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

Roche

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Alzheimers Disease

Treatments: Drug: Placebo; Drug: RO7126209

Study type: Interventional

Funder types: Industry

Identifiers

NCT04639050

2023-509678-52-00 (Other Identifier)

2020-002477-98 (EudraCT Number)

BP42155

Details and patient eligibility

About

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.

Enrollment: 285 estimated patients

Sex: All

Ages: 50 to 85 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: Quadruple Blind

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285 participants in 21 patient groups, including a placebo group

Part 1 (Dose Finding) Cohort 1: Dose Level 1 of RO7126209

Experimental group

Description:

Participants will receive multiple doses of RO7126209 at dose level 1 once every 4 weeks (Q4W) for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 1 (Dose Finding) Cohort 1: Placebo

Placebo Comparator group

Description:

Participants will receive matching placebo to dose level 1 Q4W for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: Placebo

Part 1 (Dose Finding) Cohort 2: Dose Level 2 of RO7126209

Experimental group

Description:

Participants will receive multiple doses of RO7126209 at dose level 2, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 1 (Dose Finding) Cohort 2: Placebo

Placebo Comparator group

Description:

Participants will receive matching placebo to dose level 2, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: Placebo

Part 1 (Dose Finding) Cohort 3: Dose Level 3 of RO7126209

Experimental group

Description:

Participants will receive multiple doses of RO7126209 at dose level 3, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 1 (Dose Finding) Cohort 3: Placebo

Placebo Comparator group

Description:

Participants will receive matching placebo to dose level 3, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: Placebo

Part 1 (Dose Finding) Cohort 4: Dose Level 4 of RO7126209

Experimental group

Description:

Participants will receive multiple doses of RO7126209 at dose level 4, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 1 (Dose Finding) Cohort 4: Placebo

Placebo Comparator group

Description:

Participants will receive matching placebo to dose level 4, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: Placebo

Part 1 (Dose Finding) Cohort 5: Dose Level 5 of RO7126209

Experimental group

Description:

Participants will receive a total of 2 doses of RO7126209 at dose level 5 Q4W, for 28 weeks followed by an 8-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 1 (Dose Finding) Cohort 5: Placebo

Placebo Comparator group

Description:

Participants will receive a total of 2 doses of matching placebo to dose level 5 Q4W, for 28 weeks followed by an 8-week safety follow-up period.

Treatment:

Drug: Placebo

Part 2 (Expansion) Cohort 1: Dose Level 1 of RO7126209

Experimental group

Description:

Participants will receive multiple doses of RO7126209 at dose level 1, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 2 (Expansion) Cohort 1: Placebo

Placebo Comparator group

Description:

Participants will receive matching placebo to dose level 1, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: Placebo

Part 2 (Expansion) Cohort 2: Dose Level 2 of RO7126209

Experimental group

Description:

Participants will receive multiple doses of RO7126209 at dose level 2, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 2 (Expansion) Cohort 2: Placebo

Placebo Comparator group

Description:

Participants will receive matching placebo to dose level 2, Q4W, for 28 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: Placebo

Part 2 (Expansion) Cohort 3: Dose Level 3 of RO7126209

Experimental group

Description:

Participants will receive a total of 2 doses of RO7126209 at dose level 3, Q4W, for 28 weeks followed by an 8-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 2 (Expansion) Cohort 3: Placebo

Placebo Comparator group

Description:

Participants will receive a total of 2 doses of matching placebo to dose level 3, Q4W, for 28 weeks followed by an 8-week safety follow-up period.

Treatment:

Drug: Placebo

Part 3 (Dose/Frequency/Pharmacodynamic (PD) Relationship): Dose Level 1: RO7126209

Experimental group

Description:

Participants will receive multiple doses of RO7126209 in an open-label treatment period at dose level 1, Q4W, for 24 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 3 Dose/Frequency/PD Relationship: Dose Level 2: RO7126209

Experimental group

Description:

Participants will receive multiple doses of RO7126209 in an open-label treatment period at dose level 2, Q12W, for 24 weeks followed by a 28-week safety follow-up period.

Treatment:

Drug: RO7126209

Part 4: Open Label Extension (OLE) phase Arm 1: RO7126209

Experimental group

Description:

Participants who completed Part 1, 2, or 3 and have reached amyloid negativity (≤ 24 centiloids) in either of the Study Parts or at the OLE baseline visit will receive RO7126209 Q12W for 101 weeks. The dose level will depend on the dose level in Part 1, 2, and 3.

Treatment:

Drug: RO7126209

Part 4 OLE Phase Arm 2: RO7126209

Experimental group

Description:

Participants who completed Part 1, 2, or 3 and who are amyloid positive (≥24 centiloids) will receive RO7126209 Q4W for 12 weeks and will have to reach amyloid negativity (≤ 24 centiloids) before they can switch to Q12W dosing in an open-label treatment period of 89 weeks. The dose level will depend on the dose level received in Part 1,2, and 3.

Treatment:

Drug: RO7126209

Part 4 OLE Phase Arm 3: RO7126209

Experimental group

Description:

Participants who completed Part 1, 2, or 3 and who are amyloid positive (≥24 centiloids) at week 12 of OLE will receive RO7126209 Q4W for an additional 12 weeks, before to switch to Q12W dosing for the remaining 77 weeks in an open-label treatment period. The dose level will depend on the dose level received in Part 1,2, and 3.

Treatment:

Drug: RO7126209