Safinamide versus placebo in patients with Parkinson’s disease for improvement of motor complications

• Register: EUCTR
• Last refreshed on: 20 February 2017
• Main ID: EUCTR2014-002600-24-SE
• Date of registration: 30/07/2015
• Prospective Registration: Yes
• Primary sponsor: Zambon S.P.A.
• Public title: Safinamide versus placebo in patients with Parkinson’s disease for improvement of motor complications
• Scientific title: A TWO YEAR, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED STUDY TO EVALUATE THE LONG TERM EFFICACY AND SAFETY OF SAFINAMIDE 100 MG, ONCE DAILY, AS ADD ON THERAPY, IN IDIOPATHIC PARKINSON’S DISEASE PATIENTS WITH MOTOR FLUCTUATIONS - EVEREST
• Date of first enrolment: 03/12/2015
• Target sample size: 556
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-002600-24
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, France, Germany, Italy, Russian Federation, Spain, Sweden, Switzerland, United Kingdom

Contacts

• Name: Clinical Trials
• Affiliation: Zambon S.P.A.

• Name: Clinical Trials
• Affiliation: Zambon S.P.A.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male or female subjects aged =40 to =85 years old.
2. Able and willing to provide informed consent.
3. Able to maintain an accurate and complete diary with the help of a caregiver.
4. Diagnosis of IPD using the United Kingdom Parkinson’s Disease Society Brain Bank criteria.
5. Subjects must be receiving treatment with a stable dose of L dopa (including controlled release [CR], immediate release [IR] or a combination of CR/IR), with and without benserazide/carbidopa, with or without addition of a catechol O-methyltransferase (COMT) inhibitor and may be receiving concomitant treatment with stable doses of a dopamine agonist, an anticholinergic and/or amantadine for at least 4 weeks prior to the randomization visit.
6. Subjects must have a Hoehn and Yahr between 2-3 inclusive. during the “ON” phase.
7. Subjects must be experiencing motor fluctuations following optimum titration of treatment medications and within the four weeks immediately prior to randomization.
8. Subjects must be experiencing a minimum of 2.0 hours/day of “OFF” time during the day (excluding morning akinesia).
9. If female, either post-menopausal for at least two years, surgically sterilized or have undergone hysterectomy. Female subjects of child-bearing potential must be willing to avoid pregnancy, have a negative pregnancy test, and should use a highly effective method of birth control for one month prior to randomization, throughout the study duration and up to one month after the last dose of study drug, which include:
• Double barrier (e.g., condom + spermicide; diaphragm + spermicide; condom + diaphragm).
• Intrauterine device.
• Oral contraception needs to be supplemented with a barrier method (e.g., condom or diaphragm).

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 445
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 111

Exclusion criteria:
1. Any form of parkinsonism other than IPD.
2. History of neurosurgical procedure.
3. History of bipolar disorder, schizophrenia or other psychotic disorder.
4. Untreated depressive disorder.
5. Imminent risk of self-harm based on Investigator’s clinical judgment, with a “yes” answer on item 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS) at Screening.
6. History of drug and/or alcohol abuse as per the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM IV-TR) criteria within 12 months prior to Baseline.
7. A Mini Mental State exam (MMSE) total score <24 at Screening.
8. Use of any investigational drug within 30 days prior to Screening or five half-lives, whichever is the longest.
9. Allergy/sensitivity to the IMPs or their excipients.
10. A severe or ongoing unstable medical condition (e.g., cardiac, pulmonary, hepatic, renal, metabolic or endocrine).
11. Any clinically significant condition which, in the opinion of the Investigator, would interfere with the study medication (e.g., capable of altering absorption, metabolism or elimination), the study evaluations or optimal participation in the study.
12. A current history of severe dizziness or fainting on standing due to postural hypotension.
13. Any significant laboratory results which, in the Investigator’s opinion, would not be compatible with study participation or represent a risk for subjects while in the study.
14. A female subject must not be pregnant, breast-feeding or considering breast feeding.
15. History of malignant disease within the five years prior to Screening, in particular melanoma (a dermatological visit will be performed at the Screening visit), with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised, treated in situ cervical cancer, treated in situ prostate cancer with a normal prostate specific antigen.
16. Moderate or severe liver failure using the Child-Pugh classification score.
17. Subjects with known history of hepatitis B or C or human immunodeficiency virus.
18. QTcF > 500 ms.
19. Second- or third-degree atrio-ventricular block or sick sinus syndrome, uncontrolled atrial fibrillation, severe or unstable angina, congestive heart failure, myocardial infarction within three months prior to the randomization visit.
20. Subjects should not have received concomitant treatment with monoamine oxidase inhibitors (MAOIs), pethidine, opioids, serotonin norepinephrine reuptake inhibitors (SNRIs), dextromethorphan or sympathomimetics including nasal and oral decongestants and cold remedies (i.e., preparations that contain vasoconstrictors such as ephedrine, pseudoephedrine, phenylephrine, and phenylpropanolamine) in the four weeks prior to the randomization visit.
21. Subjects should not have received treatment with an oral or depot neuroleptic within 12 weeks prior to the randomization visit.
22. Subjects should not have severe, disabling peak dose or biphasic dyskinesia and/or unpredictable or widely swinging fluctuations.
23. Subjects should not have signs and symptoms suggestive of transmissible spongiform encephalopathy or family member who suffer(ed) from such.
24. Subjects should not have ophthalmologic history including any of the following conditions: albinism, uveitis, retinitis pigmentosa, retinal degeneration, active retinopathy, severe progressive diabetic retinopathy, inherited retinopathy or family hist

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Idiopathic Parkinson's Disease
MedDRA version: 18.0 Level: PT Classification code 10061536 Term: Parkinson's disease System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Trade Name: Xadago
Product Name: safinamide
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SAFINAMIDE
CAS Number: 133865-89-1
Other descriptive name: SAFINAMIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Xadago
Product Name: safinamide
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SAFINAMIDE
CAS Number: 133865-89-1
Other descriptive name: SAFINAMIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

Primary end point(s): Primary Efficacy Endpoint:
• Mean change in the daily “OFF” time from Baseline to Endpoint (Week 96).

Secondary Objective: Key secondary:
To evaluate the change from Baseline to Endpoint in the daily “ON” time without dyskinesia.
Other main secondary:
To evaluate the change from Baseline to Endpoint in PDQ-39, UDysRS, UPDRS II, UPDRS III, UPDRS total score, NMS, daily “ON” time with troublesome dyskinesia
Safety:
To evaluate the long-term safety and tolerability of safinamide compared with placebo

Timepoint(s) of evaluation of this end point: 96 weeks

Main Objective: To evaluate the change from Baseline to Endpoint in the daily “OFF” time of safinamide compared to placebo

Secondary Outcome(s)

Secondary end point(s): Secondary Efficacy Endpoints:
Key secondary efficacy endpoint:
• Mean change in the daily “ON” time without dyskinesia from Baseline to Endpoint (Week 96).
Other secondary efficacy endpoints:
• Mean change in the PDQ-39 total score from Baseline to Endpoint (Week 96).
• Mean change in the UDysRS total score during the “ON” phase from Baseline to Endpoint (Week 96).
• Mean change in the daily “ON” time with troublesome dyskinesia from Baseline to Endpoint (Week 96).
• Mean change in the UPDRS Part II (ADL) score during the “ON” phase from Baseline to Endpoint (Week 96).
• Mean change in the UPDRS motor score Part III during the “ON” phase from Baseline to Endpoint (Week 96).
• Mean change in the UPDRS total score during the “ON” phase from Baseline to Endpoint (Week 96).
• Mean change in the NMS assessment scale for PD score from Baseline to Endpoint (Week 96).
• Mean change in dyskinesia score (using the UDysRS scale) at the end of the study in patients with or without dyskinesia at baseline.
Exploratory Secondary Efficacy Endpoints:
• Mean change in the UPDRS Part IV score of items 32-34 during the “ON” phase from Baseline to Endpoint (Week 96).
• Time to first intervention (increase of at least 20% of the L dopa dose, add-on of other anti-Parkinsonian drugs or increase of their dosages).
• Percentage of patients with dyskinesia unchanged, improved or deteriorated at the end of the study, based on baseline condition (patients with or without dyskinesia at baseline) and UDysRS total score.
• Mean change in the UPDRS Part II (ADL) score during the “OFF” phase from Baseline to Endpoint (Week 96).
• Percentage of responders, defined as defined as meeting at least 1 of the following 3 criteria:
- improvement =30 minutes in “ON” time, “OFF” time and “ON” + “OFF”;
- improvement =30 minutes in “ON” time, “OFF” time and “ON” + “OFF” time with no increase in troublesome dyskinesia;
- improvement =30% in motor symptoms (UPDRS part III).
• Percentage of patients with <25% “OFF” time.
• Change from Baseline to Endpoint (Week 96) in the daily “OFF” time following the first morning dose of L dopa.
• Percentage of reduction in L dopa dose from Baseline to Endpoint (Week 96).
Safety Endpoints:
• The nature, frequency, severity, relationship (to study drug), actions taken, and outcome of TEAEs and SAEs.
• Changes in physical examination findings.
• Changes in vital sign (heart rate, systolic and diastolic blood pressure) values, including occurrence of abnormalities.
• Changes in 12-lead ECG parameter measures, including occurrence of abnormalities.
• Changes in clinical chemistry and hematology values, including shifts from Baseline and occurrence of abnormalities.

Timepoint(s) of evaluation of this end point: 96 weeks.
An optional interim analysis will be conducted if a regulatory approval body requests an analysis of the primary efficacy endpoint after all subjects have completed 6 months of treatment in the study. If conducted, this interim analysis will only include the analysis of the primary efficacy endpoint, at Week 24 instead of Week 96.

Secondary ID(s)

Z7219L02

Source(s) of Monetary Support

Zambon S.P.A.