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    Summary
    EudraCT Number:2014-001489-85
    Sponsor's Protocol Code Number:FRM-0334-002
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-10-02
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2014-001489-85
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalating, Phase 2a Safety, Tolerability, and Pharmacodynamic Study of Two Doses of an Histone Deacetylase Inhibitor (FRM-0334) in Subjects with Prodromal to Moderate Frontotemporal Dementia with Granulin Mutation
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate 2 doses of investigational drug on patients with Prodromal to Moderate Frontotemporal Dementia with Granulin Mutation
    A.4.1Sponsor's protocol code numberFRM-0334-002
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02149160
    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 SponsorFORUM 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 supportFORUM Pharmaceuticals Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationWorldwide Clinical Trials
    B.5.2Functional name of contact pointRochelle Suffern
    B.5.3 Address:
    B.5.3.1Street Address3800 Paramount Parkway, Suite 400
    B.5.3.2Town/ cityMorrisville
    B.5.3.3Post codeNC 27560
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1919674 2916
    B.5.5Fax number+1919465 3820
    B.5.6E-mailrochelle.suffern@wwctrials.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.3.2Product code FRM-0334
    D.3.4Pharmaceutical form Capsule, hard
    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 INNHistone Deacetylase Inhibitor
    D.3.9.1CAS number 1024007-21-3
    D.3.9.2Current sponsor codeFRM-0334
    D.3.9.3Other descriptive nameEVP-0334
    D.3.9.4EV Substance CodeSUB166988
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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, hard
    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
    Prodromal to Moderate Frontotemporal Dementia with Granulin Mutation
    E.1.1.1Medical condition in easily understood language
    memory loss
    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 17.0
    E.1.2Level PT
    E.1.2Classification code 10068968
    E.1.2Term Frontotemporal dementia
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    •Evaluate the safety and tolerability of 2 fixed doses of FRM-0334 (300 and 500 mg daily in 2 sequential periods) over 28 days in subjects with prodromal to moderate frontotemporal dementia with granulin mutation (FTD-GRN)
    •Assess the pharmacodynamic (PD) effects of FRM-0334 on the change from baseline in plasma concentrations of progranulin (PGRN) after 28 days
    E.2.2Secondary objectives of the trial
    •Assess the PD effects of FRM-0334 on the change from baseline in cerebrospinal fluid (CSF) concentrations of PGRN after 28 days
    •Characterize the plasma and CSF concentrations of FRM-0334 and metabolites following once daily dosing after 28 days
    •Characterize the intra- and inter-individual variability in plasma and CSF concentrations of PGRN
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Informed consent form (ICF) signed by the subject or legally acceptable representative indicating that the subject or legally acceptable representative understands the purpose of and procedures required for the study before any study-specific procedures are performed
    2.A support person may be required to participate in the study (in the judgment of the investigator at screening or as required by local regulations). The support person must sign an acknowledgement of responsibilities form at the study center before any study-specific activities required for the support person are performed. The first required activity will be performed at screening. The support person will accompany the subject to the study center at screening and on Days 1 and 28 (or be available by telephone on Days 1 and 28), and if not living in the same household, interacts with the subject approximately 4 times per week, and be able to complete the study
    3.Male or female subjects aged ≥21 and ≤75 years
    4.Genotyped positive for a FTD-GRN mutation
    5.Prodromal to moderate FTD-GRN, and for subjects who require a support person (refer to inclusion criterion No. 2), a Clinical Dementia Rating Sum of the Boxes (CDR SB) score <16 at screening
    6. Heterosexually active subjects (men and women) of childbearing potential and their partners must practice true abstinence (periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable) or use 2 highly-effective methods of contraception, including at least 1 barrier method, from informed consent until 1 week after last dose. Non-childbearing potential and highly-effective methods of contraception are defined in Section 4.4
    7.Women of childbearing potential must have a negative pregnancy test at screening and Day 1
    8.Resides in a stable living situation, living at home, senior residential setting, or an institutional setting without the need for continuous (ie, 24-hour) nursing care
    9.Proficiency (oral and written) in the language in which study-related documents, including the ICF and standardized tests, will be administered
    10.Able to swallow capsules
    11.Be in good general health, willing and able to comply with the protocol requirements, and expected to complete the study as designed (in the judgment of the investigator)
    E.4Principal exclusion criteria
    1.Employees of Inv.or study center or family members or employees of FORUM Pharma orWCT directly involved in conduct of study
    2.Female subj.who are pregnant,breastfeeding or planning to become pregnant during study
    3.Unstable medical condition that is C.S.(in Inv.judgment)within 30days before screen
    4.Untreated vitamin B12or folate deficiency(must be stably treated for at least 6months before screen)
    5.C.S.untreated hypothyroidism(if treated,thyroid-stimulating hormone lev. and thyroid supplementation dose must stable for at least 6months before screen)
    6.C.S.abnormal serum electrolytes(sodium,potassium and magnesium)after repeat testing(in Inv.judgment)
    7.ALTorAST>2.5times upper limit of normal
    8.Renal insufficiency with serum creatinine>2.0mg/dL,unless receiving current treatment with an ACE inh.in which case M.M. should be contacted
    9.Insufficiently controlled diabetes mellitus(in Inv.judgment)
    10.C.S.hematologic abnormalities including thrombocytopenia and leukocytosis(in Inv.judgment)
    11.Malign. tumor within 3years before screen.with exception of squamous and basal cell carcinoma or cervical carcinoma in situ or brachytherapy for localized prostate cancer
    12.Systemic infection of any kind or any acute,subacute or chronic inflammatory process(eg, rheumatoid arthritis,chronic obstructive pulmonary dis.or gastrointestinal inflammatory dis.)
    13.MRI/CT scan performed within 12mnths before screen.with findings with C.S.comorbid pathology other than FTD.If MRI/CT is unavailable or occurred>12mnts screen, an MRI scan must be be done & findings confirmed before the Day -7 procedures are performed, a copy of the DICOM standard image &report must be available
    14.Diagnosis of motor neuron disease,including probable amyotrophic lateral sclerosis
    15.History of brain tumor,subdural hematoma or other C.S.(in Inv.judgment)space-occupying lesion on CTorMRI
    16.Stroke within 18months before screening or history of stroke concomitant with onset of dementia
    17.Head trauma with C.S.(in Inv.judgment)loss of consciousness within 12months before screen.or concurrent with onset of dementia
    18.Onset of dementia within 12months before screen.secondary(in Inv. judgment)to cardiac arrest,surgery with general anesthesia or resuscitation
    19.Specific degenerative CNSdisease diagnosis other thanFTD(eg.Parkinson’s,Alzheimer’s,Huntington’s,Creutzfeldt Jakob,Down’s)
    20.Wernicke’s encephalopathy
    21.Epilepsy if present antiseizure therapy is required for seize control
    22.Current diagnosis of severe major depressive disorder with psychotic features,if present condition or treatment interferes with subj’s ability to complete study(in Inv. judgment)
    23.Significant suicide risk as defined by1)suicidal ideations as endorsed on items 4or5 on Columbia Suicide Severity Rating Scale within past year at screen.or baseline2)suicidal behaviors detected by C-SSRS within 2years before screen3)Inv.assessment
    24.History or current diagnosis of psychosis
    25.History within 2years before screen or current evidence of substance abuse as defined by Diagnostic and Statistical Manual of Mental Disorders 4th Edition Text Rev
    26.C.S.urine drug screen or serum alcohol test result(in Inv. judgment)at screen(may be repeated once)
    27.C.S.abnormality on screen.or baseline ECG,including but not necessarily limited to confirmed corrected QTc value≥450msec for males or≥470msec for fem.In subj.with QRS value>120msec those with QTc value>480msec are NOTeligible
    28.History of myocardial infarction or unstable angina within 6months before screen.or history of>1myocardial infarction within 5years before screen
    29.C.S.(in Inv.judgment)cardiac arrhythmia(including atrial fibrillation),cardiomyopathy or cardiac conduction defect(subj.with pacemaker are acceptable)
    30.Cardiovascular disease history including symptomatic hypotension or hypertension(supine diastolic blood pressure>95mmHg)not stabilized by medical therapy(in Inv.judgment)
    31.IMP,biologic or m.d. within 30days before screen.or planning to use IMP(other than FRM0334)during study
    32.Sensitive and/or narrow therapeutic range cytochrome P450(CYP)1A2 substrates including alosetron,duloxetine,melatonin,ramelteon,theophylline and tizanidine
    33.Warfarin-derived anticoagulants,heparin,NSAIDs and anti-platelet drugs(clopidogrel and others)10days before CSF sample collection on D-7andD28
    34.Hypersensitivity to histone deacetylase inhibitor medication or currently receiving treatment with an HDACi,including valproic acid and amisulpride
    35.Immunosuppressants including systemic corticosteroids and NSAIDs(occasional use of NSAIDs is allowed,with the except. of 10days before CSFsample collection on D-7andD28)
    36.Chronic intake of opioid containing analgesics
    37.Psychostimulants including amphetamines
    38.Clozapine and amisulpride;other antipsychotics are allowed if on stable dose(no change in dose or frequency)for at least 30days before screen.and expected to remain stable during the study
    E.5 End points
    E.5.1Primary end point(s)
    The primary hypothesis being tested is that treatment with FRM-0334, 300 or 500 mg daily, increases mean plasma PGRN concentrations (1-sided test, alpha=0.05; no correction for multiplicity).
    The primary PD analysis will be the percent change from baseline to Day 28 in plasma PGRN concentration for FRM-0334 treatment, using a mixed-effects model for repeated measures (MMRM), with fixed effects for treatment, time, treatment by time interaction, baseline as a covariate, and subject as a random effect. Analysis of PGRN mRNA will be performed using a similar method.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From baseline to Day 28
    E.5.2Secondary end point(s)
    Secondary PD endpoints include: the effect FRM-0334 on plasma, PGRN, and PGRN mRNA (comparing Day 1 and 28 postdose values to respective predose values, as well as to baseline); and the percent change from baseline to Day 28 in CSF concentration of PGRN, data will be listed and summarized in tabular format by descriptive statistics as appropriate.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline and Day 28
    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 No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 No
    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 trial4
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    Belgium
    France
    Italy
    Netherlands
    United Kingdom
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months12
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months13
    E.8.9.2In all countries concerned by the trial days0
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    The study allows the subjects legal representatives to sign the ICF.
    F.3.3.7Others No
    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 19
    F.4.2.2In the whole clinical trial 30
    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)
    On Day 28, subjects will remain in the study centre overnight and be discharged on Day 29 after all scheduled procedures and assessments have been completed.
    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 Decision2014-11-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-12-22
    P. End of Trial
    P.End of Trial StatusCompleted
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