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    Summary
    EudraCT Number:2016-000429-38
    Sponsor's Protocol Code Number:PLX108-15
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-07-06
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2016-000429-38
    A.3Full title of the trial
    A Phase 2a Study of the Safety, Tolerability, and Pharmacodynamic Effects of Pexidartinib in Subjects with Mild to Moderate Alzheimer’s Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate Pexidartinib for Mild to Moderate Alzheimer’s Disease
    A.4.1Sponsor's protocol code numberPLX108-15
    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 SponsorPlexxikon 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 supportPlexxikon Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCCBR, Clinical Research
    B.5.2Functional name of contact pointAnna Areovimata
    B.5.3 Address:
    B.5.3.1Street AddressHobrovej 42 D. 2. Floor.
    B.5.3.2Town/ cityAalborg
    B.5.3.3Post code9000
    B.5.3.4CountryDenmark
    B.5.4Telephone number+45 96334720
    B.5.5Fax number+45 98139048
    B.5.6E-mailCCBR@CCBR.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 namePexidartinib Capsules
    D.3.2Product code PLX3397 HCl
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPexidartinib HCl
    D.3.9.1CAS number 1029044-16-3
    D.3.9.2Current sponsor codePLX3397 HCl
    D.3.9.4EV Substance CodeSUB33175
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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 placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alzheimer's Disease
    E.1.1.1Medical condition in easily understood language
    Alzheimer'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 19.0
    E.1.2Level LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10012293
    E.1.2Term Dementia of the Alzheimer's type, uncomplicated
    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 this study is to evaluate the safety and tolerability of three dose levels of pexidartinib in subjects with Alzheimer’s Disease.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are:
    To evaluate the effect of pexidartinib treatment on microglial neuroinflammation by [11C](R)PK11195 PET imaging at Weeks 3 and 10 compared with screening.
    To evaluate the effects of pexidartinib on cognitive and functional measures of AD at baseline, Weeks 4 and 12, and at the Follow up visit (Week 16).
    To evaluate the pharmacokinetics of pexidartinib, including the assessment of cerebrospinal fluid (CSF) to plasma ratio (CSF:plasma).
    To evaluate effects of pexidartinib on relevant CSF1R biomarkers in blood.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Signed and dated written informed consent from the subject has been obtained in accordance with the local regulations. The subject’s study partner must also consent to participate in the study.
    2.Diagnosis of probable AD according to the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders (NINCDS-ADRDA) criteria.
    3.Aged 55 to ≤85 years, inclusive.
    4.At the time of screening assessments, resides in the community (not in an assisted living facility or long term care nursing facility).
    5.Mini-Mental State Examination score of 16 to 26, inclusive, at screening.
    6.Adequate hematologic, hepatic, and renal function.
    7.Able to ingest oral medication.
    8.For subjects participating in Part 2 only: evidence of microglial neuroinflammation: [11C](R)PK11195 uptake at screening that is ≥20% above the normal mean.
    9.Subject has a reliable study partner or caregiver (eg, spouse, sibling, close friend) who, in the investigator’s judgement, has frequent, direct contact with the subject at least 4 days a week, can accompany the subject to all visits, and is also able to provide information to study investigator/staff via telephone contact.
    10.Subject or study partner understands the study procedures and agrees to return for follow-up visits and procedures in the event of discontinuation of study drug.
    11.Reliable study partner must supervise administration of study medication.
    12.Stable use of cholinesterase inhibitors and memantine is permitted if the doses are stable for 3 months prior to enrollment. The dose of these medications should be stable throughout the study unless it becomes clinically necessary to adjust the dosage.
    13.Stable use of antidepressants is permitted if the doses are stable for 4 weeks prior to enrollment. The dose of these medications should be stable throughout the study unless it becomes clinically necessary to adjust the dosage.
    14.Women must be surgically sterile (bilateral tubal ligation, both ovaries removed, or hysterectomy) or postmenopausal for at least 2 years.
    15.Fertile men must agree to use an effective method of birth control during the study and for up to 3 months after the last dose of the study drug.
    16.Agrees not to participate in any other investigational study while participating in this protocol.
    E.4Principal exclusion criteria
    1.Has significant neurological disease other than AD that may affect cognition.
    2.Has history or screening brain MRI scan results indicative of any other significant abnormality.
    3.Has a history of clinically significant stroke.
    4.Has a Modified Hachinski Ischemia Score ≥4.
    5.For subjects participating in Part 2 only: Is unsuitable for magnetic resonance imaging (MRI) scanning as assessed by the investigator.
    6.Has current evidence or history in the past 2 years of epilepsy; seizure; focal brain lesion; head injury with loss of consciousness; or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, or severe alcohol or substance abuse.
    7.Has sensory impairment that would prevent him/her from participating in the study or cooperating with the protocol.
    8.Has used another investigational agent within 1 month of screening.
    9.Has prior exposure to pexidartinib.
    10.Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
    11.If receiving behavioral medications (including antidepressants, antipsychotics, or anxiolytics), doses must have been stable for at least 4 weeks prior to enrollment.
    12.Has active neoplastic disease or any medical condition that requires concurrent immunosuppression.
    13.At screening, has psychosis or hallucinations as determined by Neuropsychiatric Inventory or Geriatric Depression Scale short form scores ≥6.
    14.Has any unstable cardiovascular disease, uncontrolled diabetes, chronic inflammatory, or infections conditions.
    15.Is using Coumadin or Coumadin related medications.
    16.Is unable to take oral medication or has significant nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption.
    17.At baseline, has mean corrected QT interval (QTc) using the Fridericia method (QTcF) ≥ 450 ms (males) or ≥ 470 ms (females).
    18.Has clinically significant cardiac arrhythmias, including bradyarrhythmias and/or requires anti arrhythmic therapy (excluding beta blockers or digoxin). Subjects who have controlled atrial fibrillation are not excluded from participation.
    19.Has congenital long QT syndrome or is taking concomitant medication(s) known to prolong the QT interval (eg, tricyclics, azithromycin, methadone).
    20.Has > Grade 1 (high or low) serum potassium, magnesium, or calcium levels.
    21.Has hypertension, which is defined as a systolic blood pressure > 140 mmHg or diastolic pressure > 95 mmHg despite optimal medical management.
    22.Has an ongoing active infection at the time of screening.
    23. Has a positive tuberculin skin test at screening.
    E.5 End points
    E.5.1Primary end point(s)
    To evaluate the safety and tolerability of three dose levels of pexidartinib in subjects with Alzheimer’s Disease.
    E.5.1.1Timepoint(s) of evaluation of this end point
    In Parts 1 and 2:

    •Safety and tolerability will be assessed on visits at Day 0, Day 1-4 (Part 1 only), and Weeks 1, 2, 3 , 4, 6, 8, 10, 12, and 16.
    •Safety laboratory tests will be performed at screening, Day 0, Day 4 (Part 1 only), and Weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16.
    •12 lead ECGs will be performed at screening, Day 0, and Weeks 2, 8, 12, and 16.
    E.5.2Secondary end point(s)
    •To evaluate the effect of pexidartinib treatment on microglial neuroinflammation by [11C](R)PK11195 PET imaging at Weeks 3 and 10 compared with screening.
    •To evaluate the effects of pexidartinib on cognitive and functional measures of AD at baseline, Weeks 4 and 12, and at the Follow up visit (Week 16).
    •To evaluate the pharmacokinetics of pexidartinib, including the assessment of cerebrospinal fluid (CSF) to plasma ratio (CSF:plasma).
    •To evaluate effects of pexidartinib on relevant CSF1R biomarkers in blood.
    E.5.2.1Timepoint(s) of evaluation of this end point
    In Parts 1 and 2:
    •Change from baseline in the clinical scales assessing cognition and/or function (ie, MMSE, ADAS Cog13, CDR SB) will be assessed at Weeks 4, 12, and 16.
    •Blood samples for pharmacodynamic analyses will be collected at Day 0 and Weeks 2, 6, 12, and 16.

    In Part 1 only:
    •Pharmacokinetic blood samples will be collected on Day 21 (± 3 days) at 30 minutes (±15 minutes) before dosing and 30 minutes (±15 minutes), 1, 2, 4, and 6 hours (±30 minutes) after dosing.
    •Lumbar puncture for collection of a pharmacokinetic CSF sample will be performed before dosing at Week 3.

    In Part 2 only:
    •Change from baseline in [11C](R)PK11195 PET signal will be assessed at Weeks 3 and 10.
    •A single pre-dose blood sample for pharmacokinetic assessment will be collected at Week 4.
    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 Yes
    E.6.7Pharmacodynamic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    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 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 concerned3
    E.8.5The trial involves multiple Member States No
    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 months15
    E.8.9.1In the Member State concerned days
    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: 2
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 32
    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 No
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects with dementia
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state34
    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)
    Adverse Events to be followed until resolution (see protocol)
    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 Decision2016-08-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-31
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-07-17
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