A Phase III, Double-Blind, Placebo-Controlled Randomised Trial to Determine the Efficacy and Safety of a Low and High Dose of Safinamide, as Add-on Therapy, in Subjects With Early Idiopathic Parkinson's Disease

Condition(s) targeted: Parkinson's Disease

Intervention: Safinimide 50 mg (Drug); Safinimide (as add-on therapy) (Drug); Safinimide (as add-on therapy) (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: EMD Serono

Official(s) and/or principal investigator(s):
David Weiner, MD, Study Director, Affiliation: Merck Serono International S.A. (non-US), EMD Serono, Inc. (US)

Overall contact:
Russ Palmer, Phone: 781-681-2662, Email: russ.palmer@emdserono.com

Parkinson's disease is a major neurodegenerative disorder in which there is a progressive loss of nigrostriatal dopaminergic neurons. The understanding that PD is a syndrome of dopamine (DA) deficiency led to the introduction in the clinical practice of L-dopa, a precursor of DA that crosses the blood brain barrier, and also to the use of selective inhibitors of MAO B, the major DA metabolising enzyme in man. Recently it has been suggested that they might also slow disease progression by reducing oxidative damage.

Glutamate also plays a role in dopaminergic transmission and may contribute to the pathogenesis of motor fluctuations and neuronal cell loss. By combining inhibition of both MAO-B and glutamate release together, safinamide may represent a new treatment strategy for subjects affected by Parkinson's Disease at the early stage by offering a better control of

the motor symptoms measured by a change in the UPDRS - Section III total score, an

improvement of the cognitive function as measured by standard validated tools together with an acceptable safety profile.

This is a double-blind, placebo-controlled, parallel-group, randomised, multi-centre, multi national, Phase III trial, comparing two doses of safinamide (50 and 100 mg p. o. q. a.m.) versus placebo as add-on therapy to a stable dose of a single dopamine agonist in subjects with early idiopathic Parkinson's Disease.

The principal efficacy measure, i. e., change in mean value of UPDRS - Section III total score

from baseline to endpoint, was chosen based on regulatory guidance and prior use in other trials in similar populations.

Official title: A Phase III, Double-Blind, Placebo-Controlled Randomised Trial to Determine the Efficacy and Safety of a Low (50 mg/Day) and High (100 mg/Day) Dose of Safinamide, as Add-on Therapy, in Subjects With Early Idiopathic Parkinson's Disease Treated With a Stable Dose of a Single Dopamine Agonist

Study design: Treatment, Randomized, Double Blind (Subject, Investigator), Parallel Assignment

Primary outcome: Evaluate the changes from baseline to W24 in motor symptoms (UPDRS Section III).

Secondary outcome: Evaluate the changes from baseline to W24 in activities of daily living, cognition, change in global clinical status and health related quality of life

Minimum age: 30 Years. Maximum age: 80 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

1. Diagnosis of idiopathic Parkinson's Disease of less than 5 years duration, with a Hoehn and Yahr stage of I-III. The diagnosis should be based on medical history and neurological examination.

2. 30 to 80 years, inclusive, at screening.

3. If female, be either post menopausal for at least 2 years, surgically sterilised or have undergone hysterectomy or, if of child bearing potential they must be willing to avoid pregnancy by using an adequate method of contraception as defined in Section Error! Reference source not found. for four weeks prior to, during and four weeks after the last dose of study medication. For the purposes of this study, women of childbearing potential are defined as all female subjects after puberty unless they are post-menopausal for at least two years, are surgically sterile or are sexually inactive.

4. Receiving treatment with a single dopamine agonist at a stable dose for at least 4 weeks prior to the screening visit.

5. Willing and able to participate in the study and have provided written, informed consent.

Exclusion Criteria:

1. Any indication of forms of Parkinsonism, other than idiopathic Parkinson's Disease.

2. If female, be pregnant or lactating.

3. Current diagnosis of substance abuse or history of alcohol or drug abuse in the past 3 months.

4. Currently experiencing end of dose wearing off or on-off phenomena, disabling peak dose or biphasic dyskinesias, or unpredictable or widely swinging fluctuations.

5. Current clinically significant gastrointestinal, renal, hepatic, endocrine, pulmonary or cardiovascular disease, including acute gastric ulcer, hypertension that is not well controlled, asthma, chronic obstructive pulmonary disease (COPD), and Type I diabetes. Subjects with a history of gastric ulcer who have not had a recent episode of acute gastritis and are not currently experiencing gastric pain will be eligible for inclusion.

6. Second- or third-degree atrioventricular block or sick sinus syndrome, uncontrolled atrial fibrillation, severe or unstable angina, congestive heart failure, myocardial infarction within 3 months of the screening visit, or significant ECG abnormality, including QTc ≥ 450 msec (males) or ≥ 470 msec (females), where QTc is based on Bazett's correction method.

7. Have received treatment with safinamide previously.

8. Concomitant disease likely to interfere with the study medication (e. g. capable of altering absorption, metabolism or elimination of the study drug).

9. History of, or current psychosis (e. g. schizophrenia or psychotic depression) or a score ≥ 3 on item 2 (thought disorder) or 3 (depression) of the UPDRS, Section I at screening.

10. Evidence of dementia or cognitive dysfunction, as indicated by a MMSE score < 24 or a score ≥ 3 on item 1 (mentation) of the UPDRS, Section I at screening.

11. Depression, as indicated by a GRID-HAMD (17-item scale) score > 17 at screening.

12. History of allergic response to anticonvulsants or anti-Parkinsonian agents.

13. Mental or physical condition (e. g., neurotic behaviour, crippling degenerative arthritis, or limb amputation), which would preclude performing efficacy or safety assessments.

14. Hypersensitivity or contraindications to MAO B inhibitors.

15. Current history of severe dizziness or fainting on standing, due to postural hypotension.

16. Neoplastic disorder, which is either currently active or has been in remission for less than one year.

17. Participation in a clinical trial within 30 days of entry into the trial (screening visit) or has received treatment with any investigational compound within 30 days or 5 half-lives, whichever is longer, prior to screening.

18. Treatment of their Parkinsonian symptoms with a medication, other than a stable dose of a single dopamine agonist, during the 8 weeks preceding the screening visit.

19. Treatment with any agent known to significantly inhibit or induce drug-metabolising enzymes (e. g., barbiturates, phenothiazines, etc.) within 4 weeks preceding the screening visit.

20. Treatment with opioids (e. g., tramadol, meperidine derivatives), SNRIs (e. g., venlafaxine, duloxetine), tri- or tetra-cyclic antidepressants, MAO inhibitors (e. g. selegiline), in the 8 weeks prior to the screening visit. Dextromethorphan will be permitted if used for treating cough.

21. Treatment with a depot neuroleptic within one injection cycle, or oral neuroleptics within 4 weeks prior to the screening visit.

22. Treatment with a drug that has hepatotoxic potential, e. g., tamoxifen, within 4 weeks, or received radiation therapy or a drug with cytotoxic potential, e. g., chemotherapy, within one year prior to the screening visit.

23. Diagnosis of HIV, or tests positive for Hepatitis C antibodies, or Hepatitis B surface antigen.

24. Any abnormality that the investigator deems to be clinically relevant, either on medical history, physical examination, ECG or in a diagnostic laboratory test.

25. Ophthalmologic history including any of the following conditions: albino subjects, family history of hereditary retinal disease, progressive and/or severe diminution of visual acuity (i. e., 20/70), retinitis pigmentosa, retinal pigmentation due to any cause, any active retinopathy or ocular inflammation (uveitis), or diabetic retinopathy.

26. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such.

Russ Palmer, Phone: 781-681-2662, Email: russ.palmer@emdserono.com

Dynamik Research Inc., Pointe-Claire, Quebec H9R 3J1, Canada; Recruiting

Starting date: November 2007
Ending date: October 2008
Last updated: August 12, 2008