PROSPERO International prospective register of systematic reviews Efficacy and safety of amyloid-beta immunotherapy for Alzheimer's disease: systematic review Marwa El-toukhy, Mohamed Zalabia, Ahmed Raslan, Karim Shady, mohamed El-moslemany Citation Marwa El-toukhy, Mohamed Zalabia, Ahmed Raslan, Karim Shady, mohamed El-moslemany. Efficacy and safety of amyloid-beta immunotherapy for Alzheimer's disease: systematic review. PROSPERO 2016:CRD42016037198 Available from http://www.crd.york.ac.uk/prospero_rebranding/display_record.asp?id=crd42016037198 Review question(s) To what extent is amyloid beta immunotherapy effective in people with Alzheimer s disease at any clinical stage? What are the adverse effects that patients may face on using amyloid beta immunotherapy against Alzheimer's disease? What is the cost-effectiveness of using amyloid-beta immunotherapy against Alzheimer s disease? Searches We will search ALOIS which is the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group. This register contains reports of trials from bibliographic databases such as MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS. It also contains references from many trial registers and grey literature sources. More details will be found here: http://www.medicine.ox.ac.uk/alois/. Additional separate searches will be done in The Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, MEDLINE, PsycINFO, CINAHL, ClinicalTrials.gov, and the WHO Portal/ICTRP in order to get the most up-to-date results. We will also search Scopus, Electronic Information For Libraries, Science Citation Index (ISI Web of Knowledge), and trial register sites. The search strategy for MEDLINE will be made available in the published protocol. We will also design structured search strategies using the search terms and syntaxes appropriate for each database listed above. The full search strategy will be available in the protocol. Searching other resources: Reference lists: we will scan reference lists of all eligible studies and reviews in the field for further possible titles and the process repeated until no new titles are found. Correspondence: we will contact the research groups who have published or are conducting work on immunization against Alzheimer s disease. All drug companies known to be developing or testing active vaccine for Alzheimer s disease will be asked including (Elan/Wyeth; Novartis; Pfizer; Affiriis AG, Merck, United Biomedical, AC Immune) to make any unpublished or missing data available for the review. Hand-searching will also be conducted. There will be restrictions on language or date of publication. We will not use search filters as overall limiters because the sensitivity of the literature base has not been established. The searches will be re-run just before the final analyses in order to ensure that up-to-date studies are included. Additional search strategy information can be found at: https://www.dropbox.com/s/tw9u7horvto9ggw/pubmed.pdf?dl=0 Page: 1 / 6
Types of study to be included All published and unpublished randomized controlled trials (RCTs) and cluster-randomized trials will be included that compare any active immunization versus placebo. Since Alzheimer s disease is a progressive disease, we will include only the data of the first period of crossover randomized trials. Condition or domain being studied Alzheimer s disease and amyloid-beta immunotherapy. Alzheimer s disease, as defined Alzheimer's Foundation of America (AFA), is a progressive, degenerative disorder that attacks the brain's nerve cells, or neurons, resulting in loss of memory, thinking and language skills, and behavioral changes. Two types of abnormal lesions clog the brains of individuals with Alzheimer's disease: Beta-amyloid plaques sticky clumps of protein fragments and cellular material that form outside and around neurons; and neurofibrillary tangles insoluble twisted fibers composed largely of the protein tau that build up inside nerve cells. Although these structures are hallmarks of the disease, scientists are unclear whether they cause it or a byproduct of it. Alzheimer's disease progresses in stages: an early, preclinical stage when the pathological process is in progress, but the person still has no symptoms; a middle stage of mild cognitive impairment; and a final stage marked by symptoms of dementia. Participants/ population Human s with dementia due to Alzheimer s disease clinically diagnosed according to standardized diagnostic criteria such as National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer s disease and Related Disorders Association (NINCDS-ADRDA) criteria, Diagnostic and Statistical Manual of Mental Disorders (DSM), International Classification of Diseases (ICD) or with positive results of biomarker tests. For MCI due to AD: people with a diagnosis of MCI according to widely accepted criteria (Petersen 1999; Petersen 2004; Winblad 2004; Albert 2011) the study has to declare evidence that the MCI is probably due to Alzheimer s disease, for example, when the study declare that it excluded participants who have vascular, traumatic, or medical causes of cognitive decline; people with symptoms suggestive of other neurodegenerative diseases; and providing evidence of longitudinal decline in cognition. We will exclude studies primarily investigating other dementia types Intervention(s), exposure(s) Active intervention: amyloid-beta immunotherapy against Alzheimer's, including active and passive immunization. Active immunization includes AN1792, Abvac40, AD 03, AD 02, AD01, CAD106., CAD105, V950, UB-311, Lu AF20513, ACI-24, Vanutide-cridificar, etc. Passive immunization includes Bapineuzemab, ABB-003, PF-04360365, Gantenerumab, Solanezumab, LY2062430, BAN2401, GSK933776, BIIB037, Aducanumab, SAR228810, MEDI1814, LY3002813, LY2599666, ABP-102, etc. Polyclonal antibodies include intravenous immunoglobulin. The final classification of the immunotherapy will be represented graphically in the paper. We will accept any study including one or more immunotherapy with any formula, administered by any route, at any dose and for any treatment duration. Comparator(s)/ control Placebo administered by the same route and according to the same schedule. Context There will be no restrictions on the basis of stage of dementia, setting, gender, ethnicity or other characteristics. Outcome(s) Primary outcomes 1. Cognitive function measured by a validated scale, e.g., Alzheimer s Disease Assessment Scale-cognitive subscale (ADAScog). Page: 2 / 6
2. Global clinical outcome, e.g. Clinical Global Impression (CGI), Clinician s Interview-Based Impression of Change (CIBIC+), Clinical Dementia Rating Scale (CDR), other validated global severity or change scales. 3. Functional performance measured with a validated scale. 4. Mortality. 5. Incidence adverse effects, serious adverse events, and who discontinued study drug because of adverse effects. 6. For participants with MCI at baseline, the time elapsed to convert to dementia 7. For participants with MCI at baseline, the proportion with dementia at follow-up Secondary outcomes 8. Neuropsychiatric symptoms. 9. Compliance with intervention 10. Quality of life. Any of the following classes of biomarker: 11. Cerebrospinal fluid measures of Aß and/or tau levels or their ratio. 12. Positron emission tomography (PET) imaging of cerebral amyloid. 13. Functional imaging, e.g. fluoride oxyglucose positron emission tomography (FDG-PET) or perfusion single photon emission computed tomography (SPECT). 14. Structural imaging. 15. Post mortem neuropathological measures of AD pathology. Data extraction, (selection and coding) Selection: Selection of the study will pass through three phases: first, we will screen all titles generated by the database searches, followed by a screening of the abstracts to identify studies that potentially meet the inclusion criteria outlined above. The full texts of these potentially eligible studies will then be retrieved and assessed for eligibility. All these steps will be conducted independently by two review authors. Any disagreements between them over the eligibility of particular studies will be resolved through discussion with the third reviewer. Papers that do not meet the inclusion criteria will be listed in a Characteristics of excluded studies table, together with the reasons for exclusion. Extraction: A data extraction form will be developed specifically for this review and will be piloted. Two review authors will extract data independently, and discrepancies will be identified and resolved through discussion including a third author. For each study, data will be extracted on: participants (including number; diagnostic criteria; age; gender; inclusion and exclusion criteria, participant recruitment, baseline investigations, co-treatments); interventions; outcomes (outcomes and time points, outcome definition, and unit of measurement); setting; study methodology; other data relevant to the risk of bias assessments for randomized controlled trials (RCTs); results (number of participants allocated to each intervention group, sample size, missing participants, and summary data for each intervention group (both intention-to-treat and per protocol results will be extracted)); and funding source. For dichotomous outcomes, data extracted will be the number of participants with the outcome of interest in each group at each time point. For continuous outcomes, such as psychometric test scores, clinical global impression scales and quality-of-life scales, data extracted will be the mean and standard deviation (SD) in each group at each time point. When different scales are used in the studies for a single outcome, the method of standardized mean difference (SMD) will be used. Where the standard deviation is not reported, we will calculate it from the confidence interval, t values, or P values. Study authors will be contacted to request missing data, for additional data or for a confirmation of the methodological aspects of the study. Page: 3 / 6
Risk of bias (quality) assessment Each study will be assessed by two authors independently using Cochrane Risk of bias tool and any disagreement will be solved in group discussion involving the 3rd author. Discussion will be taken by consensus. A judgment will be made about the overall risk of bias for each outcome across studies using the GRADE system for rating the quality of evidence for summary of finding table. Cochrane Risk of bias tool considers the following characteristics: sequence generation, Allocation concealment, Blinding of participants, personnel and outcome, Incomplete outcome data, Selective outcome reporting, Other sources of bias. We will consider any study having a dropout rate higher than 20% to have a high risk of attrition bias or the reasons for dropouts are not balanced across intervention groups Strategy for data synthesis We anticipate that meta-analysis will be conducted as there are an adequate number of studies using the same immunotherapy against placebo and measuring the same outcome. When all authors agree on the studies as being sufficiently clinically and methodologically similar, we will conduct a formal meta-analysis using Review Manager software. A fixed-effect model will be used for all analyses in the first instance. If I-squared is greater than 50% for the studies in a meta-analysis, then the analysis will be repeated using a random-effects model and the two results will be compared. For dichotomous outcomes, we will use the Mantel-Haenszel method. For continuous outcomes, we will use the inverse-variance method. Both the Chi-squared test and the I-squared statistic will be used to assess heterogeneity, an I-squared value greater than 50% being regarded as indicative of substantial heterogeneity. Sensitivity analyses will be conducted, excluding any studies identified as having a high risk of bias in any domain. Other sensitivity analyses may be conducted if decisions have to be taken during the conduct of the review which may affect its results. We will also assess fr evidence of publication bias. The studies will be divided into three main categories; AD dementia, MCI and preclinical AD. Each will be analyzed separately. Within each category, three different pooled meta-analyses will be performed if the review authors consider that the different studies are sufficiently clinically homogeneous. In the first, all groups of immunotherapy will be combined to create a single pair-wise comparison with the placebo to conduct one set of analyses for active and passive separately unless there is evidence of considerable heterogeneity (I-squared > 75 % approximately). On the second, passive and active data will be pooled separately, and then each subtype of vaccine will be pooled separately, e.g. coupled with carrier, liposomes-containing, T-helper cell epitope, monoclonal, polyclonal, etc. Also, if possible, we will conduct separate analyses for each vaccine. If data are available for the different doses of the same vaccine, then a judgment will be made about whether or not the doses are sufficiently similar to be pooled. If so, then subgroup analyses may also be used to examine the doses separately. Analysis of subgroups or subsets We will perform subgroup analyses if possible according to: 1. The severity of the dementia. 2. The criteria used to identify eligible participants. 3. The dose of vaccine. 4. The Apo-E status (presence or absence of an Apo E alleles). 5. For different classes of active and passive immunization. 6. For different adjuvants to the same vaccine. 7. For route of vaccine. Contact details for further information Page: 4 / 6
Dr El-toukhy marwa.alsayed31@med.menofia.edu.eg Organisational affiliation of the review None Review team Dr Marwa El-toukhy, Faculty of Medicine, Menoufia University; Shebin Al-Kom, Egypt. Dr Mohamed Zalabia, Faculty of Medicine, Menoufia University; Shebin Al-Kom, Egypt. Dr Ahmed Raslan, Faculty of Medicine, Menoufia University; Shebin Al-Kom, Egypt. Dr Karim Shady, Faculty of Medicine, Menoufia University; Shebin Al-Kom, Egypt. Dr mohamed El-moslemany, Faculty of Medicine, Menoufia University; Shebin Al-Kom, Egypt. Anticipated or actual start date 11 December 2016 Anticipated completion date 30 January 2018 Funding sources/sponsors Not funded Conflicts of interest None known Language English Country Egypt Subject index terms status Subject indexing assigned by CRD Subject index terms Alzheimer Disease; Amyloid beta-peptides; Humans; Safety; Vaccination Stage of review Ongoing Date of registration in PROSPERO 01 April 2016 Date of publication of this revision 19 December 2016 Stage of review at time of this submission Started Completed Preliminary searches Yes Yes Piloting of the study selection process No No Formal screening of search results against eligibility criteria No No Data extraction No No Risk of bias (quality) assessment No No Data analysis No No Page: 5 / 6
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