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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.
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
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| APL-130277, sublingual thin film | Experimental | APL-130277, sublingual thin film, once daily |
|
| Subcutaneous APO-go | Active Comparator | Subcutaneous APO-go, once daily |
|
| Subcutaneous APOKYN | Active Comparator | Subcutaneous APOKYN, once daily |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| APL-130277 | Drug | APL-130277 sublingual thin film |
|
| Measure | Description | Time Frame |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | Dose normalized maximum observed plasma concentration (Cmax) | Day 1 |
| Observed Time of the Maximum Concentration (Tmax) | Time from dosing to Cmax, observed by inspection of individual subject plots of plasma concentration versus time. | Day 1 |
| 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. | Day 1 |
| 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. | Day 1 |
| 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. | Day 1 |
| Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | Metabolite (apomorphine sulfate) to Parent exposure ratio, Cmax, corrected for molecular weight differences. | Day 1 |
| 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. |
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Inclusion Criteria:
Male or female ≥ 18 years of age.
Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank Criteria (excluding the "more than one affected relative" criterion).
Clinically meaningful response to Levodopa (L-Dopa) with well-defined "OFF" episodes, as determined by the Investigator.
Receiving APOKYN® of ≤ 5 mg per dose for at least 4 weeks before the Screening Visit.
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.
No planned medication change(s) or surgical intervention anticipated during the course of study.
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
Stage III or less on the modified Hoehn and Yahr scale in the "ON" state.
Mini-Mental State Examination (MMSE) score > 23.
If female and of childbearing potential, must agree to use one of the following methods of birth control:
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.
Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study-related procedures to complete the study.
Able to understand the consent form, and to provide written informed consent
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| CNS Mecdical Director | Sunovion Pharmacetuicals Inc. | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Parkinson's Disease and Movement Disorders Center of Boca Raton | Boca Raton | Florida | 33486 | United States | ||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33991326 | Derived | Agbo F, Isaacson SH, Gil R, Chiu YY, Brantley SJ, Bhargava P, Navia B. Pharmacokinetics and Comparative Bioavailability of Apomorphine Sublingual Film and Subcutaneous Apomorphine Formulations in Patients with Parkinson's Disease and "OFF" Episodes: Results of a Randomized, Three-Way Crossover, Open-Label Study. Neurol Ther. 2021 Dec;10(2):693-709. doi: 10.1007/s40120-021-00251-6. Epub 2021 May 15. |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| First Intervention |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 10, 2017 | Jun 20, 2020 |
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| APO-go | Drug | Subcutaneous APO-go |
|
|
| Apokyn | Drug | Subcutaneous APOKYN |
|
|
| Day 1 |
| Apparent Volume of Distribution After Non-intravenous Administration (V/F) | Apparent volume of distribution after extravascular administration, calculated as Dose/(AUCinf * λz). | Day 1 |
| Terminal-phase Half-life (t½) | Terminal phase half-life, as calculated by the following equation: t½ = ln(2)/λz. | Day 1 |
| 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. | Day 1 |
| Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | Metabolite (apomorphine sulfate) to Parent exposure ratio, AUClast, corrected for molecular weight differences. | Day 1 |
| Parkinson's Disese Treatment Center of SW Florida |
| Port Charlotte |
| Florida |
| 33980 |
| United States |
| QUEST Research Institute | Farmington Hills | Michigan | 48334 | United States |
| FG001 | 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. |
| FG002 | 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. |
| FG003 | 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. |
| FG004 | 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. |
| FG005 | 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. |
| COMPLETED |
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| NOT COMPLETED |
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| First Washout |
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| Second Intervention |
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| Second Washout |
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| Third Intervention |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| BG001 | 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. |
| BG002 | 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. |
| BG003 | 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. |
| BG004 | 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. |
| BG005 | 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. |
| BG006 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
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| Age, Continuous | Mean | Standard Deviation | Years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Country | Count of Participants | Participants |
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| Height (cm) at Baseline | Mean | Standard Deviation | cm |
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| Body Weight (kg) at Baseline | Mean | Standard Deviation | kg |
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| BMI (kg/m2) at Baseline | Mean | Standard Deviation | kg/m^2 |
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| ON State Mod. Hoehn & Yahr Score | The modified Hoehn and Yahr Scale (HYS) provides a global assessment of severity in Parkinson's Disease based on clinical findings and functional disability.•Stage 0:(No signs of disease, through Stage 5: Wheelchair bound or bedridden unless aided. Higher rates describe an increase severity of the disease. | Mean | Standard Deviation | Score |
| ||||||||||||||
| Mini-Mental Status Total Score | Mini-Mental State Examination (MMSE) is used to evaluate a person's cognitive and mental function. Score range is 0-30 with lower scores showing higher impairment. | Mean | Standard Deviation | Score |
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| Child-bearing potential | Count of Participants | Participants |
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| Smoking Status | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Maximum Observed Plasma Concentration (Cmax) | Dose normalized maximum observed plasma concentration (Cmax) | Posted | Geometric Least Squares Mean | 90% Confidence Interval | (ng/mL)/(mg) | Day 1 |
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| 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. | Tmax summary statistics were summarized by dose levels and the inferential statistics was done across all dose levels. | Posted | Median | Full Range | hour | Day 1 |
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| 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. | Posted | Geometric Least Squares Mean | 90% Confidence Interval | (hxng/mL)/(mg) | Day 1 |
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| 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. | Posted | Geometric Least Squares Mean | 90% Confidence Interval | (hxng/mL)/(mg) | Day 1 |
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| 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. | MRT was summarized by dose level | Posted | Geometric Mean | Geometric Coefficient of Variation | h | Day 1 |
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| Primary | Metabolite/Parent (M/P) Drug Concentration Ratio -Cmax | Metabolite (apomorphine sulfate) to Parent exposure ratio, Cmax, corrected for molecular weight differences. | Metabolite/Parent Cmax summarized by dose level | Posted | Geometric Mean | Geometric Coefficient of Variation | no unit | Day 1 |
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| 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. | CL/F summarized by dose level | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Day 1 |
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| Primary | Apparent Volume of Distribution After Non-intravenous Administration (V/F) | Apparent volume of distribution after extravascular administration, calculated as Dose/(AUCinf * λz). | V/F summarized by dose level | Posted | Geometric Mean | Geometric Coefficient of Variation | L | Day 1 |
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| Primary | Terminal-phase Half-life (t½) | Terminal phase half-life, as calculated by the following equation: t½ = ln(2)/λz. | Terminal-phase half-life summarized by dose level | Posted | Geometric Mean | Geometric Coefficient of Variation | h | Day 1 |
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| 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. | terminal-phase rate constant summarized by dose level | Posted | Geometric Mean | Geometric Coefficient of Variation | /h | Day 1 |
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| Primary | Metabolite/Parent (M/P) Drug Concentration Ratio -AUC Last | Metabolite (apomorphine sulfate) to Parent exposure ratio, AUClast, corrected for molecular weight differences. | Metabolite/Parent (M/P) drug concentration Ratio -AUC last summarized by dose level | Posted | Geometric Mean | Geometric Coefficient of Variation | no unit | Day 1 |
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16 days
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | APL-130277, Sublingual Thin Film | APL-130277, sublingual thin film, once daily | 0 | 8 | 1 | 8 | 1 | 8 |
| EG001 | Subcutaneous APOKYN | Subcutaneous APOKYN, once daily | 0 | 7 | 0 | 7 | 1 | 7 |
| EG002 | Subcutaneous APO-go | Subcutaneous APO-go, once daily | 0 | 8 | 0 | 8 | 3 | 8 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fall | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
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| Rib fracture | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
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| Splenic rupture | Injury, poisoning and procedural complications | MedDRA 19.1 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 19.1 | Systematic Assessment |
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| Injection site bruising | General disorders | MedDRA 19.1 | Systematic Assessment |
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| Dyskinesia | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA 19.1 | Systematic Assessment |
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| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 19.1 | Systematic Assessment |
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In the event the Study is part of a multi-center study, the first publication of the results of the Study shall be made in conjunction with the results of other participating study sites as a multi-center publication; provided however, if a multi-center publication is not forthcoming within twenty-four (24) months following completion of the Study at all sites, Institution and Investigator shall be free to publish.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| CNS Medical Director | Sunovion Pharmaceuticals Inc. | 1-866-503-6351 | clinicaltrialsdisclosure@sunovion.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 7, 2019 | Jun 20, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |
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| ID | Term |
|---|---|
| D001058 | Apomorphine |
| ID | Term |
|---|---|
| D001060 | Aporphines |
| D044182 | Benzylisoquinolines |
| D000470 | Alkaloids |
| D006571 | Heterocyclic Compounds |
| D007546 | Isoquinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006576 | Heterocyclic Compounds, 4 or More Rings |
Not provided
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| Between 18 and 65 years |
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| >=65 years |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
|
| Unknown or Not Reported |
|
| No |
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| N/A |
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| Former Smoker |
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| Geometric Mean ratio (APL-130277/APO-go) | 10.3 | 2-Sided | 90 | 6.5 | 16.3 | Other |
| Geometric Mean ratio (APOKYN/APO-go) | 83.4 | 2-Sided | 90 | 50.5 | 137.6 | Other | relative bioavailibilty |
| Ratio | 0.21 | The comparative bioavailability calculated as the ratio of the Test/Reference between APL 20 mg and APO-Go 3 mg | Other |
| Ratio | 0.13 | The comparative bioavailability calculated as the ratio of the Test/Reference between APL 20 mg and APOKYN 3 mg | Other |
| Ratio | 1.16 | The comparative bioavailability calculated as the ratio of the Test/Reference between APO-Go 3 mg and APOKYN 3 mg | Other |
| Ratio | 0.16 | The comparative bioavailability calculated as the ratio of the Test/Reference between APL 25 mg and APO-Go 4 mg | Other |
| Ratio | 0.17 | The comparative bioavailability calculated as the ratio of the Test/Reference between APL 25 mg and APOKYN 4 mg | Other |
| Ratio | 1.12 | The comparative bioavailability calculated as the ratio of the Test/Reference between APO-Go 4 mg and APOKYN 4 mg | Other |
| Ratio | 0.08 | The comparative bioavailability calculated as the ratio of the Test/Reference between APL 30 mg and APO-Go 5 mg | Other |
| Ratio | 0.09 | The comparative bioavailability calculated as the ratio of the Test/Reference between APL 30 mg and APOKYN 5 mg | Other |
| Ratio | 1.04 | The comparative bioavailability calculated as the ratio of the Test/Reference between APO-Go 5 mg and APOKYN 5 mg | Other |
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