MIcroglial Colony Stimulating Factor-1 Receptor (CSF1R) in Alzheimer's Disease

NCT04121208 | Terminated Phase 1 DMC

• 2 other identifiers: 40346527ALZ10012018-004149-17
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 3

Brief Summary

A phase 1 randomised, placebo-controlled, single-blind study to characterise the biomarker effects of the CSF-1 receptor antagonist JNJ-40346527 in participants with mild cognitive impairment. A maximum of 54 participants will be recruited to the two part study. The first part of the study will identify whether it is possible to identify biomarkers that may be used in future studies with JNJ-40346527 and part 2 will investigate a minimal efficacious JNJ-40346527 dose.

Conditions

Alzheimer Disease; Mild Cognitive Impairment

Outcome Measures

Primary Outcomes (1)

• Placebo-controlled change from baseline in cerebrospinal fluid (CSF) protein marker concentration levels.

  Change from baseline in concentration levels of CSF fluid protein markers including but not limited to interleukin (IL)-34 and CSF-1.

  Baseline and visit 3 (Days 14)

Secondary Outcomes (5)

• Placebo-controlled change from baseline in CSF and blood biomarker concentration levels

  Baseline and visit 3 (Days 14)

• Placebo-controlled change from baseline in amount of CSF extracellular vesicles and cell population.

  Baseline and visit 3 (Days 14)

• Measurement of plasma/CSF JNJ-40346527 levels

  Baseline and visit 3 (Days 14)

• Measurement of cerebrospinal fluid (CSF) protein marker concentration levels following different JNJ-40346527 doses

  Baseline and visit 3 (Days 14)

• Occurrence of adverse events during the study

  Baseline and visit 3 (Days 14). Serious Adverse Events (Day 14 plus 30 days)

Study Arms (2)

Active drug: JNJ-40346527

ACTIVE COMPARATOR

A single initial randomisation site will be set up for Part 1 that will assign participants to JNJ-40346527 300 mg Bis in die - twice a day (BID) or placebo in a 2:1 ratio. A second randomisation site will be setup for Part 2 depending on which scenario is adopted. Either a "Part 2, Scenario 1" site will assign participants to JNJ-40346527 150 mg BID, JNJ-40346527 50 mg BID or placebo in a 2:2:1 ratio or a "Part 2, Scenario 2" site will assign participants to JNJ-40346527 150-50 mg BID or placebo in a 2:1 ratio.

Drug: JNJ-40346527

Placebo

PLACEBO COMPARATOR

Non-active study drug

Other: Placebo

Interventions

JNJ-40346527 DRUG

Active study drug

Active drug: JNJ-40346527

Placebo OTHER

Non-active study drug

Placebo

Eligibility Criteria

• Age: 50 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Any gender over and including 50 years old.
• Willing and able to provide informed consent.
• Clinical Dementia Rating (Scale) (CDR) Global Score = 0.5.
• Self and/or study partner report and impairment on objective cognitive tasks (performance on Hopkin's verbal learning task-revised (HVLT-R) - delay recall and/or free recall \> 1 standard deviation (SD) below mean for age/education level).
• Study Partner available, that spends at least 4 hours per week with the participant. The Study Partner must be willing and able to assist with the CDR interview, and will be provided with their own Information Sheet and Informed Consent form.
• Able to read and write in English and with minimum 7 years of formal education.
• Be considered eligible according to the following Tuberculosis (TB) screening criteria:
• Have no history of latent or active TB at screening. An exception is made for participants who have a history of latent TB (defined for the purpose of this study as having had a positive result from either the tuberculin skin test or the QuantiFERON-TB® Gold test prior to screening) and documentation of having completed an adequate treatment regimen for latent TB within 1 year prior to the first administration of study agent. Adequate treatment for latent TB is defined according to local country guidelines for immunocompromised patients. If no local guidelines for immunocompromised patients exist, United States (US) guidelines must be followed. It is the responsibility of the Investigator to verify the adequacy of previous anti-TB treatment and provide appropriate documentation.
• Have no signs or symptoms suggestive of active TB upon medical history and/or physical examination.
• Have had no recent (within approximately 3 months) close contact with a person with active TB or if there has been such contact, have been evaluated by a physician specialising in TB and found not to have evidence of, or require treatment for latent TB.
• At screening, the results of the following laboratory tests performed at the local laboratory must be within the limits specified below (note: the Investigator may consider the participant eligible if the previously abnormal laboratory test result is within acceptable range on repeat testing. Repeat testing to be done 28 days before dose administration. If results from the laboratory test completed on the same day as the lumbar Puncture are outside the limits specified below, the Investigator may choose to repeat tests and continue the participant in the study, depending on their clinical assessment of any likely outcome/risks).
• Haemoglobin ≥8.5 g/dL (International System of Units \[SI\]: ≥85 g/L)
• White Blood Cells (WBC) count ≥3.0 x 103 cells/mm3 (SI:≥ 3.0 x 109 cells/L)
• Neutrophils ≥1.5 x 103 cells/mm3 (SI:≥ 1.5 x 109 cells/L)
• Lymphocyte count (absolute) ≥450 cells/mm3 (SI: ≥0.45 x 109 cells/L)

You may not qualify if:

• Research participants who fulfil diagnostic criteria for any type of dementia (e.g. Alzheimer Dementia, Frontotemporal Dementia (FTD), Diffuse Lewy Body Dementia (DLBD), Vascular Dementia (VAD), etc) CDR ≥1.
• Known carriers of a presenilin 1 (PSEN1), presenilin 2 (PSEN2) or Amyloid Precursor Protein (APP) mutation associated with Autosomal Dominant AD or any other neurodegenerative disease.
• Prohibited or restricted concomitant medication as detailed in Section 10.1.7.
• Presence of any neurological, psychiatric or medical conditions associated with a long-term risk of significant cognitive impairment or dementia including but not limited to pre-manifest Huntington's disease, multiple sclerosis, Parkinson's disease, Down syndrome, active alcohol/drug abuse or major psychiatric disorders including current major depressive disorder, schizophrenia, schizoaffective or bipolar disorder. To quantify abuse is to define this as history of drug or alcohol abuse according to Diagnostic and Statistical Manual of Mental Disorders (5th Edition) (DSM-V) criteria within 6 months before screening or positive test result for alcohol and/or drugs of abuse at screening/admission.
• History of latent or active infection of one of the following infectious diseases at screening: Listeria infection, Histoplasma, Coccidioides, Paracoccidioides, Pneumocystis, nontuberculous mycobacteria, Blastomyces, Aspergillus, cytomegalovirus generalised or Herpes zoster infection
• Any cancer or history of cancer in the preceding 5 years (excluding cutaneous basal or squamous cell cancer resolved by excision).
• Any conditions that are clinically significant and may deem the participant's participation in an investigational trial unsafe, e.g., symptomatic cardiovascular disease (including re-vascularisation procedures within the previous year), severe renal or hepatic failure, any clinically relevant abnormalities in blood parameters included in local routine assessments, severe loss of vision, hearing or communicative ability, conditions preventing co-operation or completing the required assessments in the trial, as judged by the Investigator.
• Any contraindications for Lumbar Puncture.
• Any evidence of intracranial pathology which may affect cognition including but not limited to brain tumours (benign or malignant), aneurysm or arteriovenous malformations, territorial stroke (excluding smaller watershed strokes), history of or recovering haemorrhage (parenchymal or subdural), or obstructive hydrocephalus. Research participants with an MRI scan demonstrating markers of small vessel disease (e.g. white matter changes or lacunar infarcts) judged to be clinically insignificant, or microbleeds are allowed.
• Participation in a clinical trial with an Investigational Medicinal Product (IMP) in the last 30 days or 90 days in case of biologics.
• Diminished decision-making capacity that renders the individual not capable of consenting.
• Any other factors in the opinion of the Investigator that could contraindicate the participation of the research participant into this trial.

Sponsors & Collaborators

• University of Oxford: lead
• Janssen Pharmaceutica: collaborator

Study Sites (3)

Cambridgeshire and Peterborough NHS Foundation Trust

Cambridge, United Kingdom

Location

South London and Maudsley Hospital NHS Foundation Trust

London, United Kingdom

Location

Oxford Health NHS Trust

Oxford, United Kingdom

Location

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Interventions

JNJ-40346527

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Study Officials

• Vanessa Raymont

  University of Oxford

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Single-blind with participants blinded to treatment.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase 1b, randomised, single-blind, placebo-controlled parallel-group trial with JNJ-40346527 in adults with Mild Cognitive Impairment (MCI)

Study Record Dates

• First Submitted: July 3, 2019
• First Posted: October 9, 2019
• Study Start: April 7, 2021
• Primary Completion: February 18, 2022
• Study Completion: February 18, 2022
• Last Updated: May 9, 2024

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)