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Trial registered on ANZCTR


Registration number
ACTRN12615000500550
Ethics application status
Approved
Date submitted
5/03/2015
Date registered
19/05/2015
Date last updated
27/04/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease study - the A4 study
Scientific title
'Study investigating the effectiveness of the anti-amyloid (solanezumab) treatment vs placebo in asymptomatic Alzheimer's disease on preventing the onset of symptoms - the A4 study.
Secondary ID [1] 286403 0
NCT02008357
Universal Trial Number (UTN)
U1111-1167-4175
Trial acronym
The A4 Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer's Disease 294381 0
Condition category
Condition code
Neurological 294691 294691 0 0
Alzheimer's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
400 mg solanezumab/placebo per intravenous infusion, four weekly for 3 years. Safety assessments: blood, MRI, ECG at intervals throughout the study.
Intervention code [1] 291322 0
Prevention
Intervention code [2] 291692 0
Treatment: Drugs
Comparator / control treatment
Placebo: 0.9% Normal saline solution
Control group
Placebo

Outcomes
Primary outcome [1] 294450 0
The primary objective of this study is to test the impact of solanezumab, administered as an intravenous infusion at a dose of 400 mg every 4 weeks for 3 years, on cognition as compared with placebo in subjects with preclinical AD using MMRM analysis of the Cognitive Function Index (CFI) .
Timepoint [1] 294450 0
168 weeks
Secondary outcome [1] 313346 0
To test the impact of solanezumab on cognition and performance of everyday activities, as compared with placebo using the Preclinical Alzheimer's Cognitive Composite (PACC).
Timepoint [1] 313346 0
168 weeks.
Secondary outcome [2] 313347 0
To assess whether decline in activities of daily living begins by the end of the treatment period, and if so,whether an effect of solanezumab, compared with placebo, can be detected using MMRM analysis of the ADCS-Activities of Daily Living (ADCS-ADL) Prevention Questionnaire.
Timepoint [2] 313347 0
168 weeks
Secondary outcome [3] 313348 0
To measure the effect of solanezumab on brain amyloid burden, as compared with placebo, as assessed using florbetapir PET imaging.
Timepoint [3] 313348 0
168 weeks
Secondary outcome [4] 313349 0
To investigate the effect of treatment with solanezumab on volumetric magnetic resonance imaging
(MRI).
Timepoint [4] 313349 0
168 weeks
Secondary outcome [5] 313350 0
Chest pain (1.1%), Slowing of heart rate (0.8%), Itchy rash, fainting, heart problems, brain swelling (1%), small bleeds in the brain (9%).

Immunogenicity data (anti-solanezumab) after treatment will be compared between the treatment groups.
Timepoint [5] 313350 0
168 weeks

Eligibility
Key inclusion criteria
[1]Male or female ages 65 to 85 years old.
[2] Has an MMSE score at screening of 25 to 30.
[3] Has a global CDR score at screening of 0.
[4] Has a Logical Memory II score at screening of 6 to 18.
[5] Has a florbetapir PET scan that shows evidence of brain amyloid pathology at
Visit 2.
[6] In general, permitted medications should be stable for 6 weeks prior to baseline (visit 6)
Minimum age
65 Years
Maximum age
85 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
[1] Is receiving a prescription acetylcholinesterase inhibitor (AChEI) and/or memantine at screening (Visit 1) or baseline (Visit 6).
[2] Lacks good venous access, such that intravenous drug delivery or multiple blood draws would be precluded.
[3] Has current serious or unstable illness including cardiovascular, hepatic, renal, gastroenterologic, respiratory, endocrinologic, neurologic, psychiatric,
immunologic, or hematologic disease or other conditions that, in the investigator’s opinion, could interfere with the analyses of safety and efficacy in this study.
[4] Has had a history within the last 5 years of a serious infectious disease affecting the brain (including neurosyphilis, meningitis, or encephalitis) or head trauma resulting in protracted loss of consciousness.
[5] Has had a history within the last 5 years of a primary or recurrent malignant disease with the exception of resected cutaneous squamous cell carcinoma in situ, basal cell carcinoma, cervical carcinoma in situ, or in situ prostate cancer with normal prostate-specific antigen posttreatment.
[6] Has allergies to humanized monoclonal antibodies.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
central randomisation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
simple randomisation by computer software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
In order to develop an appropriate measure of cognitive decline in a preclinical population, we tested several combinations of measures using data from longitudinal studies in clinically normal populations, including the Alzheimer’s Disease Neuroimaging Initiative (ADNI); the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL); and the ADCS-PI trial. Once the ADCS-PACC measure was adopted for the A4 study, powering estimates were performed by applying appropriate assumptions regarding treatment difference,
standard deviation, and attrition for a 3-year study in a preclinical AD population to derived ADCS-PACC results from the ADNI and AIBL studies. In ADNI, the difference in 24-month composite change between subjects with and without elevated brain amyloid was 1.239 (95%, confidence interval [CI] 0.215 to 2.26). Similarly, in AIBL, the difference in 36-month composite change between subjects with and without elevated brain amyloid was 1.40 (95%, CI 0.52 to 2.29). Therefore, the projected group difference at 36 months would be in the range of 1.40 to 1.80. Given the AIBL derived estimate of standard deviation at month 36 of sigma=2.44 and 30% attrition, N=500 provides 80% power (5% 2-sided alpha) to detect a treatment difference of 0.473. This treatment difference represents a 33.7% difference between subjects with and without elevated brain amyloid in AIBL; assuming subjects without elevated brain amyloid do not show disease progression, this can be interpreted to parallel a slowing of progression for solanezumab-treated subjects relative to placebo-treated subjects.
In addition, a Data and Safety Monitoring Board (DSMB) may also assess for sample size re-estimation (SSR) once during the study. A blinded review of aggregate data on the ADCS-PACC will be done by the DSMB. Decision factors will be prespecified and appropriate measures will be taken to maintain study blinding. The method for this blinded SSR is outlined below.
To ensure that the trial is adequately powered, approximately 3 to 6 months before completing
recruitment of the trial, a blinded sample size re-estimation (bSSR) procedure may be performed. The purpose of the re-estimation is to assess the accuracy of key powering assumptions regarding the ADCS-PACC score, the decline, and the variance in the change to endpoint in the score. Combined with the other powering assumptions, these results would be used to derive a posterior distribution for the sample size necessary to achieve the pre-specified power of the trial. This posterior distribution of necessary sample size would be used to inform a DSMB
recommendation regarding the decision on the final sample size, with the requirement that the final sample size is (approximately) constrained to be between the planned minimum and maximum sample size of the trial. The bSSR procedure would provide a recommended sample
size within the allowed range and would be considered in addition to other factors such as: rate/feasibility of enrollment to this point, and the expected impact of any sample size increase on improving the power of the trial.
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 0.05; 2-sided confidence intervals will be displayed with a 95% confidence level. All tests of interactions between treatment and other factors will be conducted at an alpha level of 0.05.
All analyses will follow the modified intent-to-treat (mITT) principle unless otherwise specified. An ITT analysis is an analysis of data by groups to which the subjects are assigned by random allocation, even if the subject does not take the assigned treatment, does not receive the correct
treatment, or otherwise does not follow the protocol. An mITT analysis is an ITT analysis for all patients who have a baseline and at least 1 postbaseline measure.
500 participants per treatment arm. The Australian group of 100 was added after the power statistics were done.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
18/12/2014
Actual
18/12/2014
Date of last participant enrolment
Anticipated
29/04/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
1100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 9345 0
3052 - Melbourne University
Recruitment outside Australia
Country [1] 6875 0
United States of America
State/province [1] 6875 0
Country [2] 6876 0
Canada
State/province [2] 6876 0

Funding & Sponsors
Funding source category [1] 290892 0
Commercial sector/Industry
Name [1] 290892 0
Eli Lilly Pty Ltd
Country [1] 290892 0
United States of America
Primary sponsor type
Charities/Societies/Foundations
Name
The FIL Foundation (FIL Investment Management Limited)
Address
Oakhill House
130 Tonbridge Road
Hildenborough
Tonbridge, KENT TN11 9DZ
Country
United Kingdom
Secondary sponsor category [1] 289572 0
Charities/Societies/Foundations
Name [1] 289572 0
The Yulgibar Foundation
Address [1] 289572 0
Level 18, 8 Exhibition St,
Melbourne. VIC. 3000
Country [1] 289572 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292494 0
Austin Health
Ethics committee address [1] 292494 0
Ethics committee country [1] 292494 0
Australia
Date submitted for ethics approval [1] 292494 0
Approval date [1] 292494 0
30/09/2014
Ethics approval number [1] 292494 0
HREC/14/Austin/211

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 55470 0
Prof Colin Masters
Address 55470 0
Florey Institute of Neuroscience and Mental Health
Level 5, Kenneth Myer Building
At Genetics Lane on Royal Parade
The University of Melbourne Vic 3010
Country 55470 0
Australia
Phone 55470 0
+613 9035 6575
Fax 55470 0
Email 55470 0
c.masters@unimelb.edu.au
Contact person for public queries
Name 55471 0
Maree Mastwyk
Address 55471 0
Florey Institute of Neuroscience and Mental Health
155 Oak St
Parkville. 3052. VIC.
Country 55471 0
Australia
Phone 55471 0
+613 9389 2943
Fax 55471 0
Email 55471 0
maree.mastwyk@florey.edu.au
Contact person for scientific queries
Name 55472 0
Colin Masters
Address 55472 0
Florey Institute of Neuroscience and Mental Health
Level 5, Kenneth Myer Building
At Genetics Lane on Royal Parade
The University of Melbourne Vic 3010
Country 55472 0
Australia
Phone 55472 0
+613 9035 6575
Fax 55472 0
Email 55472 0
c.masters@unimelb.edu.au

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
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Documents added automatically
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