Parkinson's Disease, Off Episodes of Parkinson Disease
Conditions
Keywords
Parkinson's Disease, Off episodes
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)
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
Interventions
DRUGPlacebo
Placebo single dose
DRUGMoxifloxacin
moxifloxacin 400mg single dose
DRUGAPL-130277
APL-130277 single dose
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind period
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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). 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
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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). |
Countries
Italy, United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Overall (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
1. APL-130277 at the dose determined in the Dose Titration Phase; OR
2. Matched placebo APL-130277; OR
3. A single 400 mg dose of moxifloxacin. Patients were randomized in equal numbers to 6 possible sequences of the above 3 study treatments determined by a 3-way balanced crossover design.
There was a 3-day washout period between treatment period dosing visits. Dosing of APL-130277 and placebo was double-blinded, and dosing of moxifloxacin was open-label. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Pre-Intervention | Withdrawal by Subject | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Titration Period | Adverse Event | 0 | 0 | 0 | 0 | 0 | 0 | 5 |
| Titration Period | Exclusion Criteria Met | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Titration Period | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Overall (Cross-Over) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 15 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Number of OFF Episodes/Day five | 9 OFF Episodes/day |
| Number of OFF Episodes/Day four | 12 OFF Episodes/day |
| Number of OFF Episodes/Day one | 0 OFF Episodes/day |
| Number of OFF Episodes/Day six | 1 OFF Episodes/day |
| Number of OFF Episodes/Day three | 14 OFF Episodes/day |
| Number of OFF Episodes/Day two | 3 OFF Episodes/day |
| Number of OFF Episodes/Day zero | 1 OFF Episodes/day |
| Presence of a Rest Tremor at the Time of Diagnosis no | 13 participants |
| Presence of a Rest Tremor at the Time of Diagnosis yes | 27 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 37 Participants |
| Region of Enrollment Italy | 16 participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 26 Participants |
| Time Since Diagnosis of PD | 8.30 years STANDARD_DEVIATION 4.322 |
| Time Since Initiationof L-dopa Treatment | 6.20 years STANDARD_DEVIATION 4.502 |
| Time Since Motor Fluctuations Started | 5.05 years STANDARD_DEVIATION 3.811 |
| Total Daily L-Dopa Dose | 620.5 mg STANDARD_DEVIATION 273.05 |
| Type of OFF Episode Experienced Delayed ON | 0 participants |
| Type of OFF Episode Experienced Dose failure | 1 participants |
| Type of OFF Episode Experienced Morning akinesia | 6 participants |
| Type of OFF Episode Experienced Other | 1 participants |
| Type of OFF Episode Experienced Sudden-off | 1 participants |
| Type of OFF Episode Experienced Wearing-off | 31 participants |
| Typical Length of OFF Episode | 1.30 hours STANDARD_DEVIATION 0.915 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 40 | 0 / 40 | 0 / 40 |
| other Total, other adverse events | 41 / 48 | 13 / 40 | 6 / 40 | 4 / 40 |
| serious Total, serious adverse events | 0 / 48 | 0 / 40 | 0 / 40 | 0 / 40 |
Outcome results
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.
Time frame: Baseline to 60 mins and 2, 3, and 4 hours post-dose for each of the 3 treatment period dosing visits.
Population: The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.~Please Note: The pre-specified primary comparison was between APL-130277 and Placebo.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) | 60 mins post-dose | 6.5 msec | Standard Error 1.98 |
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) | 2 hours post-dose | 9.3 msec | Standard Error 1.99 |
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) | 3 hours post-dose | 9.3 msec | Standard Error 1.98 |
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) | 4 hours post-dose | 8.8 msec | Standard Error 1.98 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) | 4 hours post-dose | -0.2 msec | Standard Error 1.98 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) | 60 mins post-dose | -3.5 msec | Standard Error 1.97 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) | 3 hours post-dose | -1.6 msec | Standard Error 1.98 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on QTcF Using ΔΔQTcF: Comparison Between Moxifloxacin and Placebo (Assay Sensitivity Analysis) | 2 hours post-dose | -3.0 msec | Standard Error 1.97 |
Comparison: 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.90% CI: [5.3, 14.8]
Comparison: 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.90% CI: [7.5, 17.1]
Comparison: 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.90% CI: [6.1, 15.7]
Comparison: 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.90% CI: [4.2, 13.8]
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.
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.
Population: The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.~Please Note: The pre-specified primary comparison was between APL-130277 and Placebo.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 30 mins post-dose | 0.3 msec | Standard Error 1.98 |
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 45 mins post-dose | 0.0 msec | Standard Error 1.98 |
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 60 mins post-dose | 2.7 msec | Standard Error 1.98 |
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 3 hours post-dose | 0.1 msec | Standard Error 1.98 |
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 2 hours post-dose | 1.8 msec | Standard Error 1.98 |
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 4 hours post-dose | -0.9 msec | Standard Error 1.98 |
| APL-130277 (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 15 mins post-dose | 0.2 msec | Standard Error 1.98 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 4 hours post-dose | -0.2 msec | Standard Error 1.98 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 15 mins post-dose | -3.7 msec | Standard Error 1.97 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 30 mins post-dose | -2.7 msec | Standard Error 1.97 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 45 mins post-dose | -3.7 msec | Standard Error 1.97 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 60 mins post-dose | -3.5 msec | Standard Error 1.97 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 2 hours post-dose | -3.0 msec | Standard Error 1.97 |
| Placebo (Cross-over) | Time-Matched Change From Baseline in QTc, Placebo-Adjusted and Corrected for Heart Rate Based on the Fridericia Correction Method (QTcF) Using Delta Delta Method (ΔΔQTcF): Comparison Between APL-130277 and Placebo (Central Tendency Analysis) | 3 hours post-dose | -1.6 msec | Standard Error 1.98 |
Comparison: 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.90% CI: [0.5, 7.4]
Comparison: 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.90% CI: [-0.5, 6.5]
Comparison: 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.90% CI: [0.2, 7.2]
Comparison: 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.90% CI: [2.7, 9.7]
Comparison: 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.90% CI: [1.3, 8.3]
Comparison: 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.90% CI: [-1.7, 5.3]
Comparison: 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.90% CI: [-4.2, 2.8]
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).
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.
Population: The PK population included all patients with at least one PK evaluation. Only patients with data available for analysis are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 7.70 h*ng/mL | Standard Deviation 4.15 |
| APL-130277 (Cross-over) | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 558 h*ng/mL | Standard Deviation 161 |
| Placebo (Cross-over) | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 9.39 h*ng/mL | Standard Deviation 3.31 |
| Placebo (Cross-over) | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 734 h*ng/mL | Standard Deviation 155 |
| 20 mg AP:-130277 PK Subset | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 7.55 h*ng/mL | Standard Deviation 3.81 |
| 20 mg AP:-130277 PK Subset | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 861 h*ng/mL | Standard Deviation 147 |
| 25 mg APL-130277 PK Subset | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 7.84 h*ng/mL | Standard Deviation 0.975 |
| 25 mg APL-130277 PK Subset | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 870 h*ng/mL | Standard Deviation 108 |
| 35 mg APL-130277 PK Subset | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 12.1 h*ng/mL | Standard Deviation 6.63 |
| 35 mg APL-130277 PK Subset | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 979 h*ng/mL | Standard Deviation 127 |
| 50 mg AP:-130277 PK Subset | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 10.9 h*ng/mL | — |
| 50 mg AP:-130277 PK Subset | AUClast of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 1980 h*ng/mL | — |
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).
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.
Population: The PK population included all patients with at least one PK evaluation. Only patients with data available for analysis are presented.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 5.14 ng/mL | Standard Deviation 3.28 |
| APL-130277 (Cross-over) | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 220 ng/mL | Standard Deviation 77.4 |
| Placebo (Cross-over) | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 6.57 ng/mL | Standard Deviation 1.22 |
| Placebo (Cross-over) | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 319 ng/mL | Standard Deviation 97.9 |
| 20 mg AP:-130277 PK Subset | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 4.23 ng/mL | Standard Deviation 2.81 |
| 20 mg AP:-130277 PK Subset | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 377 ng/mL | Standard Deviation 82 |
| 25 mg APL-130277 PK Subset | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 4.16 ng/mL | Standard Deviation 2.54 |
| 25 mg APL-130277 PK Subset | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 446 ng/mL | Standard Deviation 46.7 |
| 35 mg APL-130277 PK Subset | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 9.29 ng/mL | Standard Deviation 9.97 |
| 35 mg APL-130277 PK Subset | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 458 ng/mL | Standard Deviation 12.7 |
| 50 mg AP:-130277 PK Subset | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 4.61 ng/mL | — |
| 50 mg AP:-130277 PK Subset | Cmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine sulfate | 1420 ng/mL | — |
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.
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.
Population: The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 30 mins post-dose | 1.5 Beats per minute | Standard Error 1.31 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 2 hours post-dose | 3.3 Beats per minute | Standard Error 1.31 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 60 mins post-dose | -3.0 Beats per minute | Standard Error 1.31 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 15 mins post-dose | 2.5 Beats per minute | Standard Error 1.31 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 4 hours post-dose | 9.5 Beats per minute | Standard Error 1.31 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 3 hours post-dose | 7.6 Beats per minute | Standard Error 1.31 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 45 mins post-dose | 0.1 Beats per minute | Standard Error 1.31 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 60 mins post-dose | 0.1 Beats per minute | Standard Error 1.3 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 15 mins post-dose | 2.1 Beats per minute | Standard Error 1.3 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 30 mins post-dose | 2.1 Beats per minute | Standard Error 1.3 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 45 mins post-dose | 0.8 Beats per minute | Standard Error 1.3 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 2 hours post-dose | 2.8 Beats per minute | Standard Error 1.3 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 3 hours post-dose | 4.6 Beats per minute | Standard Error 1.31 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 4 hours post-dose | 6.2 Beats per minute | Standard Error 1.31 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 2 hours post-dose | 1.5 Beats per minute | Standard Error 1.32 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 30 mins post-dose | 0.5 Beats per minute | Standard Error 1.31 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 4 hours post-dose | 2.9 Beats per minute | Standard Error 1.31 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 3 hours post-dose | 3.3 Beats per minute | Standard Error 1.31 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 60 mins post-dose | 1.8 Beats per minute | Standard Error 1.31 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 45 mins post-dose | 3.6 Beats per minute | Standard Error 1.31 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Heart Rate During Randomized Crossover Assessment Phase | 15 mins post-dose | 0.1 Beats per minute | Standard Error 1.31 |
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.
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.
Population: The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -1.6 msec | Standard Error 1.73 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | -0.2 msec | Standard Error 1.72 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | 2.5 msec | Standard Error 1.72 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | 0.4 msec | Standard Error 1.72 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | -3.7 msec | Standard Error 1.73 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | -1.5 msec | Standard Error 1.73 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | 1.2 msec | Standard Error 1.72 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | -0.3 msec | Standard Error 1.71 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -1.9 msec | Standard Error 1.71 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -0.2 msec | Standard Error 1.71 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | 0.1 msec | Standard Error 1.71 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | -1.7 msec | Standard Error 1.71 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | -2.2 msec | Standard Error 1.72 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | -3.1 msec | Standard Error 1.72 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | -0.1 msec | Standard Error 1.73 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -0.2 msec | Standard Error 1.72 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | 0.8 msec | Standard Error 1.72 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | 1.6 msec | Standard Error 1.72 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | 1.5 msec | Standard Error 1.72 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | -1.1 msec | Standard Error 1.72 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for PR Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -1.1 msec | Standard Error 1.72 |
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.
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.
Population: The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -0.4 msec | Standard Error 0.94 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | 1.1 msec | Standard Error 0.94 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | -0.8 msec | Standard Error 0.94 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -0.7 msec | Standard Error 0.94 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | 0.5 msec | Standard Error 0.94 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | -0.2 msec | Standard Error 0.94 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | -1.2 msec | Standard Error 0.94 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | -1.4 msec | Standard Error 0.93 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -1.2 msec | Standard Error 0.93 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -0.9 msec | Standard Error 0.93 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | -0.1 msec | Standard Error 0.93 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | -1.3 msec | Standard Error 0.93 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | -0.9 msec | Standard Error 0.94 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | -0.6 msec | Standard Error 0.94 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | -1.1 msec | Standard Error 0.95 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -0.1 msec | Standard Error 0.94 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | 0.4 msec | Standard Error 0.94 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | -1.0 msec | Standard Error 0.94 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | -0.4 msec | Standard Error 0.94 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | -0.9 msec | Standard Error 0.94 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QRS Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -0.7 msec | Standard Error 0.94 |
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.
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.
Population: The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | 1.9 msec | Standard Error 2.24 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | 4.7 msec | Standard Error 2.24 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | -0.1 msec | Standard Error 2.24 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | 2.7 msec | Standard Error 2.24 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | 8.1 msec | Standard Error 2.24 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | 7.2 msec | Standard Error 2.24 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | 0.1 msec | Standard Error 2.24 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | -3.3 msec | Standard Error 2.22 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -1.7 msec | Standard Error 2.22 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -0.7 msec | Standard Error 2.22 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | -3.2 msec | Standard Error 2.22 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | -0.4 msec | Standard Error 2.22 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | 2.7 msec | Standard Error 2.24 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | 5.5 msec | Standard Error 2.24 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | 11.1 msec | Standard Error 2.25 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | 1.4 msec | Standard Error 2.23 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | 12.1 msec | Standard Error 2.23 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | 12.8 msec | Standard Error 2.23 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | 8.4 msec | Standard Error 2.23 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | 7.8 msec | Standard Error 2.23 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for QTcB Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -2.5 msec | Standard Error 2.23 |
90% CI: [0.3, 8.6]
90% CI: [-1.6, 6.7]
90% CI: [-0.9, 7.4]
90% CI: [-0.9, 7.5]
90% CI: [0.8, 9.2]
90% CI: [0.4, 8.8]
90% CI: [-1.6, 6.9]
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.
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.
Population: The ECG Population included all randomized patients who had evaluable baseline 12-lead ECG (Holter) data at P1V1 and at least one evaluable post-dose 12-lead ECG (Holter) assessment during the Randomized Crossover Assessment Phase.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -2.2 msec | Standard Error 3.05 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | -2.6 msec | Standard Error 3.05 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | 8.3 msec | Standard Error 3.05 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -3.9 msec | Standard Error 3.05 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | -16.4 msec | Standard Error 3.05 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | -12.0 msec | Standard Error 3.05 |
| APL-130277 (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | 0.3 msec | Standard Error 3.05 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | -3.5 msec | Standard Error 3.02 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -7.1 msec | Standard Error 3.02 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -6.1 msec | Standard Error 3.02 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | -4.2 msec | Standard Error 3.02 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | -7.6 msec | Standard Error 3.02 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | -8.9 msec | Standard Error 3.04 |
| Placebo (Cross-over) | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | -10.1 msec | Standard Error 3.05 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 2 hours post-dose | 6.2 msec | Standard Error 3.07 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 30 mins post-dose | -0.7 msec | Standard Error 3.04 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 4 hours post-dose | 2.8 msec | Standard Error 3.04 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 3 hours post-dose | 3.0 msec | Standard Error 3.04 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 60 mins post-dose | 3.5 msec | Standard Error 3.04 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 45 mins post-dose | -2.2 msec | Standard Error 3.04 |
| 20 mg AP:-130277 PK Subset | ECG Assessments: Mean Change From Baseline to Post-Baseline Value for Uncorrected QT Interval During Randomized Crossover Assessment Phase | 15 mins post-dose | -2.7 msec | Standard Error 3.04 |
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.
Time frame: Baseline (pre-dose) and at 30, 60 and 90 minutes after dosing during the Dose Titration Phase.
Population: The Efficacy Population included all patients who had efficacy assessments at the lowest dose level resulting in a full 'ON' and at a higher dose level during the Dose Titration Phase.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277 (Cross-over) | Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase | 30 mins post-dose (day 1) | -21.1 units on a scale | Standard Error 1.79 |
| APL-130277 (Cross-over) | Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase | 30 mins post-dose (day 2) | -26.7 units on a scale | Standard Error 1.78 |
| APL-130277 (Cross-over) | Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase | 60 mins post-dose (day 1) | -26.3 units on a scale | Standard Error 1.46 |
| APL-130277 (Cross-over) | Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase | 60 mins post-dose (day 2) | -31.3 units on a scale | Standard Error 1.72 |
| APL-130277 (Cross-over) | Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase | 90 mins post-dose (day 1) | -25.2 units on a scale | Standard Error 1.43 |
| APL-130277 (Cross-over) | Mean Change From Pre-Dose to Post-Baseline Value in the Movement Disorders Society Unified Parkinson's Disease Rating Scale Part III Motor Examination (MDS-UPDRS Part III) Score During the Dose Titration Phase | 90 mins post-dose (day 2) | -28.9 units on a scale | Standard Error 1.68 |
Secondary
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.
Time frame: Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.
Population: The Efficacy Population included all patients who had efficacy assessments at the lowest dose level resulting in a full 'ON' and at a higher dose level during the Dose Titration Phase.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| APL-130277 (Cross-over) | Median Duration of 'ON' During the Dose Titration Phase | Day 1 | NA minutess |
| APL-130277 (Cross-over) | Median Duration of 'ON' During the Dose Titration Phase | Day 2 | NA minutess |
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.
Time frame: Time of dosing up to 90 minutes post-dose during the Dose Titration Phase.
Population: The Efficacy Population included all patients who had efficacy assessments at the lowest dose level resulting in a full 'ON' and at a higher dose level during the Dose Titration Phase.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| APL-130277 (Cross-over) | Median Time to 'ON' During the Dose Titration Phase | Day 2 | 30 minutes |
| APL-130277 (Cross-over) | Median Time to 'ON' During the Dose Titration Phase | Day 1 | 30 minutes |
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.
Time frame: From first dose of study medication up to last study visit for Randomized Crossover Assessment Phase, approximately up to 2 weeks
Population: The Crossover Phase Safety Population consisted of all patients who were randomized and received at least one post-randomization dose of study medication (APL-130277, moxifloxacin or placebo) during the Randomized Crossover Assessment Phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| APL-130277 (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 0 participants |
| APL-130277 (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Drug-related TEAE | 12 participants |
| APL-130277 (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to death | 0 participants |
| APL-130277 (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 13 participants |
| APL-130277 (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Severe TEAE | 1 participants |
| Placebo (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 6 participants |
| Placebo (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 0 participants |
| Placebo (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Severe TEAE | 0 participants |
| Placebo (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to death | 0 participants |
| Placebo (Cross-over) | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Drug-related TEAE | 2 participants |
| 20 mg AP:-130277 PK Subset | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | TEAE leading to death | 0 participants |
| 20 mg AP:-130277 PK Subset | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Drug-related TEAE | 0 participants |
| 20 mg AP:-130277 PK Subset | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Severe TEAE | 0 participants |
| 20 mg AP:-130277 PK Subset | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAE | 0 participants |
| 20 mg AP:-130277 PK Subset | Number of Patients With Treatment-Emergent Adverse Events (TEAEs) | Any TEAE | 4 participants |
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).
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.
Population: The PK population included all patients with at least one PK evaluation. Only patients with data available for analysis are presented.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| APL-130277 (Cross-over) | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 0.75 hours |
| APL-130277 (Cross-over) | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphne sulfate | 2.00 hours |
| Placebo (Cross-over) | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 0.75 hours |
| Placebo (Cross-over) | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphne sulfate | 1.52 hours |
| 20 mg AP:-130277 PK Subset | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 1.00 hours |
| 20 mg AP:-130277 PK Subset | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphne sulfate | 2.00 hours |
| 25 mg APL-130277 PK Subset | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 1.50 hours |
| 25 mg APL-130277 PK Subset | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphne sulfate | 1.50 hours |
| 35 mg APL-130277 PK Subset | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 0.58 hours |
| 35 mg APL-130277 PK Subset | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphne sulfate | 2.13 hours |
| 50 mg AP:-130277 PK Subset | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphine | 0.78 hours |
| 50 mg AP:-130277 PK Subset | Tmax of Apomorphine and Apomorphine Sulfate (Metabolite) Following the Administration of APL-130277 | Apomorphne sulfate | 0.52 hours |