AB1601

Araclon Biotech, S.L. a Grifols company

Vía de la Hispanidad, 21, Zaragoza, Spain, 50009

Araclon Biotech, S.L. a Grifols company, Araclon Biotech, S.L. a Grifols company, info@araclon.com

Maria Pascual Lucas, Araclon Biotech, S.L. a Grifols company, mpascual@araclon.com

No

No

No

Final

18 Aug 2023

Yes

23 Mar 2023

Yes

23 Mar 2023

No

Primary Safety Objective: - To evaluate the safety and tolerability of repeated doses of ABvac40 in a population of patients with amnestic mild cognitive impairment (a-MCI) or very mild Alzheimer’s Disease (vm-AD). Primary Efficacy (Immunogenicity) Objective: - To assess (quantify) the immune response produced during the study by repeated doses of ABvac40 in a population of a-MCI or vm-AD.

Documented approvals to the study (including the protocol, all amendments and informed consents) were obtained for all participating centers/countries prior to study start from appropriate Institutional Review Board/Ethics Committee (IRBs/ECs), according to ICH good clinical practice (GCP) guidelines, local laws, regulations and organizations. The procedures described in the clinical study protocol, pertaining to the conduct, evaluation, and documentation of the study were designed to ensure that the sponsor and investigator abide by ICH GCP guidelines. The study was also carried out in keeping with applicable local law(s) and regulation(s). Written informed consent form (ICF) was obtained from the patients (or legal representatives, if applicable) and from a close relative/caregiver before any study specific procedure took place. Subjects records and personal data were handled in strictest confidence and in accordance with local data protection laws and with the European General Data Protection Regulation (2016/679) (GDPR). No medical waivers for protocol inclusion/exclusion criteria were allowed by the sponsor, and that in case the need for a change to the protocol was identified, it was submitted as a protocol amendment to the competent regulatory authority and/or IRBs/ECs as applicable per regulations. Direct advertising was used in this study in order to solicit subject participation. Direct advertising included, but were not necessarily limited to: newspaper, radio, television, bulletin boards, posters that were intended for candidate subjects. Any advertisement was submitted for review and approval to the IRBs/ECs charged with this responsibility to ensure that the information contained in the advertisement was not misleading and that the procedure for recruiting subjects gave adequate protection for the rights and welfare of the subjects.

01 Dec 2017

No

Yes

Spain: 107

Sweden: 3

France: 12

Italy: 2

124

124

0

0

0

0

0

0

20

104

0

Part A (18-24 months duration)

Randomised - controlled

Only the independent representative of the Sponsor and the independent statistician worked without blinding in order to label study medication and to prepare all the data safety monitoring board (DSMB) documentation, respectively. Blinding was only to be broken for safety concerns requiring immediate medical treatment.

Yes

Placebo

Injection

Subcutaneous use

Six administrations: the first five administered once every 4 weeks (28±3 days) and the sixth at week 42 (Visit 18), 26 weeks after the fifth. Each administration consisted of 1 mL injection of ABvac40 vehicle without its active ingredient.

ABvac40

Injection

Subcutaneous use

Six administrations: the first five administered once every 4 weeks (28±3 days) and the sixth at week 42 (Visit 18), 26 weeks after the fifth. Each administration consisted of 1 mL injection of ABvac40 (containing 0.2 mg of Aβx-40).

Part B (18 months duration)

Non-randomised - controlled

For the Part B of the study, both the sites’ principal investigators and the patients remained blinded. Blinding was only to be broken for safety concerns requiring immediate medical treatment.

Yes

ABvac40

Injection

Subcutaneous use

Six administrations: the first five administered once every 4 weeks (28±3 days) and the sixth at week 42 (Visit 18B), 26 weeks after the fifth immunization. Each administration consisted of 1 mL injection of ABvac40 (containing 0.2 mg of Aβx-40).

Placebo

Injection

Subcutaneous use

Five administrations: the first four administered once every 4 weeks (28±3 days) and the fifth at week 42 (Visit 18B), 30 weeks after the forth. Each administration consisted of 1 mL injection of ABvac40 vehicle without its active ingredient.

ABvac40

Injection

Subcutaneous use

One administration (booster) at week 16 (Visit 13B). The administration consisted of 1 mL injection of ABvac40 (containing 0.2 mg of Aβx-40).

Placebo arm Part A

ABvac40 arm Part A

SAF

The Safety (SAF) analysis set consisted of all randomized subjects who received any amount of IMP. All safety analyses used the SAF analysis set. Subjects were analyzed according to the treatment received, regardless of the treatment assigned. Note: Subjects S04-002 and S14-006 were randomized to the Placebo arm in Part A and inadvertently received ABvac40 on Visit 10 and Visit 7 respectively. They received ABvac40 in Part B. These 2 subjects were summarized for the SAF analysis set in ABvac40 arm for Part A and Part B.

ITT

The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.

mITT

The Modified Intent-to-treat (mITT) analysis set comprised all subjects in the ITT analysis set who had a Baseline- and at least 1 post-Baseline anti-Aβ40 antibody assessment (optical density [OD] in ELISA without pre-adsorption). Analysis of the primary efficacy endpoint was carried out using the mITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.

PP (Part A)

The Per protocol (PP) analysis set (Part A) comprised all subjects in the ITT analysis set who received all doses of the IMP (on V1, V4, V7, V10, V13 and V18 in Part A), attended the safety visit after Booster (V20 in Part A) and had no major protocol deviations that could have affected the efficacy analyses. Analysis of the primary efficacy endpoint and secondary efficacy endpoints relating to the characterization of immune response and the assessment of disease biomarkers in Part A was repeated using the Part A PP analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received. Note: Summaries of the primary efficacy endpoint and secondary efficacy endpoints relating to the characterization of immune response and the assessment of disease biomarkers over the entire duration of the study (Parts A and B combined) were repeated using subjects who were in Part A PP analysis set and the Part B PP analysis set.

PPc (Part A)

Per protocol cognition (PPc) analysis set (Part A) comprised all subjects in the ITT analysis set who received all doses of the IMP (on V1, V4, V7, V10, V13 and V18 in Part A), attended the safety visit after Booster (V20 in Part A), had no major protocol deviations that could have affected the efficacy analyses or major protocol deviations that were classified as “Use of disallowed concomitant medication”, relating to use of anti-AD medication. Analysis of secondary efficacy endpoints relating to the assessment of cognition and quality of life in Part A was repeated using the Part A PPc analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received. Note: Analysis of secondary efficacy endpoints relating to the assessment of cognition and quality of life over the entire duration of the study (Parts A and B combined), were repeated using subjects who were in Part A PPc analysis set and the Part B PPc analysis set.

PP (Part B)

The Per protocol (PP) analysis set (Part B) comprised all subjects in the ITT analysis set who received all doses of the IMP (on V1B, V4B, V7B, V10B, V13B and V18B in Part B), attended the safety visit after Booster (V20B in Part B) and had no major protocol deviations that could have affected the summary of efficacy. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received Note: Summaries of the primary efficacy endpoint and secondary efficacy endpoints relating to the characterization of immune response and the assessment of disease biomarkers over the entire duration of the study (Parts A and B combined) were repeated using subjects who were in Part A PP analysis set and the Part B PP analysis set.

PPc (Part B)

Per protocol cognition (PPc) analysis set (Part B) comprised all subjects in the ITT analysis set who received all doses of the IMP (on V1B, V4B, V7B, V10B, V13B and V18B in Part B), attended the safety visit after Booster (V20B in Part B), had no major protocol deviations that could have affected the efficacy analyses or major protocol deviations that were classified as “Use of disallowed concomitant medication”, relating to use of anti-AD medication. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received. Note: Analysis of secondary efficacy endpoints relating to the assessment of cognition and quality of life over the entire duration of the study (Parts A and B combined), were repeated using subjects who were in Part A PPc analysis set and the Part B PPc analysis set

Placebo arm Part A

ABvac40 arm Part A

Placebo arm Part A/ABvac40 arm Part B

ABvac40 arm Part A/Placebo+Booster arm Part B

SAF

The Safety (SAF) analysis set consisted of all randomized subjects who received any amount of IMP. All safety analyses used the SAF analysis set. Subjects were analyzed according to the treatment received, regardless of the treatment assigned. Note: Subjects S04-002 and S14-006 were randomized to the Placebo arm in Part A and inadvertently received ABvac40 on Visit 10 and Visit 7 respectively. They received ABvac40 in Part B. These 2 subjects were summarized for the SAF analysis set in ABvac40 arm for Part A and Part B.

ITT

The Intent-to-treat (ITT) analysis set consisted of all subjects randomized who received any IMP. Analysis of all secondary efficacy endpoints was carried out using the ITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.

mITT

The Modified Intent-to-treat (mITT) analysis set comprised all subjects in the ITT analysis set who had a Baseline- and at least 1 post-Baseline anti-Aβ40 antibody assessment (optical density [OD] in ELISA without pre-adsorption). Analysis of the primary efficacy endpoint was carried out using the mITT analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received.

PP (Part A)

The Per protocol (PP) analysis set (Part A) comprised all subjects in the ITT analysis set who received all doses of the IMP (on V1, V4, V7, V10, V13 and V18 in Part A), attended the safety visit after Booster (V20 in Part A) and had no major protocol deviations that could have affected the efficacy analyses. Analysis of the primary efficacy endpoint and secondary efficacy endpoints relating to the characterization of immune response and the assessment of disease biomarkers in Part A was repeated using the Part A PP analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received. Note: Summaries of the primary efficacy endpoint and secondary efficacy endpoints relating to the characterization of immune response and the assessment of disease biomarkers over the entire duration of the study (Parts A and B combined) were repeated using subjects who were in Part A PP analysis set and the Part B PP analysis set.

PPc (Part A)

Per protocol cognition (PPc) analysis set (Part A) comprised all subjects in the ITT analysis set who received all doses of the IMP (on V1, V4, V7, V10, V13 and V18 in Part A), attended the safety visit after Booster (V20 in Part A), had no major protocol deviations that could have affected the efficacy analyses or major protocol deviations that were classified as “Use of disallowed concomitant medication”, relating to use of anti-AD medication. Analysis of secondary efficacy endpoints relating to the assessment of cognition and quality of life in Part A was repeated using the Part A PPc analysis set. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received. Note: Analysis of secondary efficacy endpoints relating to the assessment of cognition and quality of life over the entire duration of the study (Parts A and B combined), were repeated using subjects who were in Part A PPc analysis set and the Part B PPc analysis set.

PP (Part B)

The Per protocol (PP) analysis set (Part B) comprised all subjects in the ITT analysis set who received all doses of the IMP (on V1B, V4B, V7B, V10B, V13B and V18B in Part B), attended the safety visit after Booster (V20B in Part B) and had no major protocol deviations that could have affected the summary of efficacy. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received Note: Summaries of the primary efficacy endpoint and secondary efficacy endpoints relating to the characterization of immune response and the assessment of disease biomarkers over the entire duration of the study (Parts A and B combined) were repeated using subjects who were in Part A PP analysis set and the Part B PP analysis set.

PPc (Part B)

Per protocol cognition (PPc) analysis set (Part B) comprised all subjects in the ITT analysis set who received all doses of the IMP (on V1B, V4B, V7B, V10B, V13B and V18B in Part B), attended the safety visit after Booster (V20B in Part B), had no major protocol deviations that could have affected the efficacy analyses or major protocol deviations that were classified as “Use of disallowed concomitant medication”, relating to use of anti-AD medication. Subjects were analyzed according to their randomized treatment assignment, regardless of the treatment received. Note: Analysis of secondary efficacy endpoints relating to the assessment of cognition and quality of life over the entire duration of the study (Parts A and B combined), were repeated using subjects who were in Part A PPc analysis set and the Part B PPc analysis set

Average maximal increment (MΔ) of plasma anti-Aβ40 antibody signal (optical density [OD] in ELISA) in each subject with regard to Baseline visit. For the primary efficacy analysis, the trial was considered successfully confirmatory regarding efficacy (immunogenicity) of ABvac40 since the average MΔ of anti-Aβ40 antibody signal in the ABvac40 arm was significantly greater that the average MΔ in anti-Aβ40 antibody signal in the Placebo arm.

Primary

Maximal increment (MΔ) from Baseline across all Part A post-Baseline visits

1-sided t-test to compare the ABvac40 and placebo groups

Placebo arm Part A v ABvac40 arm Part A

121

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

121

Pre-specified

The average MΔ of anti-Aβ40 antibody signal between the two treatment groups was compared using an ANCOVA model, using the MΔ anti-Aβ40 antibody signal as the dependent variable, baseline anti-Aβ40 antibody signal (OD in ELISA) as covariate and treatment group and amyloid positivity as fixed effects.

Placebo arm Part A v ABvac40 arm Part A

121

Pre-specified

3.15

2-sided

Standard error of the mean

0.1

1-sided t-test to compare the ABvac40 and placebo groups

Placebo arm Part A v ABvac40 arm Part A

121

Pre-specified

The change in anti-Aβ40 antibody signal from baseline to each post-baseline efficacy visit was analyzed using a Mixed-Model Repeated Measures (MMRM), using the mITT Analysis Set. Dependent variable: change from baseline in anti-Aβ40 antibody signal. Fixed effects: treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity. Covariates: baseline anti-Aβ40 antibody signal and baseline age; Repeated measure: measures within-patient at each visit. (See chart)

Placebo arm Part A v ABvac40 arm Part A

121

Pre-specified

Number of withdrawn subjects due to treatment-emergent adverse events (TEAEs) during the whole study. There were 7 TEAEs leading to study withdrawal in 7 subjects (2 [2.0%] subjects in the ABvac40 (Part A)/ABvac40 (Part B) group, 4 [6.5%] subjects in the Placebo (Part A) group, and 1 [2.5%] in the Placebo (Part B)/Booster (Part B) group).

Secondary

Whole study duration (Part A+Part B; up to 42 months)

Clinically significant (CS) abnormalities in physical examination during the study. There were a total of 14 CS abnormalities in 11 subjects: 3 subjects presented a total of 5 CS abnormalities in treatment sequence ABvac40 arm Part A/Placebo+Booster arm Part B 8 subjects presented a total of 9 CS abnormalities in treatment sequence Placebo arm Part A/ABvac40 arm Part B No consistently recurrent or persistent CS abnormalities were observed in the physical examination, suggesting no IMP impact.

Secondary

Whole study duration (Part A+Part B; up to 42 months)

Clinically significant (CS) abnormalities in neurological examination during the study. There were a total of 110 CS abnormalities in 13 subjects: 6 subjects presented a total of 67 CS abnormalities in treatment sequence ABvac40 arm Part A/Placebo+Booster arm Part B 7 subjects presented a total of 43 CS abnormalities in treatment sequence Placebo arm Part A/ABvac40 arm Part B The most frequently reported CS abnormalities were related to cortical functions, which may be anticipated in this study population. No other consistently recurrent or persistent CS abnormalities were observed in the neurological examination, suggesting no IMP impact.

Secondary

Whole study duration (Part A+Part B; up to 42 months)

Clinically significant (CS) abnormalities in hematology parameters during the study. There were a total of 60 CS abnormalities in 12 subjects: 7 subjects presented a total of 24 CS abnormalities in treatment sequence ABvac40 arm Part A/Placebo+Booster arm Part B 5 subjects presented a total of 36 CS abnormalities in treatment sequence Placebo arm Part A/ABvac40 arm Part B No consistently recurrent or persistent clinically significant abnormalities were observed in the hematology parameters, suggesting no IMP impact.

Secondary

Whole study duration (Part A+Part B; up to 42 months)

Clinically significant (CS) abnormalities in biochemistry parameters during the study. There were a total of 91 CS abnormalities in 24 subjects: 9 subjects presented a total of 24 CS abnormalities in treatment sequence ABvac40 arm Part A/Placebo+Booster arm Part B 15 subjects presented a total of 67 CS abnormalities in treatment sequence Placebo arm Part A/ABvac40 arm Part B No consistently recurrent or persistent clinically significant abnormalities were observed in the biochemistry parameters, suggesting no IMP impact.

Secondary

Whole study duration (Part A+Part B; up to 42 months)

Clinically significant (CS) abnormalities in coagulation parameters during the study. There were a total of 16 CS abnormalities in 8 subjects: 3 subjects presented a total of 7 CS abnormalities in treatment sequence ABvac40 arm Part A/Placebo+Booster arm Part B 5 subjects presented a total of 9 CS abnormalities in treatment sequence Placebo arm Part A/ABvac40 arm Part B No consistently recurrent or persistent clinically significant abnormalities were observed in the coagulation parameters, suggesting no IMP impact.

Secondary

Whole study duration (Part A+Part B; up to 42 months)

The change in levels of anti-Aβ40 antibodies in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were differences (p<0.05) between groups at Week 50A and Week 104A. The MMRM included the recorded outcome value as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used.

Secondary

Part A

ABvac40 arm Part A v Placebo arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in levels of anti-Aβ40 antibodies in plasma from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were differences (p<0.05) between groups at each Part A visit (except at Week 2A, Week 77A and Week 104A). The MMRM included the recorded outcome value as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. A compound symmetric variance-covariance matrix was used.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in levels of antibody-secreting cells from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were differences (p<0.05) between groups at each Part A visit (except at Week 2A and Week 104A). The MMRM included the recorded outcome value as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factor was significantly associated with the response measure (p < 0.15) and was included in the model: clinical subgroup – mild cognitive impairment or very mild Alzheimer Disease.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in levels of anti-Aβ40 peptides in plasma (ABtest-IA) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were differences (p<0.05) between groups at each Part A visit (except at Week 2A, Week 6A and Week 10A). The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors were significantly associated with the response measure (p < 0.15) and were included in the model: baseline use of Alzheimer Disease symptomatic medication and clinical subgroup – mild cognitive impairment or very mild Alzheimer Disease.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in levels of anti-Aβ42 peptides in plasma (ABtest-IA) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were differences (p<0.05) between groups only at Week 40A and Week 44A. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factor was significantly associated with the response measure (p < 0.15) and was included in the model: baseline use of Alzheimer Disease symptomatic medication.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in levels of anti-Aβ40 peptides in plasma (ABtest-MS) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were differences (p<0.05) between groups at each Part A visit between Week 14A and Week 50A. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. A compound symmetric variance-covariance matrix was used.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in levels of anti-Aβ42 peptides in plasma (ABtest-MS) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were no differences of note between groups at applicable Part A visits (referring to MMRM p-values). The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factors were significantly associated with the response measure (p < 0.15) and were included in the model: ApoE carrier status and clinical subgroup – mild cognitive impairment or very mild Alzheimer Disease.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in amyloid-PET (a-PET) standard centiloid global cortical area (reference Pons) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were no differences between groups at either Week 50A (P=0.1058) or Week 104A. The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factor was significantly associated with the response measure (p < 0.15) and was included in the model: baseline use of Alzheimer Disease symptomatic medication.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The percent change in brain volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were no differences of note between groups at applicable Part A visits (referring to MMRM p-values). The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The percent change in right and left hippocampal volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were no differences of note between groups at applicable Part A visits (referring to MMRM p-values). The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factor was significantly associated with the response measure (p < 0.15) and was included in the model (only for left hippocampus): clinical subgroup – mild cognitive impairment or very mild Alzheimer Disease.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The percent change in ventricular volume from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were no differences of note between groups at applicable Part A visits (referring to MMRM p-values). The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factor was significantly associated with the response measure (p < 0.15) and was included in the model: baseline use of Alzheimer Disease symptomatic medication.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in levels of Aβ42 peptides in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were no differences of note between groups at applicable Part A visits (referring to MMRM p-values). The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in levels of Aβ40 peptides in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were no differences of note between groups at applicable Part A visits (referring to MMRM p-values). The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

The change in Aβ42/Aβ40 ratio in cerebrospinal fluid (CSF) from baseline to each applicable post-baseline efficacy visit (Part A) was analyzed using a Mixed-Model Repeated Measures (MMRM), and the ITT analysis set. There were no differences of note between groups at applicable Part A visits (referring to MMRM p-values). The MMRM included change from baseline in the efficacy parameter as the dependent variable; treatment, protocol-specified visits, treatment-by-visit interaction, and amyloid positivity as the fixed effects; baseline efficacy parameter and baseline age as covariates; and measures within-patient at each visit as a repeated measure. An unstructured variance-covariance matrix was used. The following factor was significantly associated with the response measure (p < 0.15) and was included in the model: baseline use of Alzheimer Disease symptomatic medication.

Secondary

Part A

Placebo arm Part A v ABvac40 arm Part A

124

Pre-specified

Placebo arm Part A v ABvac40 arm Part A

124