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    Summary
    EudraCT Number:2016-003456-70
    Sponsor's Protocol Code Number:CTH-302
    National Competent Authority:Austria - BASG
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2017-11-16
    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 ConcernedAustria - BASG
    A.2EudraCT number2016-003456-70
    A.3Full title of the trial
    An Open-Label, Randomized, Crossover Trial utilizing a Single-Blinded Rater to evaluate APL-130277 compared to s.c. Apomorphine in Levodopa Responsive Subjects with Parkinson’s Disease Complicated by Motor Fluctuations
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to compare APL-130277 sublingual film to Subcutaneous Apomorphine in Parkinson’s Disease patients
    A.4.1Sponsor's protocol code numberCTH-302
    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 SponsorSunovion Pharmaceuticals Inc.
    B.1.3.4CountryUnited States
    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 supportSunovion Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSyneos Health / INC Research Hungary Kft.
    B.5.2Functional name of contact pointEniko Dalanics
    B.5.3 Address:
    B.5.3.1Street AddressKiralyhago ter 8-9./V.
    B.5.3.2Town/ cityBudapest
    B.5.3.3Post codeH-1126
    B.5.3.4CountryHungary
    B.5.4Telephone number+36 14578307
    B.5.6E-maileniko.dalanics@syneoshealth.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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 No
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name APO-go
    D.2.1.1.2Name of the Marketing Authorisation holderBritannia Pharmaceuticals Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 names.c. apomorphine
    D.3.4Pharmaceutical form Solution for injection
    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 INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 No
    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.IMP: 3
    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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 No
    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.IMP: 4
    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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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 No
    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.IMP: 5
    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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 No
    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.IMP: 6
    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 nameApomorphine hydrochloride
    D.3.2Product code APL-130277
    D.3.4Pharmaceutical form Sublingual film
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSublingual use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.2Current sponsor codeAPL-130277
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    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 No
    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.IMP: 7
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name APO-go
    D.2.1.1.2Name of the Marketing Authorisation holderStada
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 names.c. apomorphine
    D.3.4Pharmaceutical form Solution for injection
    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 INNApomorphine hydrochloride
    D.3.9.1CAS number 41372-20-7
    D.3.9.3Other descriptive nameAPOMORPHINE HYDROCHLORIDE
    D.3.9.4EV Substance CodeSUB12924MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 No
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSublingual film
    D.8.4Route of administration of the placeboSublingual use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Levodopa Responsive Patients with Parkinson’s Disease Complicated by Motor Fluctuations ("OFF episodes")
    E.1.1.1Medical condition in easily understood language
    Central nervous system disease affecting the movement
    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 22.1
    E.1.2Level LLT
    E.1.2Classification code 10034006
    E.1.2Term Parkinson's disease aggravated
    E.1.2System Organ Class 100000004852
    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 is to demonstrate the efficacy of sublingual (sl)
    APL-130277 compared to subcutaneous (sc) apomorphine as a
    treatment of "OFF" episodes in subjects with Parkinson's Disease (PD)
    as measured by the change from pre-dose to 90 minutes post-dose in
    Movement Disorder Society Unified Parkinson's Disease Rating Scale
    (MDS-UPDRS) Part III score.
    E.2.2Secondary objectives of the trial
    The secondary objectives are to demonstrate the efficacy of sublingual
    (sl) APL-130277 compared to subcutaneous (sc) apomorphine as a
    treatment of "OFF" episodes in subjects with Parkinson's Disease (PD)
    as measured by:
    • Durability of effect, defined as Investigator confirmed full "ON" within
    30 minutes post-dose and at 90 minutes post-dose;
    • Subject preference for APL-130277 treatment (either somewhat or
    definitely prefer APL) as recorded for question 9 of the TPQ. This
    assessment is scheduled to be performed after the subject has
    completed both APL-130277 and sc apomorphine treatment regimens;
    • Subject confirmed durability of effect, defined as subject confirmed full
    "ON" within 30 minutes post-dose and at 90 minutes post-dose;
    • Patient Global Impression of Change of "OFF" episodes (PGI-C).
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Optional Pharmacokinetic (PK) evaluation : Blood draws for APL-130277 and s.c. apomorphine PK analyses will occur during PART B at V2, V3, V5, and V6 at selected sites (dependent on feasibility). Blood draws will occur at t = 0 (just prior to dosing) and at t = 10, 20, 30, 60, 90, 120, 180 and 240 minutes post-dose. Sampling should occur as close as possible to the target time. Subjects must consent in order to participate in optional PK sub-study
    E.3Principal inclusion criteria
    1 The subject (and caregiver, if applicable) must be fully informed of and
    understand the objectives, procedures, and possible benefits and risks of
    the study, and give written informed consent prior to performing any
    study-related activities.
    2 Male or female = 18 years of age.
    3 Clinical diagnosis of Idiopathic PD, consistent with UK Brain Bank
    Criteria (excluding the "more than one affected relative" criterion).
    4 Clinically meaningful response to levodopa (L-Dopa), as determined by
    the Investigator.
    5 Subjects at Screening must demonstrate an adequate L-Dopa response
    on the MDS-UPDRS Part III in the "ON" state compared to the MDS
    UPDRS
    Part III in the "OFF" state and on the Hoehn and Yahr, as
    determined during the review by Enrollment Adjudication Committee
    (EAC), Sponsor, and Medical Monitor.
    6 Receiving stable doses of L-Dopa/carbidopa and/or L-Dopa/
    benserazide and/or L-Dopa/carbidopa/entacapone (immediate or
    chronic release) administered at least 4 times per day OR RytaryTM
    administered at least 3 times per day for at least 4 weeks before the
    Initial Screening Visit (SV1). Adjunctive PD medication regimens are
    permitted but must be maintained at a stable dose for at least 4 weeks
    prior to SV1 with the exception of monoamine oxidase B (MAO-B)
    inhibitors, which must be maintained at a stable level for at least 8
    weeks prior to SV1. Use of Madopar PRN in the 4 weeks prior to screening is permitted. Current use of a sc apomorphine by injection at the time of screening is permitted.

    7 No planned medication change(s) or surgical intervention anticipated
    during the course of study.
    8 Subjects must experience at least one well defined "OFF" episode per
    day and have a total daily "OFF" time duration of > 2 hours during the
    waking day, based on judgment of physician and subject self
    assessment.
    9 Subject must have predictable morning "OFF" periods, based on
    judgment of physician and subject self-assessment.
    10 Subject, and where appropriate caregiver, must be trained in
    completing the home dosing diaries and able to recognize "ON" and
    "OFF" states.
    11 Stage III or less on the modified Hoehn and Yahr scale in the "ON"
    state.
    12 Mini–Mental State Examination (MMSE) score > 25.
    13 Female subject of childbearing potential and male subject with
    female partner of childbearing potential must agree to either remain
    abstinent or use adequate and reliable contraception (see Section 10.4.1
    for additional information on acceptable methods of birth control)
    throughout the study and for at least 7 days after the last dose of study
    drug has been taken. Note: Continued use of adequate and reliable
    contraception is recommended through 30 days after study completion.
    14 Willing and able to comply with scheduled visits, treatment plan,
    laboratory tests, and other study-related procedures to complete the
    study.
    15 Must be approved as a satisfactory candidate by the Enrollment
    Adjudication Committee (EAC), Medical Monitor, and Sponsor.
    E.4Principal exclusion criteria
    1 Atypical or secondary parkinsonism.
    2 Major focal brain disorders including malignancy or stroke.
    3 Prior treatment with any of the following: a neurosurgical procedure
    for PD; continuous subcutaneous (sc) apomorphine infusion; sc
    apomorphine injection; Duodopa/Duopa; or APL-130277.
    4. Subjects who have permanently stopped use of s.c. apomorphine
    (injection).
    5 Female who is pregnant or lactating.
    6 Participation in an interventional clinical study and/or receipt of any
    investigational (ie, unapproved) medication within 30 days prior to SV1.
    7 Currently taking selective 5HT3 antagonists (ie, ondansetron,
    granisetron, dolasetron, palonosetron, alosetron), dopamine antagonists
    (excluding quetiapine or clozapine) or dopamine depleting agents.
    Subjects receiving anti-depressants must be on a stable daily dose for at
    least 8 weeks prior to SV1.
    8 current diagnosis or history of substance abuse (excluding nicotine
    and caffeine) or alcohol abuse (in the opinion of the investigator) < 6
    months prior to SV1.
    9 positive urine drug screen result. NOTE: Benzodiazepines, opiates, and
    oxycodone will be allowed provided the subject has been on a stable
    dose for 4 weeks prior to SV1, provided the subject has a valid
    prescription. Cotinine is not exclusionary.
    10 The recreational use of cannabinoids and hallucinogenic(including
    formulations of CBD) and hallucinogenics are excluded, as well any use
    of a sublingual formulation of any drug.
    11 history of malignancy within 5 years prior to SV1, except for
    adequately treated basal cell or squamous cell skin cancer or in situ
    cervical cancer.
    12 clinically significant abnormality on screening evaluation including
    physical examination, vital signs, electrocardiogram (ECG), or laboratory
    tests that the Investigator considers to be inappropriate to allow
    participation in the study.
    13 screening laboratory test results of: BUN value = 1.5 times the upper
    limit of normal (ULN) for the reference range; serum creatinine > 1.5
    times the ULN for the reference range; or ALT or AST value = 2 times the
    ULN for the reference laboratory.
    14 random (non-fasting) screening glucose of = 200 mg/dL (11.1
    mmol/L) or HbA1c > 7.0%.
    15 Subjects with type 1 diabetes, or insulin-dependent diabetics are
    excluded. Subjects with type 2 diabetes are eligible for study inclusion if
    the following conditions are met:
    • Subject's screening glucose is < 200 mg/dL (11.1 mmol/L). Note:
    Subjects with random (non-fasting) blood glucose at screening = 200
    mg/dL (11.1 mmol/L) must be retested in a fasted state; and
    • Subject's HbA1c = 7.0%; and
    • If the subject is currently being treated with oral anti-diabetic
    medication(s), the dose must have been stable for at least 4 weeks prior
    to SV1. Such medication may be adjusted or discontinued during the
    study, as clinically indicated.
    16 The subject's screening ECG results of corrected QT interval using
    Fridericia's formula (QTcF) = 450 msec for male subjects or = 470 msec
    for female subjects. Eligibility will be based on the core laboratory ECG
    interpretation report.
    17 positive screening laboratory test result for HIV.
    18 positive screening laboratory test result for hepatitis B surface
    antigen or hepatitis C antibodies and has liver function test results at
    screening above the ULN for the reference laboratory.
    19 any other medical disorder that, in the opinion of the Investigator,
    could interfere with the subject's participation in the study.
    20 major psychiatric disorder(s), including but not limited to: bipolar
    disorder, psychosis (eg, Parkinson's Disease Psychosis), major
    depressive episode, or any disorder that, in the opinion of the
    Investigator, would require treatment that could make study
    participation unsafe or make treatment compliance difficult.
    21 History of clinically significant impulse control disorder(s).
    22 History of symptomatic orthostatic hypotension requiring medication.
    23 History of severe dyskinesia based on a score of 4 on the MDS-UPDRS
    Part IV. for either "time spent with dyskinesia" OR "the functional
    impact of dyskinesia"
    24 Current/recent suicidal ideation as evidenced by answering "yes" to
    "Suicidal Ideation" item 4 (active suicidal ideation with some intent to
    act, without specific plan) or item 5 (active suicidal ideation with specific
    plan and intent) on the C-SSRS assessment at Screening (using the
    "Screening/Baseline Version" scale, in the past 12 months) or attempted
    suicide within the last 5 years.
    25 Presence of canker or mouth sores in the 30 days prior to SV1, or
    other clinically significant oral pathology in the opinion of the
    Investigator. The Investigator should follow-up with an appropriate
    specialist on any finding, if indicated, before enrolling a subject into the
    study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy variable is the change from pre-dose to 90 minutes
    post-dose in MDS-UPDRS Part III score after 4 weeks of dosing in each
    crossover period (assessed by the blinded-rater in-clinic at V3 and V6 of
    PART B).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The change from pre-dose to 90 minutes post-dose in MDS-UPDRS Part
    III score after 4 weeks of dosing in each crossover period (assessed by
    the blinded-rater in-clinic at V3 and V6 of PART B).
    E.5.2Secondary end point(s)
    1 Durability of effect, defined as an Investigator confirmed full "ON"
    within 30 minutes post-dose and at 90 minutes post-dose, after 4 weeks
    of dosing in each crossover period (assessed by the blinded-rater inclinic
    at V3 and V6 of PART B).
    2 Subject preference for APL-130277 treatment (either somewhat or
    definitely prefer APL-130277) for treatment regimen as measured by the Subject
    Preference Visual Analog Scale (VAS) after the subject has completed
    both APL-130277 and sc apomorphine treatment regimens (assessed inclinic
    at V6 of PART B).
    3 Subject confirmed durability of effect, defined as subject confirmed full
    "ON" within 30 minutes post-dose and at 90 minutes post-dose, after 4
    weeks of dosing in each crossover period (assessed in-clinic at V3 and
    V6 of PART B).
    4 Patient Global Impression of Change (PGI-C): Subject improvement of
    "OFF" episodes, defined as very much better, much better or a little
    better after 4 weeks of dosing in each crossover period (assessed inclinic
    at V3 and V6 of PART B).
    Other Efficacy Endpoints (PART B):
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    Other efficacy variables will include analysis of: Clinical Global
    Impression of Improvement (CGI-I), MDS-UPDRS – Parts I, II, III and
    IV Score, Time to Full and Partial "ON", Expanded Home Dosing Diaries
    including percent of "ON" episodes without troublesome dyskinesia
    based on the 3 consecutive days prior to V2, V3, V5, and V6, dyskinesia
    questionnaire, Parkinson's Disease Questionnaire-39 (PDQ-39) Total
    Index Score and subscale scores, European Quality of Life – 5
    Dimensions (EQ-5D-5L), and Ease of Use questionnaire. Methodology concerning the analysis of these
    variables will be provided in the Statistical Analysis Plan (SAP).
    Safety Endpoints:
    Evaluation of safety and tolerability of APL-130277 compared to sc
    apomorphine as measured by AEs, physical examination including
    assessment of oropharyngeal AEs and injection-site related AEs, 12-lead
    ECGs, vital signs including OH, clinical laboratory tests, and C-SSRS and
    QUIP-RS assessments.
    Pharmacokinetic Endpoints:
    Pharmacokinetic concentration-time data for apomorphine and
    metabolites (apomorphine sulfate, norapomorphine, and others as
    deemed necessary) will be evaluated and PK parameters (including but
    not limited to Cmax, tmax, AUCt, parent-to-metabolite ratios of Cmax
    and AUCt) will be estimated by noncompartmental methods from plasma
    samples using actual elapsed time from dosing. Details and methodology
    concerning the analysis of these variables will be provided in a separate
    PK analysis plan. A separate and stand‑alone PK report will be
    provided.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Refer to section E.5.2
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    Ease of use and Tolerability
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    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 No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years
    E.8.9.1In the Member State concerned months44
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months44
    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: 64
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 42
    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 No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 106
    F.4.2.2In the whole clinical trial 106
    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)
    None
    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 Decision2018-01-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-12-07
    P. End of Trial
    P.End of Trial StatusOngoing
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