A study to investigate 2 doses of investigational drug on patients with Prodromal to Moderate Frontotemporal Dementia with Granulin Mutation

• Register: EUCTR
• Last refreshed on: 8 August 2016
• Main ID: EUCTR2014-001489-85-BE
• Date of registration: 24/10/2014
• Prospective Registration: Yes
• Primary sponsor: FORUM Pharmaceuticals Inc.
• Public title: A study to investigate 2 doses of investigational drug on patients with Prodromal to Moderate Frontotemporal Dementia with Granulin Mutation
• Scientific title: 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
• Date of first enrolment: 05/03/2015
• Target sample size: 30
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-001489-85
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, France, Italy, Netherlands, United Kingdom, United States

Contacts

• Name: Rochelle Suffern
• Affiliation: Worldwide Clinical Trials

• Name: Rochelle Suffern
• Affiliation: Worldwide Clinical Trials

Key inclusion & exclusion criteria

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)

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 20
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

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 my

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Prodromal to Moderate Frontotemporal Dementia with Granulin Mutation
MedDRA version: 18.1 Level: PT Classification code 10068968 Term: Frontotemporal dementia System Organ Class: 10029205 - Nervous system disorders

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Code: FRM-0334
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Histone Deacetylase Inhibitor
CAS Number: 1024007-21-3
Current Sponsor code: FRM-0334
Other descriptive name: EVP-0334
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: •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

Primary 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.

Secondary Objective: •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

Timepoint(s) of evaluation of this end point: From baseline to Day 28

Secondary Outcome(s)

Secondary 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.

Timepoint(s) of evaluation of this end point: Baseline and Day 28

Secondary ID(s)

NCT02149160

FRM-0334-002

2014-001489-85-GB

Source(s) of Monetary Support

FORUM Pharmaceuticals Inc.