| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10013113 |
| E.1.2 | Term | Disease Parkinson's |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To investigate the effect of repeated dosing of BIA 9-1067 (5 mg, 15 mg and 30 mg, once-daily) on the levodopa
pharmacokinetics, in comparison to placebo, in Parkinson’s Disease (PD) patients with motor fluctuations. |
|
| E.2.2 | Secondary objectives of the trial |
- To investigate the tolerability and safety of repeated dosing of BIA 9-1067 (5 mg, 15 mg and 30 mg, oncedaily),
in comparison with placebo, in PD patients with motor fluctuations.
- To investigate the effect of repeated dosing of BIA 9-1067 (5 mg, 15 mg and 30 mg, once-daily) on motor
response to standard-release levodopa/carbidopa 100 mg/25 mg or levodopa/benserazide 100 mg/25 mg, in
comparison with placebo, in PD patients with motor fluctuations.
- To investigate the effect of repeated dosing of BIA 9-1067 (5 mg, 15 mg and 30
mg, once-daily) on erythrocyte soluble catechol-O-methyltransferase (S-COMT) activity, in comparison with
placebo, in PD patients with motor fluctuations.
- To investigate the pharmacokinetics of BIA 9-1067 following repeated dosing (5 mg, 15 mg and 30 mg, oncedaily)
in PD patients with motor fluctuations. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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;
|
|
| E.4 | Principal 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 imipraminics [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.
E |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- for levodopa, 3-OMD, BIA 9-1067 and BIA 9-1079: maximum observed plasma concentration (Cmax); time of
occurrence of Cmax (tmax); area under the plasma concentration-time curve (AUC) from time zero to 6 h postdose
(AUC0-6), and AUC from time zero to the last quantified concentration (AUC0-t), calculated by the linear
trapezoidal rule; AUC from time zero to infinity (AUC0-∞), calculated from AUC0-t + (Clast/λz).
- maximum inhibition of S-COMT activity (Emax), time of occurrence of Emax (tEmax); maximum percent (%)
inhibition of S-COMT activity, calculated as [(E0-Emax)/E0]*100
- Second levodopa test versus first levodopa test: Change in “on” duration, change in time to “on”, and change in
time to best “on”
- BIA 9-1067/Placebo period versus baseline period: Change in absolute “off”-time (patient’s diaries), change
in the percentage of “off”-time (patient’s diaries), change in the percentage of “on” time without troublesome
dyskinesia (patient’s diaries), change in UPDRS Section I, change in UPDRS Section II at “off” stage, change in
UPDRS Section III, change in UPDRS Section V, change in UPDRS Section VI, investigator’s global assessment
of change; patient’s global assessment of change, and change in daily number of doses of levodopa/DDCI. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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