|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Parkinson´s disease inadequately controlled on a stable regimen of anti-Parkinsonian medications.
|E.1.2 Medical condition or disease under investigation
|E.1.2||Classification code ||10013113
|E.1.2||Term ||Disease Parkinson's
|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 evaluate the safety, tolerability and efficacy of SYN118 when administered to subjects with PD who are inadequately controlled on a stable regimen of anti-Parkinson‟s medications.
|E.2.2||Secondary objectives of the trial ||
|To improve control of PD symptoms for subjects inadequatelly treated with antiparkinsonian medication.
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
|1. Male and female subjects with a confirmed diagnosis of
idiopathic Parkinson‟s disease (PD), meeting the UK
Parkinson‟s Disease Society Brain Bank diagnostic criteria
[Daniel et al., 1993], of a greater than 1 year duration, who
are otherwise healthy and fulfill all of the inclusion criteria
and none of the exclusion criteria.
2. Age range 40 – 85 years.
3. Modified Hoehn and Yahr Stage 2-4.
4. Subjects in the “fluctuating” stage of PD with an average of at
least 2 hours and no more than 6 hours “off” time during
awake hours from the 24-hour patient diaries taken during the
2 consecutive days directly preceding the scheduled
Baseline/Day 1 visit.
5. Subjects who have been levodopa-responsive for at least
1 year and taking at least 4 doses per day (or at least 3 doses
per day if 2 or more are a sustained-release formulation).
Note: Combination products containing levodopa and
levodopa/carbidopa with a COMT inhibitor in one fixed
dosage form (Stalevo®) are permitted.
6. If receiving allowed anti-Parkinson‟s medication(s) other than
levodopa, subjects must have been clinically stable on the
same dose for a minimum of 30 days before randomization.
7. A Unified Parkinson‟s Disease Rating Scale (UPDRS) III
Motor Examination score greater than 25 in defined “off”
state at the screening and baseline assessment.
8. Mini-mental state examination (MMSE) score greater than 24
to rule out dementia.
9. Good general health, free from significant co-morbid illnesses
that could interfere with evaluation of study drug, as
ascertained by detailed medical history and physical and
10. Able to provide and have signed an Institutional Review
Board/Independent Ethics Committee-approved written
informed consent form to participate in this study.
11. Plasma creatinine less than or equal to 2.2 mg/dL or
12. Women with no childbearing potential; ie, woman who are
surgically sterile or woman who have been post-menopausal
for at least 1 year as confirmed by follicle-stimulating
hormone (FSH) greater than or equal to 40 mIU/mL or
Men who have a sterile or post-menopausal sexual partner or
have agreed to use contraception (eg, use of a condom with
spermicide or use by partner of oral, implantable or injectable
contraceptives, intrauterine device [IUD], diaphragm with
spermicide), starting at the time of study drug administration
and for a period of 1 month after the end of the study.
13. Achieved the following results for PD diary training and
baseline diary recordings:
a. Completed the protocol-specified diary training during the
screening period and achieved at least 75% diary
concordance with the site trainer/rater.
b. Returned diary recordings for the 2 consecutive days (ie, 2
consecutive 24-hour periods) directly preceding the
Baseline/Day 1 visit that have not more than 4 invalid
entries per 24-hour period. An invalid diary entry is
defined as more than 1 entry recorded in a given half-hour
interval or the absence of an entry in a given half-hour
Note: Subjects who are otherwise eligible but do not meet the
criteria for proper diary completion may be retrained and can
return for another baseline assessment within the 3-week
window of the screening period.
14. Able to understand study requirements and able and willing to
follow instructions, attend all required study visits, and
undergo all planned tests.
|E.4||Principal exclusion criteria||
|1. Atypical or secondary parkinsonism.
2. Prior neurosurgical operation for Parkinson‟s disease (PD).
3. Subjects being treated concomitantly with both a COMT and a
4. Subjects taking or requiring adjunctive therapy for
Parkinson‟s disease (PD) with apomorphine.
5. Subjects treated with intraduodenal preparations of levodopa
(eg, Duodopa) or with intradermal levodopa delivered with a
6. Subjects with a dyskinesia score of 3 or 4 on UPDRS subscale
IV, Item 33 at the screening or baseline assessment; peak-dose
dyskinesia will not exclude otherwise eligible subjects.
7. Any 12-lead ECG with any of the following abnormalities at
screening: 2nd or 3rd degree heart block, conduction
disorders, ventricular and/or atrial arrhythmias; (1st degree
bradycardia: non-specific ST and T wave changes are
acceptable if reviewed, approved and documented as not
clinically significant [NCS] by the Investigator).
8. Subjects with active ocular disease (not including cataracts)
including but not limited to: infection, inflammation, macular
degeneration, optic nerve degeneration.
9. History of conjunctivitis, corneal opacity, keratitis,
photophobia, or blepharitis in the past 2 years.
10. Subjects who have been diagnosed and/or require therapy to
treat a psychiatric disorder other than depression including but
not limited to Parkinson‟s dementia or drug induced
hallucinations/paranoia, dementia, schizophrenia or bipolar
11. Geriatric Depression Scale (short form) score greater than 8.
12. Subjects receiving treatment for depression with antidepressants
if they have not been on a stable dose for 30 days
prior to randomization.
13. Any other condition or clinically significant abnormal
findings on the physical or neurological examination (eg,
multiple system atrophy, recent stroke), medical and
psychiatric history, or clinical laboratory results at screening
that, in the opinion of the Investigator, make the subject
unsuitable for the study or put the subject at additional risk.
14. Potential exposure to SYN118 (Orfadin®, nitisinone) outside
the context of the present trial.
15. Subjects who require drugs that are inducers of the P450
CYP3A4 isoenzyme including, HIV antivirals (efavirenz,
nevirapine), barbiturates, carbamazepine, glucocorticoids,
modafinil, phenobarbital, phenytoin, rifampin, St. John's
wort, troglitazone, oxcarbazepine, pioglitazone, rifabutin.
The following site may be referred to in determining whether
drugs not listed can induce this enzyme:
16. Preparations containing iron and/or amino acids, for example
some multi-vitamin/mineral preparations or nutritional
17. Received treatment with any other investigational drug within
5 half-lives or 30 days prior to signature of informed consent,
whichever is longer, or any investigational device within 30
days prior to signature of informed consent.
18. Pregnant or lactating females.
|E.5 End points
|E.5.1||Primary end point(s)||
|This is an exploratory study, no primary endpoints defined.
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| 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.126.96.36.199||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.8.1.3||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.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| No
|E.8.2.2||Placebo || Yes
The trial involves single site in the Member State concerned
|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||5
|E.8.5||The trial involves multiple Member States|| Yes
|E.8.5.1||Number of sites anticipated in the EEA||13
|E.8.6 Trial involving sites outside the EEA
|E.8.6.1||Trial being conducted both within and outside the EEA|| No
|E.8.6.2||Trial being conducted completely outside of the EEA|| Information not present in EudraCT
|E.8.7||Trial has a data monitoring committee|| No
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||1
|E.8.9.1||In the Member State concerned months||3
|E.8.9.1||In the Member State concerned days||0
|E.8.9.2||In all countries concerned by the trial years||1
|E.8.9.2||In all countries concerned by the trial months||3
|E.8.9.2||In all countries concerned by the trial days||0