Parkinson's Disease
Conditions
Keywords
Parkinson Disease, BIA 9-1067
Brief summary
The purpose of this study is to investigate the tolerability and the effect of BIA 9-1067 at steady-state on the levodopa pharmacokinetics in Parkinson's Disease (PD) patients treated with levodopa/dopa-decarboxylase inhibitor.
Detailed description
Multicentre, double-blind, randomised, placebo-controlled study in four parallel groups of PD patients treated with standard-release levodopa/carbidopa 100/25 mg (Sinemet®) or levodopa/benserazide 100/25 mg (Madopar®/Restex®) and with motor fluctuations (wearing-off phenomenon)
Interventions
DRUGPlacebo
once-daily
DRUGBIA 9-1067
BIA 9-1067 - 5 mg single-dose
Levodopa 100 mg Carbidopa 25 mg
Levodopa 100 mg Benzerazide 25 mg
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
Healthy volunteers
No
Inclusion criteria
At screening (admission to the baseline period): * Male or female of non-childbearing potential (by reason of surgery or postmenopausal); * Age ≥ 30 years; * A diagnosis of PD according to the UK PDS Brain Bank diagnostic criteria (bradykinesia and at least one of the following: muscular rigidity, rest tremor and postural instability); * Predictable signs of end-of-dose deterioration despite optimal levodopa/carbidopa or levodopa/benserazide therapy; * Modified Hoehn and Yahr stage of less than 5 in the off state; mean duration of off state ≥ 1.5 h during waking hours (based on historical information); * Results of clinical laboratory tests acceptable by the investigator (not clinically significant for the well-being of the patient or for the purpose of the study); * Able and willing to give written informed consent. At randomisation (completion of the baseline period): * Been treated with a stable regimen of 3 to 8 doses per day of standard-release levodopa/carbidopa 100/25 mg (Sinemet®) or levodopa/benserazide 100/25 mg (Madopar®/Restex®) for at least 1 week prior to randomisation; * Mean duration of off state ≥ 1.5 h during waking hours (average of recordings of last 3 evaluable days on patient's diary); * Concomitant anti-Parkinsonian medication (other than apomorphine, entacapone or tolcapone) in stable doses for at least 4 weeks prior to admission.
Exclusion criteria
At screening (admission to the baseline period): * Non-idiopathic parkinsonism (atypical parkinsonism, symptomatic parkinsonism, Parkinson-plus syndrome); * Treated with entacapone, tolcapone, neuroleptics, antidepressants (except serotonin-specific reuptake inhibitors or imipramines \[desipramine, imipramine, clomipramine and amitriptyline\]), monoamine oxidase inhibitors (except selegiline up to 10 mg/day in oral formulation or 1.25 mg/day in buccal absorption formulation or rasagiline up to 1 mg/day) or antiemetics (except domperidone) within 2 weeks prior to admission; * Treated with any investigational product within 1 month prior to admission (or within 5 half-lives, whichever is longer); * A psychiatric or any medical condition that might place him/her at increased risk or interfere with assessments; * Known hypersensitivity to any of the ingredients of the investigational products; * A history of abuse of alcohol, drugs or medications within the last 2 years; * A clinically relevant ECG abnormality; * A history or current evidence of heart disease, including but not limited to myocardial infarction, angina, congestive heart failure and cardiac arrhythmia; * Unstable concomitant disease being treated with changing doses of medication; * A history or current evidence of any relevant disease in the context of this study, i.e., with respect to the safety of the patient (e.g., hepatic impairment) or related to the study conditions; * A test positive for the HIV-1 or HIV-2 antibodies, or hepatitis B surface antigen (HbsAg), or hepatitis C antibody (HCVAb); * Donated blood or received blood or blood products within the 6 months prior to admission; * Pregnant, breast-feeding or of childbearing potential; * Other condition or circumstance that, in the opinion of the investigator, may compromise the patient's ability to comply with the study protocol. At randomisation (completion of the baseline period): * Treated with levodopa/DDCI in a 10:1 ratio or in a controlled-release formulation during the baseline period; * Treated with apomorphine during the baseline period; * A clinically relevant ECG abnormality.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax - Observed Maximum Concentration | 28 days | Baseline period - to be switched respectively to standard-release levodopa/carbidopa 100/25 mg (Sinemet®) or levodopa/benserazide 100/25 mg (Madopar®/Restex®) and to adjust the number of daily doses. Test Period - After the baseline period during the 21 to 28 days |
| Tmax - Time to Observed Maximum Concentration | 28 days | Baseline period - to be switched respectively to standard-release levodopa/carbidopa 100/25 mg (Sinemet®) or levodopa/benserazide 100/25 mg (Madopar®/Restex®) and to adjust the number of daily doses. Test Period - After the baseline period during the 21 to 28 days |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | 28 days | Baseline period - to be switched respectively to standard-release levodopa/carbidopa 100/25 mg (Sinemet®) or levodopa/benserazide 100/25 mg (Madopar®/Restex®) and to adjust the number of daily doses. Test Period - After the baseline period during the 21 to 28 days |
Countries
Romania, Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo PLC, Placebo | 10 |
| BIA 9-1067 (5 mg) 5 mg BIA 9-1067 - OPC, Opicapone | 10 |
| BIA 9-1067 (15 mg) 15 mg BIA 9-1067 - OPC, Opicapone | 10 |
| BIA 9-1067 (30 mg) 30 mg BIA 9-1067 - OPC, Opicapone | 10 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 1 |
| Overall Study | Ineligibility | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | BIA 9-1067 (5 mg) | BIA 9-1067 (15 mg) | BIA 9-1067 (30 mg) | Total |
|---|---|---|---|---|---|
| Age, Customized ≤ 49 years | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age, Customized ≥ 88 years | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Age, Customized Between 49 and 88 years | 10 participants | 10 participants | 10 participants | 10 participants | 40 participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 4 Participants | 5 Participants | 20 Participants |
| Sex: Female, Male Male | 5 Participants | 4 Participants | 6 Participants | 5 Participants | 20 Participants |
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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 10 | 1 / 10 | 1 / 10 | 4 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Cmax - Observed Maximum Concentration
Baseline period - to be switched respectively to standard-release levodopa/carbidopa 100/25 mg (Sinemet®) or levodopa/benserazide 100/25 mg (Madopar®/Restex®) and to adjust the number of daily doses. Test Period - After the baseline period during the 21 to 28 days
Time frame: 28 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Cmax - Observed Maximum Concentration | Cmax (levodopa) Test | 1203 ng/mL | Standard Deviation 29.4 |
| Placebo | Cmax - Observed Maximum Concentration | Cmax (3-OMD) Baseline | 4701 ng/mL | Standard Deviation 46.7 |
| Placebo | Cmax - Observed Maximum Concentration | Cmax (levodopa) Baseline | 1484 ng/mL | Standard Deviation 26 |
| Placebo | Cmax - Observed Maximum Concentration | Cmax (3-OMD) Test | 3770 ng/mL | Standard Deviation 45 |
| Placebo | Cmax - Observed Maximum Concentration | Cmax (BIA 9-067) Test | NA ng/mL | — |
| BIA 9-1067 5 mg | Cmax - Observed Maximum Concentration | Cmax (BIA 9-067) Test | 240 ng/mL | Standard Deviation 186 |
| BIA 9-1067 5 mg | Cmax - Observed Maximum Concentration | Cmax (levodopa) Test | 1868 ng/mL | Standard Deviation 31.8 |
| BIA 9-1067 5 mg | Cmax - Observed Maximum Concentration | Cmax (3-OMD) Test | 2633 ng/mL | Standard Deviation 21.2 |
| BIA 9-1067 5 mg | Cmax - Observed Maximum Concentration | Cmax (levodopa) Baseline | 1446 ng/mL | Standard Deviation 37.6 |
| BIA 9-1067 5 mg | Cmax - Observed Maximum Concentration | Cmax (3-OMD) Baseline | 4631 ng/mL | Standard Deviation 31.6 |
| BIA 9-1067 15 mg | Cmax - Observed Maximum Concentration | Cmax (3-OMD) Baseline | 3529 ng/mL | Standard Deviation 50.7 |
| BIA 9-1067 15 mg | Cmax - Observed Maximum Concentration | Cmax (3-OMD) Test | 1197 ng/mL | Standard Deviation 71.8 |
| BIA 9-1067 15 mg | Cmax - Observed Maximum Concentration | Cmax (levodopa) Baseline | 1753 ng/mL | Standard Deviation 43.4 |
| BIA 9-1067 15 mg | Cmax - Observed Maximum Concentration | Cmax (levodopa) Test | 1806 ng/mL | Standard Deviation 28.4 |
| BIA 9-1067 15 mg | Cmax - Observed Maximum Concentration | Cmax (BIA 9-067) Test | 233 ng/mL | Standard Deviation 71.8 |
| BIA 9-1067 30 mg | Cmax - Observed Maximum Concentration | Cmax (3-OMD) Test | 1603 ng/mL | Standard Deviation 36.2 |
| BIA 9-1067 30 mg | Cmax - Observed Maximum Concentration | Cmax (levodopa) Baseline | 1832 ng/mL | Standard Deviation 49.1 |
| BIA 9-1067 30 mg | Cmax - Observed Maximum Concentration | Cmax (3-OMD) Baseline | 6222 ng/mL | Standard Deviation 63.6 |
| BIA 9-1067 30 mg | Cmax - Observed Maximum Concentration | Cmax (BIA 9-067) Test | 480 ng/mL | Standard Deviation 64.4 |
| BIA 9-1067 30 mg | Cmax - Observed Maximum Concentration | Cmax (levodopa) Test | 2584 ng/mL | Standard Deviation 33.7 |
Primary
Tmax - Time to Observed Maximum Concentration
Baseline period - to be switched respectively to standard-release levodopa/carbidopa 100/25 mg (Sinemet®) or levodopa/benserazide 100/25 mg (Madopar®/Restex®) and to adjust the number of daily doses. Test Period - After the baseline period during the 21 to 28 days
Time frame: 28 days
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Tmax - Time to Observed Maximum Concentration | Cmax (3-OMD) Test | 2.0 ng/mL |
| Placebo | Tmax - Time to Observed Maximum Concentration | Cmax (levodopa) Test | 1.0 ng/mL |
| Placebo | Tmax - Time to Observed Maximum Concentration | Cmax (BIA 9-067) Test | NA ng/mL |
| Placebo | Tmax - Time to Observed Maximum Concentration | Cmax (3-OMD) Baseline | 2.0 ng/mL |
| Placebo | Tmax - Time to Observed Maximum Concentration | Cmax (levodopa) Baseline | 1.0 ng/mL |
| BIA 9-1067 5 mg | Tmax - Time to Observed Maximum Concentration | Cmax (3-OMD) Baseline | 3.0 ng/mL |
| BIA 9-1067 5 mg | Tmax - Time to Observed Maximum Concentration | Cmax (3-OMD) Test | 1.5 ng/mL |
| BIA 9-1067 5 mg | Tmax - Time to Observed Maximum Concentration | Cmax (BIA 9-067) Test | 2.0 ng/mL |
| BIA 9-1067 5 mg | Tmax - Time to Observed Maximum Concentration | Cmax (levodopa) Test | 1.0 ng/mL |
| BIA 9-1067 5 mg | Tmax - Time to Observed Maximum Concentration | Cmax (levodopa) Baseline | 1.0 ng/mL |
| BIA 9-1067 15 mg | Tmax - Time to Observed Maximum Concentration | Cmax (3-OMD) Baseline | 2.25 ng/mL |
| BIA 9-1067 15 mg | Tmax - Time to Observed Maximum Concentration | Cmax (levodopa) Baseline | 0.5 ng/mL |
| BIA 9-1067 15 mg | Tmax - Time to Observed Maximum Concentration | Cmax (levodopa) Test | 0.75 ng/mL |
| BIA 9-1067 15 mg | Tmax - Time to Observed Maximum Concentration | Cmax (3-OMD) Test | 3.0 ng/mL |
| BIA 9-1067 15 mg | Tmax - Time to Observed Maximum Concentration | Cmax (BIA 9-067) Test | 2.0 ng/mL |
| BIA 9-1067 30 mg | Tmax - Time to Observed Maximum Concentration | Cmax (3-OMD) Test | 3.0 ng/mL |
| BIA 9-1067 30 mg | Tmax - Time to Observed Maximum Concentration | Cmax (levodopa) Test | 0.5 ng/mL |
| BIA 9-1067 30 mg | Tmax - Time to Observed Maximum Concentration | Cmax (levodopa) Baseline | 1.0 ng/mL |
| BIA 9-1067 30 mg | Tmax - Time to Observed Maximum Concentration | Cmax (3-OMD) Baseline | 3.0 ng/mL |
| BIA 9-1067 30 mg | Tmax - Time to Observed Maximum Concentration | Cmax (BIA 9-067) Test | 2.0 ng/mL |
Secondary
AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6])
Baseline period - to be switched respectively to standard-release levodopa/carbidopa 100/25 mg (Sinemet®) or levodopa/benserazide 100/25 mg (Madopar®/Restex®) and to adjust the number of daily doses. Test Period - After the baseline period during the 21 to 28 days
Time frame: 28 days
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (3-OMD) Test | 21228 ng.h/mL | Standard Deviation 45.4 |
| Placebo | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (levodopa) Baseline | 2841 ng.h/mL | Standard Deviation 30.6 |
| Placebo | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (BIA 9-067) Test | NA ng.h/mL | — |
| Placebo | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (3-OMD) Baseline | 23301 ng.h/mL | Standard Deviation 39.7 |
| Placebo | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (levodopa) Test | 2510 ng.h/mL | Standard Deviation 27.7 |
| BIA 9-1067 5 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (3-OMD) Baseline | 23934 ng.h/mL | Standard Deviation 28.3 |
| BIA 9-1067 5 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (3-OMD) Test | 14883 ng.h/mL | Standard Deviation 22.2 |
| BIA 9-1067 5 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (levodopa) Baseline | 3451 ng.h/mL | Standard Deviation 45.2 |
| BIA 9-1067 5 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (levodopa) Test | 4041 ng.h/mL | Standard Deviation 18.3 |
| BIA 9-1067 5 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (BIA 9-067) Test | 627 ng.h/mL | Standard Deviation 202 |
| BIA 9-1067 15 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (3-OMD) Baseline | 18748 ng.h/mL | Standard Deviation 58.8 |
| BIA 9-1067 15 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (levodopa) Baseline | 2734 ng.h/mL | Standard Deviation 50.4 |
| BIA 9-1067 15 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (levodopa) Test | 4044 ng.h/mL | Standard Deviation 38.7 |
| BIA 9-1067 15 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (3-OMD) Test | 6685 ng.h/mL | Standard Deviation 73.1 |
| BIA 9-1067 15 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (BIA 9-067) Test | 698 ng.h/mL | Standard Deviation 73.1 |
| BIA 9-1067 30 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (3-OMD) Test | 9059 ng.h/mL | Standard Deviation 36.5 |
| BIA 9-1067 30 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (levodopa) Test | 6297 ng.h/mL | Standard Deviation 25.5 |
| BIA 9-1067 30 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (levodopa) Baseline | 3862 ng.h/mL | Standard Deviation 35.1 |
| BIA 9-1067 30 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (3-OMD) Baseline | 34177 ng.h/mL | Standard Deviation 61.9 |
| BIA 9-1067 30 mg | AUC0-6 - Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to to 6 h Postdose (AUC [0-6]) | AUC0-6 (BIA 9-067) Test | 1188 ng.h/mL | Standard Deviation 54.8 |