Parkinson Disease
Conditions
Keywords
Off Episodes, Parkinson Disease
Brief summary
A study that compares the extent to which apomorphine becomes available in the body after taking either an investigational drug containing apomorphine or apomorphine that is injected under the skin in people with PD complicated by OFF episodes.
Detailed description
This multi-center study will aim to evaluate the pharmacokinetics (PK) and comparative bioavailability of a single dose of APL-130277 sublingual thin film with subcutaneous (s.c.) APO-go® and s.c. APOKYN® in subjects with Parkinson's disease (PD). The dose of APOKYN® (≤ 5 mg) will be based on the subjects' current prescribed dose. The study is designed as an open-label, randomized, three-way crossover. Subjects will receive all three treatment arms with a minimum 1-day wash-out between each visit (excluding the screening visit) and will be randomly assigned to one of the six sequences
Interventions
DRUGAPL-130277
APL-130277 sublingual thin film
DRUGAPO-go
Subcutaneous APO-go
DRUGApokyn
Subcutaneous APOKYN
Sponsors
Sumitomo Pharma America, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
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) with well-defined OFF episodes, as determined by the Investigator. 4. Receiving APOKYN® of ≤ 5 mg per dose for at least 4 weeks before the Screening Visit. 5. Receiving stable doses of L-Dopa/carbidopa (immediate or sustained release) administered at least 4 times per day OR Rytary™ administered 3 times per day, for at least 4 weeks before the Screening Visit. Adjunctive PD medication regimens must be maintained at a stable dose for at least 4 weeks prior to the Screening Visit with the exception that MAOB inhibitors must be maintained at a stable level for at least 8 weeks prior to the Screening Visit. 6. No planned medication change(s) or surgical intervention anticipated during the course of study. 7. Patients must experience a well-defined OFF episode in the morning if they do not take their morning PD medications on schedule, and must be willing to delay morning doses on the 3 study dosing days 8. Stage III or less on the modified Hoehn and Yahr scale in the ON state. 9. Mini-Mental State Examination (MMSE) score \> 23. 10. If female and of childbearing potential, must agree to use one of the following methods of birth control: * 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). 11. Male patients must be either surgically sterile, agree to be sexually abstinent or use a barrier method of birth control (e.g., condom) or maintain a monogamous relationship with a person who is not of child-bearing potential from first study drug administration until 30days after final drug administration. 12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures to complete the study. 13. Able to understand the consent form, and to provide written informed consent
Exclusion criteria
1. Atypical or secondary parkinsonism. 2. Previous treatment with any of the following: continuous subcutaneous (s.c.) apomorphine infusion; or Duodopa/Duopa. 3. Contraindications to APO-go® or APOKYN® or hypersensitivity to apomorphine hydrochloride or any marcrolide antibiotic or any of the ingredients APO-go® or APOKYN® (notably sodium metabisulfite). 4. Female who is pregnant or lactating. 5. Participation in a clinical trial within 30 days prior to the Screening Visit. 6. Receipt of any investigational (ie, unapproved) medication within 30 days prior to the Screening Visit. 7. Any selective 5HT3 antagonists (ie, ondansetron, granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists (excluding quetiapine and clozapine) or dopamine depleting agents within 30 days prior to the Screening Visit. 8. Drug or alcohol dependency in the past 12 months. 9. History of malignant melanoma. 10. Clinically significant medical, surgical, or laboratory abnormality in the opinion of the Investigator. 11. Major psychiatric disorder including, but not limited to, dementia, bipolar disorder, 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. 12. History of clinically significant hallucinations during the past 6 months. 13. History of clinically significant impulse control disorder(s). 14. Dementia that precludes providing informed consent or would interfere with participation in the study. 15. Current suicidal ideation within one year prior to the Screening Visit 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. 16. Donation of blood plasma in the 30 days prior to first dosing. 17. Cankers or mouth sores within 30 days prior to the Screening Visit, or other clinically significant oral pathology in the opinion of the Investigator. The Investigator should follow-up with an appropriate specialist on any finding, if indicated, before enrolling a patient into the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | Day 1 | Dose normalized maximum observed plasma concentration (Cmax) |
| Observed Time of the Maximum Concentration (Tmax) | Day 1 | Time from dosing to Cmax, observed by inspection of individual subject plots of plasma concentration versus time. |
| Area Under the Concentration- Time Curve (AUC Last) | Day 1 | area under the concentration-time curve from time zero to the last measurable plasma concentration-time curve using the linear up log down trapezoidal rule. |
| Area Under the Concentration- Time Curve (AUC Inf) | Day 1 | area under the concentration-time curve from time zero extrapolated to infinity using the linear up log down trapezoidal rule. |
| Mean Residence Time (MRT) | Day 1 | Mean residence time during one dosing interval calculated using the following equation: MRT = AUMCinf/AUC inf. AUMCinf is the area under the first moment (time.plasma concentration vs. time) curve. |
| Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | Day 1 | Metabolite (apomorphine sulfate) to Parent exposure ratio, Cmax, corrected for molecular weight differences. |
| Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | Day 1 | Apparent total clearance of the drug from plasma extravascular administration, calculated as Dose/AUCinf. |
| Apparent Volume of Distribution After Non-intravenous Administration (V/F) | Day 1 | Apparent volume of distribution after extravascular administration, calculated as Dose/(AUCinf \* λz). |
| Terminal-phase Half-life (t½) | Day 1 | Terminal phase half-life, as calculated by the following equation: t½ = ln(2)/λz. |
| Terminal-phase Rate Constant ( λz) | Day 1 | Apparent terminal elimination rate constant, determined by log linear regression of the plasma concentration versus time data that was judged to be in the log-linear elimination phase. At least 3 data points in the terminal phase will be used in the determination of the rate constant. |
| Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | Day 1 | Metabolite (apomorphine sulfate) to Parent exposure ratio, AUClast, corrected for molecular weight differences. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| APL-130277, Then APOKYN, Then APO-go Sequence 1: Participants first received APL-130277 (approximate equivalent dose to current APOKYN dose: 15 mg/ 20 mg/ 25 mg/ 30 mg) in the 'OFF' state. After a washout period of at least one day, they received APOKYN (current prescribed dose : 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. After a washout period of at least one day, they received APO-go ( same dose as APOKYN: 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. | 1 |
| APL-130277, Then APO-go, Then APOKYN Sequence 2: Participants first received APL-130277 (approximate equivalent dose to current APOKYN dose: 15 mg/ 20 mg/ 25 mg/ 30 mg) in the 'OFF' state. After a washout period of at least one day, they received APO-go (same dose as APOKYN 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. After a washout period of at least one day, they received APOKYN (current prescribed dose : 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. | 1 |
| APOKYN, Then APL-130277, Then APO-go Sequence 3: Participants first received APOKYN (current prescribed dose : 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. After a washout period of at least one day, they received APL-130277 (approximate equivalent dose to current APOKYN dose: 15 mg/ 20 mg/ 25 mg/ 30 mg) in the 'OFF' state. After a washout period of at least one day, they received APO-go (same dose as APOKYN 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. | 2 |
| APOKYN, Then APO-go, Then APL-130277 Sequence 4: Participants first received APOKYN (current prescribed dose : 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. After a washout period of at least one day, they received APO-go (same dose as APOKYN 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. After a washout period of at least one day, they received APL-130277 (approximate equivalent dose to current APOKYN dose: 15 mg/ 20 mg/ 25 mg/ 30 mg) in the 'OFF' state. | 1 |
| APO-go, Then APL-130277, Then APOKYN Sequence 5: Participants first received APO-go (same dose as APOKYN 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. After a washout period of at least one day, they received APL-130277 (approximate equivalent dose to current APOKYN dose: 15 mg/ 20 mg/ 25 mg/ 30 mg) in the 'OFF' state. After a washout period of at least one day, they received APOKYN (current prescribed dose : 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. | 1 |
| APO-go, Then APOKYN, Then APL-130277 Sequence 6: Participants first received APO-go (same dose as APOKYN 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. After a washout period of at least one day, they received APOKYN (current prescribed dose : 2 mg/3 mg/4mg/5 mg) in the 'OFF' state. After a washout period of at least one day, they received APL-130277 (approximate equivalent dose to current APOKYN dose: 15 mg/ 20 mg/ 25 mg/ 30 mg) in the 'OFF' state. | 2 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Second Washout | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | APO-go, Then APL-130277, Then APOKYN | APO-go, Then APOKYN, Then APL-130277 | APL-130277, Then APOKYN, Then APO-go | APL-130277, Then APO-go, Then APOKYN | APOKYN, Then APL-130277, Then APO-go | APOKYN, Then APO-go, Then APL-130277 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Age, Continuous | 73 Years | 68.5 Years STANDARD_DEVIATION 9.19 | 75 Years | 51 Years | 67.5 Years STANDARD_DEVIATION 9.19 | 67 Years | 67.3 Years STANDARD_DEVIATION 8.7 |
| BMI (kg/m2) at Baseline | 26.7 kg/m^2 | 23.8 kg/m^2 STANDARD_DEVIATION 3.111 | 28.9 kg/m^2 | 23.9 kg/m^2 | 28.1 kg/m^2 STANDARD_DEVIATION 3.111 | 23.8 kg/m^2 | 25.89 kg/m^2 STANDARD_DEVIATION 2.826 |
| Body Weight (kg) at Baseline | 84.4 kg | 71.2 kg STANDARD_DEVIATION 25.032 | 86.3 kg | 59.4 kg | 86.7 kg STANDARD_DEVIATION 20.506 | 73 kg | 77.36 kg STANDARD_DEVIATION 15.895 |
| Child-bearing potential N/A | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 6 Participants |
| Child-bearing potential No | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Child-bearing potential Yes | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Country United States | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height (cm) at Baseline | 177.8 cm | 171.25 cm STANDARD_DEVIATION 19.445 | 172.7 cm | 157.5 cm | 174.95 cm STANDARD_DEVIATION 11.243 | 175.3 cm | 171.96 cm STANDARD_DEVIATION 10.545 |
| Mini-Mental Status Total Score | 27 Score | 27.5 Score STANDARD_DEVIATION 3.54 | 30 Score | 30 Score | 26.5 Score STANDARD_DEVIATION 2.12 | 25 Score | 27.5 Score STANDARD_DEVIATION 2.33 |
| ON State Mod. Hoehn & Yahr Score | 3 Score | 2.5 Score STANDARD_DEVIATION 0.707 | 2 Score | 2 Score | 2.5 Score STANDARD_DEVIATION 0 | 2.5 Score | 2.44 Score STANDARD_DEVIATION 0.417 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 6 Participants |
| Smoking Status Former Smoker | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Smoking Status Has never smoked | 1 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 7 | 0 / 8 |
| other Total, other adverse events | 1 / 8 | 1 / 7 | 3 / 8 |
| serious Total, serious adverse events | 1 / 8 | 0 / 7 | 0 / 8 |
Outcome results
Primary
Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F)
Apparent total clearance of the drug from plasma extravascular administration, calculated as Dose/AUCinf.
Time frame: Day 1
Population: CL/F summarized by dose level
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277, Sublingual Thin Film | Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 1952.1 L/h | Geometric Coefficient of Variation 44.3 |
| APL-130277, Sublingual Thin Film | Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 1097.8 L/h | Geometric Coefficient of Variation 99.5 |
| APL-130277, Sublingual Thin Film | Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 2766.9 L/h | Geometric Coefficient of Variation 52.4 |
| Subcutaneous APOKYN | Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 350.6 L/h | Geometric Coefficient of Variation 4 |
| Subcutaneous APOKYN | Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 407.9 L/h | Geometric Coefficient of Variation 33.3 |
| Subcutaneous APOKYN | Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 250.2 L/h | Geometric Coefficient of Variation 140.6 |
| Subcutaneous APO-go | Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 253.7 L/h | Geometric Coefficient of Variation 169.6 |
| Subcutaneous APO-go | Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 375.6 L/h | Geometric Coefficient of Variation 32.2 |
| Subcutaneous APO-go | Apparent Total Clearance of the Drug From Plasma After Oral Administration (CL/F) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 299.2 L/h | Geometric Coefficient of Variation 41 |
Primary
Apparent Volume of Distribution After Non-intravenous Administration (V/F)
Apparent volume of distribution after extravascular administration, calculated as Dose/(AUCinf \* λz).
Time frame: Day 1
Population: V/F summarized by dose level
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277, Sublingual Thin Film | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 1733.4 L | Geometric Coefficient of Variation 52.8 |
| APL-130277, Sublingual Thin Film | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 3419.5 L | Geometric Coefficient of Variation 67.4 |
| APL-130277, Sublingual Thin Film | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 4440.2 L | Geometric Coefficient of Variation 72 |
| Subcutaneous APOKYN | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 452.0 L | Geometric Coefficient of Variation 14.7 |
| Subcutaneous APOKYN | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 577.5 L | Geometric Coefficient of Variation 44.3 |
| Subcutaneous APOKYN | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 420.8 L | Geometric Coefficient of Variation 193.7 |
| Subcutaneous APO-go | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 372.2 L | Geometric Coefficient of Variation 231.1 |
| Subcutaneous APO-go | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 324.2 L | Geometric Coefficient of Variation 73.7 |
| Subcutaneous APO-go | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 469.3 L | Geometric Coefficient of Variation 19.1 |
Primary
Area Under the Concentration- Time Curve (AUC Inf)
area under the concentration-time curve from time zero extrapolated to infinity using the linear up log down trapezoidal rule.
Time frame: Day 1
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| APL-130277, Sublingual Thin Film | Area Under the Concentration- Time Curve (AUC Inf) | 0.52 (hxng/mL)/(mg) |
| Subcutaneous APOKYN | Area Under the Concentration- Time Curve (AUC Inf) | 2.97 (hxng/mL)/(mg) |
| Subcutaneous APO-go | Area Under the Concentration- Time Curve (AUC Inf) | 3.04 (hxng/mL)/(mg) |
90% CI: [13.7, 22.5]Mixed Models Analysis
90% CI: [13.7, 21.6]Mixed Models Analysis
90% CI: [76.6, 124.8]Mixed Models Analysis
Primary
Area Under the Concentration- Time Curve (AUC Last)
area under the concentration-time curve from time zero to the last measurable plasma concentration-time curve using the linear up log down trapezoidal rule.
Time frame: Day 1
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| APL-130277, Sublingual Thin Film | Area Under the Concentration- Time Curve (AUC Last) | 0.500 (hxng/mL)/(mg) |
| Subcutaneous APOKYN | Area Under the Concentration- Time Curve (AUC Last) | 2.91 (hxng/mL)/(mg) |
| Subcutaneous APO-go | Area Under the Concentration- Time Curve (AUC Last) | 3.00 (hxng/mL)/(mg) |
90% CI: [13.1, 22.5]Mixed Models Analysis
90% CI: [13, 21.3]Mixed Models Analysis
90% CI: [74.2, 126.4]
Primary
Maximum Observed Plasma Concentration (Cmax)
Dose normalized maximum observed plasma concentration (Cmax)
Time frame: Day 1
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| APL-130277, Sublingual Thin Film | Maximum Observed Plasma Concentration (Cmax) | 0.281 (ng/mL)/(mg) |
| Subcutaneous APOKYN | Maximum Observed Plasma Concentration (Cmax) | 2.29 (ng/mL)/(mg) |
| Subcutaneous APO-go | Maximum Observed Plasma Concentration (Cmax) | 2.74 (ng/mL)/(mg) |
Comparison: Sample size of 12 subjects, a two-sided 90% CI for the difference in paired PK parameter means on the log scale will have an interval that extends no more than 0.221 units from the observed difference with 90% coverage probability. Assumes CV of 35% for the difference on the original scale.90% CI: [7.5, 20.3]Mixed Models Analysis
90% CI: [6.5, 16.3]
90% CI: [50.5, 137.6]
Primary
Mean Residence Time (MRT)
Mean residence time during one dosing interval calculated using the following equation: MRT = AUMCinf/AUC inf. AUMCinf is the area under the first moment (time.plasma concentration vs. time) curve.
Time frame: Day 1
Population: MRT was summarized by dose level
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277, Sublingual Thin Film | Mean Residence Time (MRT) | APL 20 mg, APOKYN 3 mg, and APO-go 3 mg | 1.69 h | Geometric Coefficient of Variation 5.2 |
| APL-130277, Sublingual Thin Film | Mean Residence Time (MRT) | APL 30 mg, APOKYN 5 mg, and APO-go 5 mg | 2.15 h | Geometric Coefficient of Variation 15.9 |
| APL-130277, Sublingual Thin Film | Mean Residence Time (MRT) | APL 25 mg, APOKYN 4 mg, and APO-go 4 mg | 1.83 h | Geometric Coefficient of Variation 41.5 |
| Subcutaneous APOKYN | Mean Residence Time (MRT) | APL 20 mg, APOKYN 3 mg, and APO-go 3 mg | 1.44 h | Geometric Coefficient of Variation 4.3 |
| Subcutaneous APOKYN | Mean Residence Time (MRT) | APL 30 mg, APOKYN 5 mg, and APO-go 5 mg | 1.23 h | Geometric Coefficient of Variation 3.4 |
| Subcutaneous APOKYN | Mean Residence Time (MRT) | APL 25 mg, APOKYN 4 mg, and APO-go 4 mg | 1.70 h | Geometric Coefficient of Variation 13.8 |
| Subcutaneous APO-go | Mean Residence Time (MRT) | APL 30 mg, APOKYN 5 mg, and APO-go 5 mg | 1.08 h | Geometric Coefficient of Variation 35.4 |
| Subcutaneous APO-go | Mean Residence Time (MRT) | APL 25 mg, APOKYN 4 mg, and APO-go 4 mg | 1.51 h | Geometric Coefficient of Variation 19 |
| Subcutaneous APO-go | Mean Residence Time (MRT) | APL 20 mg, APOKYN 3 mg, and APO-go 3 mg | 1.21 h | Geometric Coefficient of Variation 19.3 |
Primary
Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last
Metabolite (apomorphine sulfate) to Parent exposure ratio, AUClast, corrected for molecular weight differences.
Time frame: Day 1
Population: Metabolite/Parent (M/P) drug concentration Ratio -AUC last summarized by dose level
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277, Sublingual Thin Film | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 98.07 no unit | Geometric Coefficient of Variation 55.4 |
| APL-130277, Sublingual Thin Film | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 98.16 no unit | Geometric Coefficient of Variation 6.4 |
| APL-130277, Sublingual Thin Film | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 45.79 no unit | Geometric Coefficient of Variation 169.9 |
| Subcutaneous APOKYN | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 36.22 no unit | Geometric Coefficient of Variation 3 |
| Subcutaneous APOKYN | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 18.70 no unit | Geometric Coefficient of Variation 162.8 |
| Subcutaneous APOKYN | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 33.63 no unit | Geometric Coefficient of Variation 6.2 |
| Subcutaneous APO-go | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 32.19 no unit | Geometric Coefficient of Variation 9.9 |
| Subcutaneous APO-go | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 16.27 no unit | Geometric Coefficient of Variation 221.6 |
| Subcutaneous APO-go | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 26.22 no unit | Geometric Coefficient of Variation 43.6 |
Primary
Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax
Metabolite (apomorphine sulfate) to Parent exposure ratio, Cmax, corrected for molecular weight differences.
Time frame: Day 1
Population: Metabolite/Parent Cmax summarized by dose level
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277, Sublingual Thin Film | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 32.0 no unit | Geometric Coefficient of Variation 157.1 |
| APL-130277, Sublingual Thin Film | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 61.6 no unit | Geometric Coefficient of Variation 28.8 |
| APL-130277, Sublingual Thin Film | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 61.2 no unit | Geometric Coefficient of Variation 87 |
| Subcutaneous APOKYN | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 9.0 no unit | Geometric Coefficient of Variation 149.3 |
| Subcutaneous APOKYN | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 15.2 no unit | Geometric Coefficient of Variation 48.9 |
| Subcutaneous APOKYN | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 13.7 no unit | Geometric Coefficient of Variation 8.2 |
| Subcutaneous APO-go | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 11.5 no unit | Geometric Coefficient of Variation 4 |
| Subcutaneous APO-go | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 11.3 no unit | Geometric Coefficient of Variation 47.6 |
| Subcutaneous APO-go | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 7.1 no unit | Geometric Coefficient of Variation 240.3 |
Primary
Observed Time of the Maximum Concentration (Tmax)
Time from dosing to Cmax, observed by inspection of individual subject plots of plasma concentration versus time.
Time frame: Day 1
Population: Tmax summary statistics were summarized by dose levels and the inferential statistics was done across all dose levels.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| APL-130277, Sublingual Thin Film | Observed Time of the Maximum Concentration (Tmax) | APL 25 mg, APOKYN 4 mg, and APO-go 4 mg | 0.63 hour |
| APL-130277, Sublingual Thin Film | Observed Time of the Maximum Concentration (Tmax) | APL 20 mg, APOKYN 3 mg, and APO-go 3 mg | 0.75 hour |
| APL-130277, Sublingual Thin Film | Observed Time of the Maximum Concentration (Tmax) | APL 30 mg, APOKYN 5 mg, and APO-go 5 mg | 0.75 hour |
| Subcutaneous APOKYN | Observed Time of the Maximum Concentration (Tmax) | APL 25 mg, APOKYN 4 mg, and APO-go 4 mg | 0.25 hour |
| Subcutaneous APOKYN | Observed Time of the Maximum Concentration (Tmax) | APL 20 mg, APOKYN 3 mg, and APO-go 3 mg | 0.38 hour |
| Subcutaneous APOKYN | Observed Time of the Maximum Concentration (Tmax) | APL 30 mg, APOKYN 5 mg, and APO-go 5 mg | 0.38 hour |
| Subcutaneous APO-go | Observed Time of the Maximum Concentration (Tmax) | APL 20 mg, APOKYN 3 mg, and APO-go 3 mg | 0.38 hour |
| Subcutaneous APO-go | Observed Time of the Maximum Concentration (Tmax) | APL 30 mg, APOKYN 5 mg, and APO-go 5 mg | 0.25 hour |
| Subcutaneous APO-go | Observed Time of the Maximum Concentration (Tmax) | APL 25 mg, APOKYN 4 mg, and APO-go 4 mg | 0.26 hour |
p-value: 0.0625Sign test
p-value: 0.0313Sign test
p-value: >0.9999Sign test
Primary
Terminal-phase Half-life (t½)
Terminal phase half-life, as calculated by the following equation: t½ = ln(2)/λz.
Time frame: Day 1
Population: Terminal-phase half-life summarized by dose level
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277, Sublingual Thin Film | Terminal-phase Half-life (t½) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 1.21 h | Geometric Coefficient of Variation 20.5 |
| APL-130277, Sublingual Thin Film | Terminal-phase Half-life (t½) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 1.09 h | Geometric Coefficient of Variation 34.3 |
| APL-130277, Sublingual Thin Film | Terminal-phase Half-life (t½) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 1.11 h | Geometric Coefficient of Variation 15.6 |
| Subcutaneous APOKYN | Terminal-phase Half-life (t½) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 0.89 h | Geometric Coefficient of Variation 18.7 |
| Subcutaneous APOKYN | Terminal-phase Half-life (t½) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 0.98 h | Geometric Coefficient of Variation 9.9 |
| Subcutaneous APOKYN | Terminal-phase Half-life (t½) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 1.17 h | Geometric Coefficient of Variation 20.6 |
| Subcutaneous APO-go | Terminal-phase Half-life (t½) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 1.02 h | Geometric Coefficient of Variation 19.7 |
| Subcutaneous APO-go | Terminal-phase Half-life (t½) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 0.87 h | Geometric Coefficient of Variation 12.6 |
| Subcutaneous APO-go | Terminal-phase Half-life (t½) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 0.75 h | Geometric Coefficient of Variation 35.5 |
p-value: 0.0313Wilcoxon (Mann-Whitney)
p-value: 0.0625Wilcoxon (Mann-Whitney)
p-value: >0.9999Wilcoxon (Mann-Whitney)
Primary
Terminal-phase Rate Constant ( λz)
Apparent terminal elimination rate constant, determined by log linear regression of the plasma concentration versus time data that was judged to be in the log-linear elimination phase. At least 3 data points in the terminal phase will be used in the determination of the rate constant.
Time frame: Day 1
Population: terminal-phase rate constant summarized by dose level
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| APL-130277, Sublingual Thin Film | Terminal-phase Rate Constant ( λz) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 0.63 /h | Geometric Coefficient of Variation 34.3 |
| APL-130277, Sublingual Thin Film | Terminal-phase Rate Constant ( λz) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 0.62 /h | Geometric Coefficient of Variation 15.6 |
| APL-130277, Sublingual Thin Film | Terminal-phase Rate Constant ( λz) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 0.57 /h | Geometric Coefficient of Variation 20.5 |
| Subcutaneous APOKYN | Terminal-phase Rate Constant ( λz) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 0.59 /h | Geometric Coefficient of Variation 20.6 |
| Subcutaneous APOKYN | Terminal-phase Rate Constant ( λz) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 0.71 /h | Geometric Coefficient of Variation 9.9 |
| Subcutaneous APOKYN | Terminal-phase Rate Constant ( λz) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 0.78 /h | Geometric Coefficient of Variation 18.7 |
| Subcutaneous APO-go | Terminal-phase Rate Constant ( λz) | APL 20 mg, APOKYN 3 mg and APO-go 3 mg | 0.80 /h | Geometric Coefficient of Variation 12.6 |
| Subcutaneous APO-go | Terminal-phase Rate Constant ( λz) | APL 30 mg, APOKYN 5 mg and APO-go 5 mg | 0.92 /h | Geometric Coefficient of Variation 35.5 |
| Subcutaneous APO-go | Terminal-phase Rate Constant ( λz) | APL 25 mg, APOKYN 4 mg and APO-go 4 mg | 0.68 /h | Geometric Coefficient of Variation 19.7 |