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    Summary
    EudraCT Number:2015-005814-31
    Sponsor's Protocol Code Number:ND0612H-012
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-02-14
    Trial 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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2015-005814-31
    A.3Full title of the trial
    A multicenter, international, open-label, safety study of ND0612, a solution of levodopa/carbidopa delivered via a pump system as a continuous subcutaneous infusion in subjects with advanced Parkinson's Disease (BeyoND)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    -
    A.3.2Name or abbreviated title of the trial where available
    BeyoND
    A.4.1Sponsor's protocol code numberND0612H-012
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02726386
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorNeuroDerm Ltd.
    B.1.3.4CountryIsrael
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNeuroDerm Ltd.
    B.4.2CountryIsrael
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNeuroDerm Ltd.
    B.5.2Functional name of contact pointLilach Zaddik
    B.5.3 Address:
    B.5.3.1Street AddressRuhrberg Science building - Bell entrance - 4th floor - 3 Pekeris St.
    B.5.3.2Town/ cityRehovot
    B.5.3.3Post code7670212
    B.5.3.4CountryIsrael
    B.5.4Telephone number+972-8-9462729
    B.5.5Fax number+972-8-9461729
    B.5.6E-maillilach@neuroderm.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namelevodopa/carbidopa solution
    D.3.2Product code ND0612
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLevodopa
    D.3.9.1CAS number 59-92-7
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameLEVODOPA
    D.3.9.4EV Substance CodeSUB08468MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNcarbidopa
    D.3.9.1CAS number 38821-49-7
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameCARBIDOPA
    D.3.9.4EV Substance CodeSUB06126MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number7.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Subjects with advanced Parkinson's disease
    E.1.1.1Medical condition in easily understood language
    Parkinson's disease
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061536
    E.1.2Term Parkinson's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to assess the long term safety
    (systemic and local) and tolerability of continuous SC infusion of
    ND0612. Assessment will be based on adverse events (AEs), with a
    focus on adverse events of special interest (AESI), i.e., infusion site
    reactions, cases of hypersensitivity, polyneuropathy.
    Tolerability will be assessed based on the percentage of subjects that
    complete the 12-month treatment period of the study and the
    percentage of subjects who discontinue from the 12 month treatment
    period due to an AE.
    E.2.2Secondary objectives of the trial
    Further safety objectives: (assessed based on 12 month data):
    •To further assess the safety and tolerability of ND0612 including suicidality (Columbia - Suicide Severity Rating Scale [C-SSRS]), Questionnaire for Impulsive-Compulsive Disorders in PD-Rating Scale (QUIP RS), excessive daytime sleepiness (Epworth Sleepiness Scale [ESS]), vital signs, laboratory tests, and electrocardiogram (ECG) data.

    Further Safety Objective assessed based on data up to 60 months (for the subjects who continue to the optional treatment extension):
    • To assess the long-term safety (systemic and local) and tolerability of continuous SC infusion of ND0612. Assessment will be based on AEs, with a focus on AESI, i.e., infusion site reactions, cases of hypersensivity, polyneuropathy.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetic sub-study for a clinical study protocol titled: A
    multicenter, international, open-label, safety study of ND0612, a solution of levodopa/carbidopa, delivered via a pump system as a continuous subcutaneous infusion in subjects with advanced Parkinson's Disease (BeyoND)- conducted in some countries; not applicable in Poland.
    E.3Principal inclusion criteria
    To be eligible for study entry subjects in Cohort 1 (previously completed the treatment period in protocol ND0612H-006 within one month prior to enrolling to ND0612H-012) must satisfy all of the following criteria:
    1.Subject is able to, and has signed an Institutional Review Board/Ethics Committee (IRB/EC)-approved informed consent form (ICF).
    2.Subject has completed the treatment period of study ND0612H-006 not more than one month prior to enrolling in ND0612H-012.
    3.Willing and able to administer the SC infusion alone or with the assistance of a study partner and able to comply with the study specific procedures.

    To be eligible for study entry subjects in Cohort 2 (ND0612 naïve subjects and subjects who completed treatment in a ND0612 clinical study more than one month before screening) must satisfy all of the following criteria:
    1.Male and female PD subjects of any race aged at least 30 years who sign an IRB/EC-approved ICF.
    2.PD diagnosis consistent with the UK Brain Bank Criteria.
    3.Modified Hoehn & Yahr scale in “ON” state of stage ≤3.
    4.Taking at least 4 doses/day of LD/DDI (or at least 3 doses/day of Rytary) and taking, or have attempted to take, at least one other PD treatment for at least 30 days.
    5.Subjects must be stable on their anti-PD medications for at least 30 days before Day 1.
    6.Subjects may have had prior exposure to SC apomorphine injections/infusion but must have stopped continous apomorphine administration at least 4 weeks before the screening visit. Treatment with apomorphine is prohibited during the entire ND0612 treatment period.
    7.Must have a minimum of 2 hrs of “OFF” time per day with predictable early morning “OFF” periods as estimated by the subject.
    8.Must have predictable and well defined early morning “OFF” periods with a good response to LD for treatment of the early morning “OFF” in the judgement of the investigator.
    9.Mini Mental State Examination (MMSE) score ≥ 26.
    10.No clinically significant medical, psychiatric or laboratory abnormalities which the investigator judges would be unsafe or non-compliant in the study.
    11.Female subjects must be surgically sterile (hysterectomy, bilateral oophorectomy, or tubal ligation), postmenopausal (defined as cessation of menses for at least 1 year), or willing to practice a highly effective method of contraception. All female participants must be non-lactating and non-pregnant and have a negative urine pregnancy test at Screening and at Baseline. Female subjects of childbearing potential must practice a highly effective method of contraception (e.g., oral contraceptives, intrauterine devices, partner with vasectomy), 1 month before enrollment, for the duration of the study, and 3 months after the last dose of study drug. Alternatively, true abstinence is acceptable when it is in line with the subject’s preferred and usual lifestyle. If a subject is usually not sexually active but becomes active, the subject and sexual partner must comply with the contraceptive requirements detailed above.
    12.Willing and able to administer the SC infusion alone or with the assistance of a study partner after a screening period of up to 40 days and willing and able to comply with study requirements.
    13. Subjects should have a named study partner
    E.4Principal exclusion criteria
    Subjects in Cohort 1 and Cohort 2 will be excluded from the study if one or more of the following criteria listed below are applicable.
    1.Previously unable to tolerate ND0612 and/or have experienced intolerable adverse drug reactions associated with its use, regardless of the dosing regimen administered.

    For Cohort 2 the following exclusion criteria apply:
    1.Atypical or secondary parkinsonism.
    2.Acute psychosis or hallucinations in past 6 months.
    3.Any relevant medical, surgical, or psychiatric condition, laboratory value, or concomitant medication which, in the opinion of the Investigator makes the subject unsuitable for study entry or potentially unable to complete all aspects of the study.
    4.Any malignancy in the 5 years prior to randomization (excluding basal cell carcinoma of the skin or cervical carcinoma in situ that have been successfully treated).
    5.Positive serum serology for Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV) at the Screening visit
    6.Prior neurosurgical procedure for PD, or Duodopa treatment
    7.Subjects with a history of drug abuse or alcoholism within the past 12 months.
    8.Clinically significant ECG rhythm abnormalities.
    9.Renal or liver dysfunction that may alter drug metabolism including: serum creatinine >1.3 mg/dL, serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x upper limit of normal (ULN), total serum bilirubin >2.5 mg/dL.
    10. Current participation in a clinical trial with an
    investigational product or past participation within the last 30 days before Day 1.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint in this study is a safety endpoint assessing the long-term safety (systemic and local) and tolerability of continuous SC infusion of ND0612 throughout the 12-month treatment period. Assessments, which constitute the primary endpoint of this study, will be based on AEs, with a focus on AESI, which will include infusion site reactions, hypersensitivity and polyneuropathy. Visual Analogue Scale (VAS) for pain assessment will also be used as primary measure.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Month 12 visit
    E.5.2Secondary end point(s)
    The secondary safety endpoints to be assessed for the 12-month
    treatment period include:
    •Assessment of suicidal behavior and ideation (C-SSRS responses,
    including the number of subjects experiencing at least 1 event of suicidal ideation, at least 1 event of suicidal behavior, at least 1 event of suicidal ideation or behavior and self-injurious behavior without suicidal intent, changes from Baseline in C-SSRS categories (No Suicidal Ideation or Behavior, Suicidal Ideation and Suicidal Behavior) and changes from Baseline in C-SSRS suicidal ideation)
    •Assessment of impulsive compulsive behavior (QUIP RS total scores)
    •Epworth Sleepiness Scale (ESS total score)
    •Vital signs with a focus on orthostatic BP (possible dopaminergic side
    effect)
    •Laboratory data (hematology and biochemistry), including dipstick
    urinalysis results evaluation
    •12-lead ECG parameters, including ECG interpretation of clinical
    significance
    •Physical examination
    •Prior and concomitant medications

    The exploratory efficacy endpoints assessed for 12 months of treatment are:
    •Change in daily "ON" time without troublesome dyskinesia (defined as the sum of "ON" time without dyskinesia and "ON" time with non-troublesome dyskinesia) from Baseline to the 12 month visit based on
    home "ON/OFF" diaries.
    * Change in daily “OFF” time from Baseline to the 12 month visit, based on "ON/OFF" home diaries
    * Change in total daily dose of oral LD/DDI from Baseline to the 12 month visit
    • Proportion of responders at the 12-month visit based on daily "OFF"
    time recorded in home "ON/OFF" diaries. A responder is defined as a subject that experiences ≥ 50% reduction in "OFF" time from Baseline.
    • Change in daily "ON" time with troublesome dyskinesia in a subset of subjects who had more than 1 hour of troublesome dyskinesia at Baseline, based on home "ON/OFF" diaries from Baseline to the 12-month visit.
    * Change in PDQ-39 scores from Baseline to the 12 month visit
    * Change in EQ-5D-5L scores from Baseline to the 12 month visit
    * Change in UPDRS Part II (ADL) from Baseline to the 12 month visit
    * Change in CGI-Severity and CGI-Improvement from Baseline to the 12 month visit
    * Change in SGI-Improvement from Baseline to the 12 month visit
    * Change in PDSS total score from Baseline to the 12 month visit
    * Change in UPDRS Part III (motor score) from Baseline to the 12 month visit
    * Change from baseline to month 12 in percentage of "OFF" time and
    percentage of 'Good' ON during the first 3 hours since the subject is
    awake after 06:00 (6 am)
    * Change from baseline to month 12 in ND0612 total dose
    * Proportion of patients who reduced ND0612 total dose at any time
    during the study
    E.5.2.1Timepoint(s) of evaluation of this end point
    Month 12 visit
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    2 dosages of IMP will be studied: Regimen 1 (720 LD/90 CD mg) vs Regimen 3 (720 LD / 90 CD mg)
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Czechia
    France
    Israel
    Italy
    Poland
    United States
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 120
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 88
    F.4.2.2In the whole clinical trial 210
    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)
    Subjects will be allowed to continue with study treatment for an optional treatment extension period of 42 more months in which clinic visits will be performed every 3 month to assess safety. At the end of the optional treatment extension period, subjects will be allowed to continue with study treatment for another optional longterm treatment extension period up to Month 102 in which clinic visits will be performed every 3 months up to Month 102, to assess subject long-term safety.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-05-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-14
    P. End of Trial
    P.End of Trial StatusOngoing
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