	Drug: Placebo
moxifloxacin	Active Comparator	moxifloxacin at a single 400mg dose	Drug: Moxifloxacin

Name	Type	Description	Arm Group Labels	Other Names
APL-130277	Drug	APL-130277 single dose	APL-130277
Placebo

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

Measure	Description	Time Frame
Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277	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).

Eligibility Module

Eligibility Criteria

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).

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

4) 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).

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

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

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

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

9) 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:

Atypical or secondary parkinsonism
Nausea associated with the use of dopamine agonists that requires treatment with an antiemetic.
Previous treatment with any of the following: a neurosurgical procedure for PD; continuous subcutaneous (s.c.) apomorphine infusion; or Duodopa/Duopa.
Treatment with any form of s.c. apomorphine within 7 days prior to the initial Screening Visit (SV1). Subjects that stopped s.c. apomorphine for any reason other than systemic safety concerns or lack of efficacy may be considered.
Contraindications to moxifloxacin or APOKYN®, or hypersensitivity to apomorphine hydrochloride or any macrolide antibiotic or any of the ingredients of APOKYN® (notably sodium metabisulfite).
Female who is pregnant or lactating.
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.
Receipt of any investigational (i.e., unapproved) medication within 30 days prior to the initial Screening Visit (SV1), with the exception of APL-13077.
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).
Drug or alcohol dependency in the past 12 months.
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.
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.
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.
HR at screening < 45 bpm or > 100 bpm.
QRS duration at screening >120 ms
PR interval at screening >200 ms.
Subjects with a history of cataplexy, unexplained syncope or seizures.
Family history of sudden cardiac death.
Heart failure (NYHA Class II or greater) and/or a myocardial infarction.
Current use of any concomitant mediations that prolong the QT/QTc interval. Refer to https://crediblemeds.org for listing.
History of additional risk factors for TdP (i.e., heart failure, hypokalemia, family history of Long QT Syndrome).
Clinically significant medical, surgical, or laboratory abnormality in the opinion of the Investigator.
Subject has a positive screening laboratory test result for human immunodeficiency virus (HIV).
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.
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.
History of clinically significant impulse control disorder(s).
Dementia that precludes providing informed consent or would interfere with participation in the study.
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.
Donation of blood plasma in the 30 days prior to first dosing.

Name	Affiliation	Role
CNS Medical Director	Sunovion Pharmacetuicals Inc.	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Movement Disorders Center of Arizona		Scottsdale	Arizona	85258	United States
Clinical Trials, Inc.

PubMed Identifier	Type	Citation	Retractions
35899977	Derived	Stocchi F, Peckham EL, De Pandis MF, Sciarappa K, Kleiman R, Agbo F, Olanow CW, Blum D, Navia B. A Randomized Thorough QT Study of Apomorphine Sublingual Film in Patients With Parkinson's Disease. Clin Pharmacol Drug Dev. 2022 Sep;11(9):1068-1077. doi: 10.1002/cpdd.1147. Epub 2022 Jul 28.

ID	Title	Description
FG000	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.
FG001	Placebo, Then Moxifloxacin, Then APL-130277

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Aug 28, 2017	Jun 19, 2020

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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)

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.

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.

Posted

Least Squares Mean

Standard Error

msec

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

ID	Title	Description
OG000	APL-130277 (Cross-over)	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.
OG001	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.

Units	Counts
Participants	OG00040 OG00140

Title

Denominators

Categories

15 mins post-dose

Title	Measurements
	OG0000.2± 1.98 OG001-3.7± 1.97

30 mins post-dose

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.					Least Square (LS) Mean Difference	4.0	Standard Error of the Mean	2.11	2-Sided	90	0.5	7.4					Non-Inferiority	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.

Secondary

Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277

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).

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

Posted

Mean

Standard Deviation

ng/mL

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

ID	Title	Description
OG000	10 mg APL-130277 PK Subset	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.
OG001	15mg AP:-130277 PK Subset

Secondary

Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277

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).

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

Posted

Median

Full Range

hours

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

ID	Title	Description
OG000	10 mg APL-130277 PK Subset	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.
OG001	15 mg APL-130277 PK Subset	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.

Secondary

AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277

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).

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

Posted

Mean

Standard Deviation

h*ng/mL

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

ID	Title	Description
OG000	10 mg APL-130277 PK Subset	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.
OG001	15 mg APL-130277 PK Subset	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.

Secondary

Number of Patients With Treatment-Emergent Adverse Events (TEAEs)

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.

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.

Posted

Number

participants

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

ID	Title	Description
OG000	APL-130277 (Cross-over)	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.
OG001	Placebo (Crossover)

Secondary

ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During 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.

Posted

Least Squares Mean

Standard Error

msec

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.

ID	Title	Description
OG000	APL-130277 (Cross-over)	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.

Secondary

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

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.

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.

Posted

Least Squares Mean

Standard Error

units on a scale

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

ID	Title	Description
OG000	APL-130277 (Titration)	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.

Secondary

Median Time to 'ON' 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.

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.

Posted

Median

Inter-Quartile Range

minutes

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

ID	Title	Description
OG000	APL-130277 (Titration)	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.

Secondary

Median Duration of 'ON' 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.

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.

Posted

Median

Inter-Quartile Range

minutess

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

ID	Title	Description
OG000	APL-130277 (Titration)	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.

Primary

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)

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.

Please Note: The pre-specified primary comparison was between APL-130277 and Placebo.

Posted

Least Squares Mean

Standard Error

msec

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

ID	Title	Description
OG000	Moxifloxacin (Crossover)	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.

Secondary

ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During 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.

Posted

Least Squares Mean

Standard Error

Beats per minute

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.

ID	Title	Description
OG000	APL-130277 (Cross-over)	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.
OG001

Secondary

ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During 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.

Posted

Least Squares Mean

Standard Error

msec

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.

ID	Title	Description
OG000	APL-130277 (Cross-over)	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.

Secondary

ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During 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.

Posted

Least Squares Mean

Standard Error

msec

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.

ID	Title	Description
OG000	APL-130277 (Cross-over)	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.

Secondary

ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During 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.

Posted

Least Squares Mean

Standard Error

msec

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.

ID	Title	Description
OG000	APL-130277 (Cross-over)	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.

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Bundle branch block left	Cardiac disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG0030 events0 affected40 at risk
Nodal arrhythmia	Cardiac disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Vertigo	Ear and labyrinth disorders	MedDRA 19.1	Systematic Assessment	EG0002 events2 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
blepharospasm	Eye disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG00035 events27 affected48 at risk EG0014 events4 affected40 at risk EG0020 events0 affected40 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG0009 events9 affected48 at risk EG0012 events2 affected40 at risk EG0020 events0 affected40 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Eructation	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Glossodynia	Gastrointestinal disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Chills	General disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Infected cyst	Infections and infestations	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected40 at risk EG0021 events1 affected40 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Contusion	Injury, poisoning and procedural complications	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Fall	Injury, poisoning and procedural complications	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Blood pressure systolic decreased	Investigations	MedDRA 19.1	Systematic Assessment	EG0002 events2 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Electrocardiogram QT prolonged	Investigations	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Weight descreased	Investigations	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected40 at risk EG0021 events1 affected40 at risk EG003
Somnolence	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG00020 events12 affected48 at risk EG0016 events6 affected40 at risk EG0022 events2 affected40 at risk EG003
Dizziness	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG0008 events8 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Dyskinesia	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG0002 events2 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Headache	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG0003 events3 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Tremor	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Sinus headache	Nervous system disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected40 at risk EG0021 events1 affected40 at risk EG003
Agitation	Psychiatric disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Spontaneous penile erection	Reproductive system and breast disorders	MedDRA 19.1	Systematic Assessment	EG0002 events1 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Yawning	Respiratory, thoracic and mediastinal disorders	MedDRA 19.1	Systematic Assessment	EG0003 events2 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Hyperhidrosis	Skin and subcutaneous tissue disorders	MedDRA 19.1	Systematic Assessment	EG0007 events7 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Hypotension	Vascular disorders	MedDRA 19.1	Systematic Assessment	EG0005 events4 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Hypertension	Vascular disorders	MedDRA 19.1	Systematic Assessment	EG0000 events0 affected48 at risk EG0010 events0 affected40 at risk EG0022 events2 affected40 at risk EG003
Hot Flush	Vascular disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0011 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Orthostatic hypertension	Vascular disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Orthostatic hypotension	Vascular disorders	MedDRA 19.1	Systematic Assessment	EG0005 events2 affected48 at risk EG0012 events1 affected40 at risk EG0020 events0 affected40 at risk EG003
Bundle branch block right	Cardiac disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003
Malaise	General disorders	MedDRA 19.1	Systematic Assessment	EG0001 events1 affected48 at risk EG0010 events0 affected40 at risk EG0020 events0 affected40 at risk EG003

ID	Term
D020734	Parkinsonian Disorders
D001480	Basal Ganglia Diseases
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases
D009069	Movement Disorders
D000080874	Synucleinopathies
D019636	Neurodegenerative Diseases

ID	Term
D001060	Aporphines
D044182	Benzylisoquinolines
D000470	Alkaloids
D006571	Heterocyclic Compounds
D007546	Isoquinolines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006576	Heterocyclic Compounds, 4 or More Rings
D024841	Fluoroquinolones
D042462	4-Quinolones
D015363	Quinolones
D011804	Quinolines

ID	Title	Description	Deaths (At Risk)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	APL-130277 (Titration)	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.	48	48	41	48
EG001	APL-130277 (Cross-over)	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.	40	40	13	40
EG002	Placebo (Crossover)	Patients who received a single dose of placebo in 1 of the 3 treatment period dosing visits during the Randomized Crossover Assessment Phase.	40	40	6	40
EG003	Moxifloxacin (Crossover)	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.	40	40	4	40