A Study to Evaluate the Safety, Tolerability and Immunogenicity of Tau Targeted Vaccines in Participants With Early Alzheimer's Disease

NCT04445831 | Completed Phase 1 Results DMC

• 2 other identifiers: ACI-35-18022018-004573-27
• Study Type: interventional
• Target: 57
• Locations: 4 countries
• Sites: 9

Brief Summary

This study is a multicenter, double blind, randomized, placebo-controlled study to evaluate the safety, tolerability and immunogenicity of different doses, regimens and combinations of Tau targeted vaccines in participants with early Alzheimer's Disease.

Conditions

Alzheimer's Disease; Cognitive Impairment; Tauopathies; Mild Cognitive Impairment; Dementia; Brain Diseases; Central Nervous System Diseases

Keywords

Alzheimer's Disease; Cognitive Impairment; Tauopathies; Mild Cognitive Impairment; Dementia; Brain Diseases; Central Nervous System Diseases

Outcome Measures

Primary Outcomes (11)

• Overview of Treatment-Emergent Adverse Events, Safety Set

  Categorical data are presented with the number of subjects with at least one event for the defined categories. Subjects are included only once, even if they experienced multiple events in a category.

  AEs falling between first dosing (week 0) and last study visit (week 74), ie up to 74 weeks, defined as Treatment-Emergent Adverse Events (TEAEs)

• Overview of Treatment-Emergent Adverse Events Assessed by Intensity, Safety Set

  Categorical data are presented with the number of subjects with at least one Treatment-Emergent Adverse Event (TEAE) assessed as: * Mild: Easily tolerated and causes minimal discomfort and does not interfere with everyday activities. * Moderate: Sufficiently discomforting to interfere with normal everyday activities; intervention may be needed. Event is not hazardous to the subject's health * Severe: Prevents normal everyday activities; treatment or other intervention usually needed. Hazard to the subject's health Although subjects may have experienced multiple events, they are included only once, in the maximum severity category

  Between the first dosing and the last study visit (week 74)

• Overview of Treatment-Emergent Adverse Events Assessed by Relationship to Study Drug, Safety Set

  Categorical data are presented with the number of subjects with at least one Treatment-Emergent Adverse Event (TEAE) assessed as: * Unrelated: Events reported as unrelated or unlikely related to study drug * Related: Events reported as possibly related or probably related to study drug Although subjects may have experienced multiple events, they are included only once, in the strongest relationship category

  Between the first dosing and the last study visit (week 74)

• Mean Change From Baseline in Diastolic Blood Pressure, ITT Set

  At reported visits, diastolic blood pressures (mmHg = millimeter of mercury) were measured in sitting position only, after the subject has been sitting down for at least 5 minutes. A change from baseline value is defined as the value at post-baseline timepoint minus the baseline value, i.e. post-baseline value - baseline value

  Endpoint is assessed from baseline (i.e. last non-missing value prior to the first immunization at week 0) to the last study visit (week 74), at weeks 26, 50 and 74.

• Mean Change From Baseline in Systolic Blood Pressure, ITT Set

  At reported visits, systolic blood pressures (mmHg = millimeter of mercury) were measured in sitting position only, after the subject has been sitting down for at least 5 minutes. A change from baseline value is defined as the value at post-baseline timepoint minus the baseline value, i.e. post-baseline value - baseline value

  Endpoint is assessed from baseline (i.e. last non-missing value prior to the first immunization at week 0) to the last study visit (week 74), at weeks 26, 50 and 74.

• Mean Change From Baseline in Heart Rate, ITT Set

  At reported visits, heart rates (bpm = beats per minute) were measured in sitting position only, after the subject has been sitting down for at least 5 minutes. A change from baseline value is defined as the value at post-baseline timepoint minus the baseline value, i.e. post-baseline value - baseline value

  Endpoint is assessed from baseline (i.e. last non-missing value prior to the first immunization at week 0) to the last study visit (week 74), at weeks 26, 50 and 74.

• Mean Change From Baseline in Body Temperature, ITT Set

  At reported visits, body temperatures (°C = degree Celsius) were measured. A change from baseline value is defined as the value at post-baseline timepoint minus the baseline value, i.e. post-baseline value - baseline value

  Endpoint is assessed from baseline (i.e. last non-missing value prior to the first immunization at week 0) to the last study visit (week 74), at weeks 26, 50 and 74.

• Number of Participants Reporting Suicidal Ideation or Behavior Using Columbia-Suicide Severity Rating Scale (C-SSRS), ITT Set

  Suicidal ideation or behavior using Columbia-Suicide Severity Rating Scale (C-SSRS) was assessed at Baseline (screening or visit 1 (Week 0)) and at weeks 26, 50 and 74. A set of questions related to suicidal behavior or ideation was directly asked by the rater to the subject.

  Endpoint is assessed from baseline (i.e. last non-missing value prior to the first immunization at Visit 1 (Week 0) or Screening) to the last study visit (week 74), at weeks 26, 50 and 74.

• Number of Participants With Abnormal MRI Results, ITT Set

  Brain MRI scans were conducted according to the schedule of assessments, i.e. at Baseline (screening) and at weeks 10, 26, 50, 74 and examined for evidence of brain pathology. Normal, abnormal not clinically significant (NCS) and abnormal clinically significant (CS) results as interpreted by the clinical site are reported.

  Endpoint is assessed from baseline (screening) to the last study visit (week 74), at weeks 10, 26, 50 and 74.

• Anti-pTau IgG Antibody Response in Serum - Antibody Titers, ITT Set

  At all visits, blood was collected for the determination of the immune response in serum. Anti-phosphorylated Tau (pTau) IgG titers were measured by Meso Scale Discovery (MSD). For each visit, the geometric means (AU/mL) and 95% Confidence Interval (CI) is given.

  Endpoint is assessed from baseline (i.e. mean of the titers measured at the screening and visit 1 before the first study drug administration) to the last study visit (week 74), at weeks 0, 2, 8, 10, 24, 26, 36, 48, 50, 67 and 74.

• Anti-ePHF IgG Antibody Response in Serum - Antibody Titers, ITT Set

  At all visits, blood was collected for the determination of the immune response in serum. Anti-enriched paired helical filaments (ePHF) IgG titers were measured by Meso Scale Discovery (MSD). For each visit, the geometric means (AU/mL) and 95% Confidence Interval (CI) is given.

  Endpoint is assessed from baseline (i.e. mean of the titers measured at the screening and visit 1 before the first study drug administration) to the last study visit (week 74), at weeks 0, 2, 8, 10, 24, 26, 36, 48, 50, 67 and 74.

Secondary Outcomes (3)

• Anti-Tau IgG Antibody Response in Serum - Antibody Titers, ITT Set

  Endpoint is assessed from baseline (i.e. mean of the titers measured at the screening and visit 1 before the first study drug administration) to the last study visit (week 74), at weeks 0, 2, 8, 10, 24, 26, 36, 48, 50, 67 and 74.

• Anti-pTau IgM Antibody Response in Serum - Antibody Titers, ITT Set

  Endpoint is assessed from baseline (i.e. mean of the titers measured at the screening and visit 1 before the first study drug administration) to the last study visit (week 74), at weeks 0, 2, 8, 10, 24, 26, 36, 48, 50, 67 and 74.

• Anti-Tau IgM Antibody Response in Serum - Antibody Titers, ITT Set

  Endpoint is assessed from baseline (i.e. mean of the titers measured at the screening and visit 1 before the first study drug administration) to the last study visit (week 74), at weeks 0, 2, 8, 10, 24, 26, 36, 48, 50, 67 and 74.

Other Outcomes (3)

• Change From Baseline of Functional Performance Using CDR-SB Scale

  from baseline up to week 74

• Change From Baseline of Cognitive Performance Using RBANS Scale

  from baseline up to week 74

• Change From Baseline of Behavior Using NPI Scale

  from baseline up to week 74

Study Arms (6)

Placebo

PLACEBO COMPARATOR

Placebo administered at predefined time points over a 48-week period.

Other: Placebo

ACI-35.030 - Low dose

EXPERIMENTAL

Active vaccine administered at predefined time points over a 48-week period.

Biological: ACI-35.030

ACI-35.030 - Medium dose

EXPERIMENTAL

Active vaccine administered at predefined time points over a 48-week period.

Biological: ACI-35.030

ACI-35.030 - High dose

EXPERIMENTAL

Active vaccine administered at predefined time points over a 48-week period.

Biological: ACI-35.030

JACI-35.054 - Low dose

EXPERIMENTAL

Active vaccine administered at predefined time points over a 48-week period.

Biological: JACI-35.054

JACI-35.054 - Medium dose

EXPERIMENTAL

Active vaccine administered at predefined time points over a 48-week period.

Biological: JACI-35.054

Interventions

ACI-35.030 BIOLOGICAL

Administration of a Low dose of ACI-35.030

ACI-35.030 - Low dose

Placebo OTHER

Administration of Placebo

Placebo

JACI-35.054 BIOLOGICAL

Administration of a Low dose of JACI-35.054

JACI-35.054 - Low dose

Eligibility Criteria

• Age: 50 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female with age from 50 and up to 75 years old inclusive.
• Mild Cognitive Impairment (MCI) due to AD or Mild AD according to NIA-AA criteria and Clinical Dementia Rating scale (CDR) global score of 0.5 or 1 respectively.
• Mini Mental State Examination (MMSE) score of 22 or above.
• Abnormal level of CSF Abeta amyloid 42 (Aß42) consistent with AD pathology at screening.
• Subjects either not taking any marketed treatment for AD or receiving a stable dose of an acetylcholinesterase inhibitor and/or memantine for at least 3 months prior to baseline.
• Subjects cared for by a reliable informant or caregiver to assure compliance, assist with clinical assessments and report safety issues.
• Women must be post-menopausal for at least one year and/or surgically sterilized.
• Subjects who in the opinion of the investigator is able to understand and provide written informed consent.
• Both subject and informant or caregiver must be fluent in one of the languages of the study and able to comply with all study procedures, including lumbar punctures.

You may not qualify if:

• Participation in previous clinical trials for AD and/or for neurological disorders using active immunization unless there is documented evidence that the subject was treated with placebo only and the placebo vaccine is not expected to induce any specific immune response.
• Participation in previous clinical trials for AD and/or for neurological disorders using any passive immunization within the past 6 months (or 5 half-lives of the investigational antibody, whichever is longer) prior to screening unless there is documented evidence that the subject was treated with placebo only and the placebo is not expected to induce any specific immune response.
• Participation in previous clinical trials for AD and/or for neurological disorders using any small molecule drug including BACE-1 inhibitors within the past 3 months prior to screening.
• Concomitant participation in any other clinical trial using experimental or approved medications or therapies.
• Presence of positive Anti-nuclear Antibody (ANA) titers at a dilution of at least 1:160 in subjects without clinical symptoms of auto-immune disease.
• Current or past history of auto-immune disease, or clinical symptoms consistent with the presence of auto-immune disease.
• Immune suppression including but not limited to the use of immunosuppressive drugs or systemic steroids unless they have been prescribed transiently more than 3 months prior to screening.
• History of severe allergic reaction (e.g., anaphylaxis) including but not limited to severe allergic reaction to previous vaccines and/or medications.
• Prior history of clinically significant hypoglycaemic episodes.
• Drug or alcohol abuse or dependence currently met or within the past five years according to Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V) criteria.
• Any clinically significant medical condition likely to interfere with the evaluation of safety and tolerability of the study treatment and/or the adherence to the full study visit schedule.
• Any clinically significant medical condition likely to impact the immune system (e.g, any history of acquired or innate immune system disorder).
• Use of hydralazine, procainamide, quinidine, isoniazide, TNF-inhibitors, minocycline within the last 12 months prior to screening.
• Use of diltiazem unless on a stable dose for at least 3 months prior to screening.
• Significant risk of suicide defined, using the Columbia-Suicide Severity Rating Scale, as the subject answering: "yes" to suicidal ideation questions 4 or 5 or answering: "yes" to suicidal behavior within the past 12 months.

Sponsors & Collaborators

• AC Immune SA: lead
• Janssen Research & Development, LLC: collaborator

Study Sites (9)

Clinical Research Services Helsinki

Helsinki, Finland

Location

Itä-Suomen Yliopisto - Kuopion Kampus

Kuopio, Finland

Location

Clinical Research Services Turku

Turku, Finland

Location

Brain Research Center - Den Bosch

's-Hertogenbosch, Netherlands

Location

Brain Research Center - Amsterdam

Amsterdam, Netherlands

Location

Minnesmottagningen - Sahlgrenska Universitetssjukhuset - Mölndal Sjukhus

Mölndal, Sweden

Location

Kognitiv Mottagning - Karolinska Universitetssjukhuset - Huddinge

Stockholm, Sweden

Location

Edinburgh Clinical Research Facility

Edinburgh, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, United Kingdom

Location

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction; Tauopathies; Dementia; Brain Diseases; Central Nervous System Diseases

Condition Hierarchy (Ancestors)

Nervous System Diseases; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Limitations and Caveats

* The study was not powered to detect differences between the active and placebo treatments for exploratory endpoints (e.g., fluid biomarkers and cognition/clinical efficacy outcomes). * The sub-cohort 1.1 (ACI-35.030 300 μg / placebo) was significantly impacted by the COVID-19 pandemic due to local travel restriction in Finland. Seven out of 8 subjects (5 active and 2 placebo) in this sub-cohort missed 1 study treatment administration.

Results Point of Contact

• Title: Olivier Sol
• Organization: AC Immune

clinicaltrials@acimmune.com

+41 21 345 91 21

Study Officials

• Philip Scheltens, MD

  Amsterdam UMC Alzheimer Center de Boelelaan Amsterdam The Netherlands

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 22, 2020
• First Posted: June 24, 2020
• Study Start: July 31, 2019
• Primary Completion: September 5, 2023
• Study Completion: September 5, 2023
• Last Updated: February 14, 2025
• Results First Posted: February 14, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

NL (2); GB (2); SE (2); FI (3)