Clinical trial NCT04639050: Brainshuttle AD: A Multiple Ascending Dose Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 Following Intravenous Infusion in Participants With Prodromal or Mild to Moderate Alzheimer's Disease
Official title: A Phase Ib/IIa, Randomized, Double Blind, Placebo-Controlled, Multiple Ascending Dose, Parallel-Group Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7126209 Following Intravenous Infusion in Patients With Prodromal or Mild to Moderate Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Alzheimers Disease
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2020-11-20
Enrollment: 285
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of multiple-ascending intravenous (IV) doses of RO7126209 in participants with prodromal or mild to moderate Alzheimer's disease (AD), who are amyloid positive based on amyloid positron emission tomography (PET) scan.


Eligibility criteria: Key inclusion criteria for part 1, 2 and 3:

* Ability to provide written consent signed by the participant
* Availability of a person (referred to as the "study partner") who: consents to participate throughout the duration of study, in the Investigator's judgment, has frequent and sufficient contact with the participant, is fluent in the language of the tests used at the study site
* Willingness and ability to complete all aspects of the study (including magnetic resonance imaging \[MRI\], lumbar puncture, clinical genotyping, and positron emission tomography \[PET\] imaging)
* Capable of completing assessments either alone or with the help of the study partner
* Adequate visual and auditory acuity, in the Investigator's judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
* Probable mild to moderate AD dementia (consistent with National Institute on Aging-Alzheimer's Association \[NIA-AA\] core clinical criteria for probable AD dementia) or prodromal AD (consistent with the NIA-AA diagnostic criteria and guidelines for mild cognitive impairment due to AD)
* Screening Mini-Mental State Examination (MMSE) score of 18 to 28 points, inclusive, within 84 days before baseline
* Clinical Dementia Rating-Global Score (CDR-GS) of 0.5, 1, or 2 within 84 days before baseline
* Positive amyloid PET scan (cut-off: \>50 Centiloid units) within 12 months before baseline
* In case of treatment with symptomatic AD medications, dosing regimen must be stable for at least 8 weeks prior to baseline and until randomization
* Agreement not to donate blood or blood products for transfusion for the duration of the study and for 1 year after final dose of study drug
* Agreement not to participate in other research studies for the duration of this study
* Agree to apolipoprotein E (APOE) genotyping

Inclusion criteria for Part 4:

- Completed the treatment period in Part 1, Part 2, or Part 3 of the study

Key exclusion criteria for part 1, 2 and 3:

* Any evidence of other relevant neurological condition, including other (non-AD) neurodegenerative and neuropsychiatric conditions, neurovascular brain disorders, seizure disorders, inflammatory and infectious disorders of the central nervous system, trauma and delirium, among several others
* Other relevant medical conditions including significant hematological diseases, any clinically significant ophthalmologic diseases, decreased visual acuity in either eye, with a BCVA letter score of less than 20 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart or the Snellen equivalent of 20/400 if the ETDRS chart is not used
* Clinically significant cardiovascular diseases, chronic kidney disease, confirmed and unexplained impaired hepatic function, abnormal thyroid function, among several others
* History of hypersensitivity to biologic agents or any of the excipients in the formulation
* Clinically significant abnormalities (as judged by the Investigator) in laboratory test results (including complete blood count, chemistry panel, routine cerebrospinal fluid \[CSF\] parameters and urinalysis)
* MRI exclusion criteria: \>2 lacunar infarcts, any territorial infarct \>1 cm\^3, any white matter lesion that corresponds to an overall Fazekas score of 3 that requires at least one confluent hyperintense lesion on the fluid-attenuated inversion recovery (FLAIR) sequence, which is ≥20 mm in any dimension
* More than 4 microhemorrhages on MRI and/or presence of any focal area of leptomeningeal hemosiderosis based on the review performed by the central MRI reader prior to randomization
* Presence of any other significant cerebral abnormalities, including amyloid-related imaging abnormality-edema/effusion (ARIA-E), as assessed on MRI
* Inability to tolerate MRI procedures or contraindication to MRI
* Inability to undergo ophthalmological assessments
* Contraindication to lumbar puncture
* Contraindication to having a PET scan

Exclusion criteria for Part 4:

* Prematurely discontinued from the treatment period for study (i.e., before the start of the follow-up period of Part 1, Part 2, or Part 3) for any reason or meeting discontinuation criteria before the baseline visit of Part 4.
* Received any active investigational treatment other than RO7126209 during or since completion of Part 1, Part 2 or Part 3
* Any passive immunotherapy (immunoglobulin) since completion of Part 1, Part 2, or Part 3 that is meant to prevent or postpone cognitive decline.
* Use of anti-coagulation medications - Evidence of ongoing ARIA-E. In this case participant may enroll into Part 4 once the ARIA-E is resolved - Evidence of ongoing infusion-related reaction (IRR) or hypersensitivity reaction. In this case participant may enroll into Part 4 once the IRR is resolved.
* MRI evidence of any of the following at OLE baseline: evidence of ongoing ARIA-E, any ARIA-H (leptomeningeal hemosiderosis or microhemorrhages) that would require permanent discontinuation of study treatment, \> 2 lacunar infarcts, Any territorial infarct \> 1 cm\^3, any white matter lesion that corresponds to an overall Fazekas score of 3 that requires at least one confluent hyperintense lesion on the FLAIR sequence, which is ≥ 20 mm in any dimension
* Any drop in hemoglobin of \> 20% compared to predose on Day 1 or hemoglobin value below 10 g/dL

Primary outcomes:
measure: Part 1, 2, 3, and 4: Percentage of Participants With Adverse Events (AEs)
timeFrame: Part 1 and 2: Up to approximately 56 weeks; Part 3: Up to approximately 52 weeks; Part 4: Up to approximately 129 weeks
measure: Part 3: Change From Baseline in Brain Amyloid Load as Measured by Amyloid Positron Emission Tomography (PET) Scan
timeFrame: Up to approximately 24 weeks
Secondary outcomes:
measure: Part 1, 2, and 4: Change From Baseline in Brain Amyloid Load as Measured by Amyloid PET Scan
timeFrame: Part 1 and 2: Up to approximately 28 weeks; Part 4: Up to approximately 101 weeks
measure: Part 1, 2, 3, and 4: Plasma Concentration of RO7126209
timeFrame: Part 1 and 2: Up to approximately 32 weeks; Part 3: Up to approximately 24 weeks; Part 4: Up to approximately 105 weeks
measure: Part 1, 2, 3, and 4: Cerebral Spinal Fluid (CSF) Concentration of RO7126209
timeFrame: Part 1 and 2: Up to approximately 25 weeks; Part 3: Up to approximately 21 weeks; Part 4: Up to approximately 101 weeks
measure: Part 1, 2, 3, and 4: Number of Participants With Anti-Drug Antibodies (ADAs) to RO7126209
timeFrame: Part 1 and 2: Up to approximately 56 weeks; Part 3: Up to approximately 52 weeks; Part 4: Up to approximately 129 weeks
Other outcomes:
Locations:
city: Atlantis
country: United States
facility: JEM Research LLC
state: Florida
city: Clermont
country: United States
facility: K2 Medical Research-Winter Garden
state: Florida
city: Lady Lake
country: United States
facility: K2 Medical Research - The Villages
state: Florida
city: Maitland
country: United States
facility: K2 Medical Research, LLC
state: Florida
city: Miami
country: United States
facility: Optimus U Corp
state: Florida
city: Orlando
country: United States
facility: Charter Research - Winter Park/Orlando
state: Florida
city: Orlando
country: United States
facility: Advent Health Orlando
state: Florida
city: Stuart
country: United States
facility: Alzheimer's Research and Treatment Center
state: Florida
city: The Villages
country: United States
facility: Charter Research - Lady Lake/The Villages
state: Florida
city: Wellington
country: United States
facility: Alzheimer?s Research and Treatment Center
state: Florida
city: Winter Park
country: United States
facility: Conquest Research, LLC
state: Florida
city: Columbus
country: United States
facility: Columbus Memory Center
state: Georgia
city: Gainesville
country: United States
facility: Center for Advanced Research & Education
state: Georgia
city: Farmington Hills
country: United States
facility: Quest Research Institute
state: Michigan
city: Portland
country: United States
facility: Summit Research Network Inc.
state: Oregon
city: Abington
country: United States
facility: Abington Neurological Associates
state: Pennsylvania
city: Dallas
country: United States
facility: Kerwin Research Center, LLC
state: Texas
city: Heidelberg West
country: Australia
facility: Heidelberg Repatriation Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Kelowna
country: Canada
facility: Okanagan Clinical Trials
state: British Columbia
city: Richmond
country: Canada
facility: Richmond Clinical Trials
state: British Columbia
city: Toronto
country: Canada
facility: Toronto Memory Program
state: Ontario
city: Santiago
country: Chile
facility: Centro de Investigación Clínica UC-CICUC
city: Santiago
country: Chile
facility: Hospital Clinico Univ de Chile
city: Kanagawa
country: Japan
facility: Yokohama City Minato Red Cross Hospital
city: Kyoto
country: Japan
facility: Koseikai Takeda Hospital
city: Kyoto
country: Japan
facility: National Hospital Organization Utano National Hospital
city: Tokyo
country: Japan
facility: Keio University Hospital
city: Tokyo
country: Japan
facility: Tokyo Metropolitan Geriatric Hospital
city: Tokyo
country: Japan
facility: Federation of National Public Service Personnel Mutual Aid Associations Tachikawa Hospital
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Szczecin
country: Poland
facility: Osrodek Badan Klinicznych Euromedis
city: Wroc?aw
country: Poland
facility: NZOZ WCA
city: Sant Cugat del Valles
country: Spain
facility: Hospital General De Catalunya
state: Barcelona
city: Donostia-san Sebastian
country: Spain
facility: Policlínica Guipuzcoa
state: Guipuzcoa
city: Barcelona
country: Spain
facility: Fundación ACE
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Hospital Universitario Dr. Peset
city: Valencia
country: Spain
facility: Hospital Universitario la Fe
city: Birmingham
country: United Kingdom
facility: Re-Cognition
city: Bristol
country: United Kingdom
facility: Recognition Health Bristol
city: London
country: United Kingdom
facility: RE:Cognition Health
city: London
country: United Kingdom
facility: UCL Institute of Neurology
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: