Clinical Trials Register

Summary
EudraCT Number:	2014-002600-24
Sponsor's Protocol Code Number:	Z7219L02
National Competent Authority:	Austria - BASG
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-09-25
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Austria - BASG

A.2

EudraCT number

2014-002600-24

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.3.2

Name or abbreviated title of the trial where available

EVEREST

A.4.1

Sponsor's protocol code number

Z7219L02

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Zambon S.P.A.
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Zambon S.P.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Zambon S.P.A.
B.5.2	Functional name of contact point	Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Via Lillo del Duca 10
B.5.3.2	Town/ city	Bresso (Milano)
B.5.3.3	Post code	20091
B.5.3.4	Country	Italy
B.5.6	E-mail	Clinicaltrials@zambongroup.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Xadago
D.2.1.1.2	Name of the Marketing Authorisation holder	Zambon S.P.A.
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	safinamide
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	133865-89-1
D.3.9.3	Other descriptive name	SAFINAMIDE
D.3.9.4	EV Substance Code	SUB32946
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Xadago
D.2.1.1.2	Name of the Marketing Authorisation holder	Zambon S.P.A.
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	safinamide
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.1	CAS number	133865-89-1
D.3.9.3	Other descriptive name	SAFINAMIDE
D.3.9.4	EV Substance Code	SUB32946
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Idiopathic Parkinson's Disease

E.1.1.1

Medical condition in easily understood language

Chronic, progressive disease of the nervous system that affects the movements

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10061536
E.1.2	Term	Parkinson's disease
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

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

E.2.2

Secondary objectives of the trial

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

E.2.3

Trial contains a sub-study

E.3

Principal 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).

E.4

Principal 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 history of hereditary retinal disease.

E.5 End points

E.5.1

Primary end point(s)

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

E.5.1.1

Timepoint(s) of evaluation of this end point

96 weeks

E.5.2

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.

E.5.2.1

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.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

Austria

France

Germany

Italy

Russian Federation

Spain

Sweden

Switzerland

United Kingdom

E.8.7

Trial has a data monitoring committee

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

490

F.4.2.2

In the whole clinical trial

556

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

The test drug, safinamide recently received marketing authorization in the EU, the drug is expected to be commercially available by the time the study is completed.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-12-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-15

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2016-01-18

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