Use of Intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment

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Clinical Effectiveness

Authors: Luca Vignatelli, Luciana Ballini, Susanna Maltoni, Jelena Barbaric, Mirjana Huic, Pernilla Östlund.

Summary

Aim

To determine whether treatment with intravenous immunoglobulins (IVIG) in adults with Mild Cognitive Impairment (MCI) or Alzheimer’s disease (AD) improves clinical outcomes and quality of life, has impact on patients’ satisfaction, hospitalization rate and institutionalization delay compared with current practice.

Secondary objective was to map available evidence against the technology’s evidence profile.

Methods

We performed a systematic review according to Cochrane methodology on evidence from biomedical databases; publicly available clinical trials registers were also searched. Qualitative and quantitative syntheses were done. To assess risk of bias of included RCTs the risk of bias method proposed by the Cochrane Handbook for Systematic Reviews of Interventions was used. Overall quality of evidence for each outcome was assessed and synthesised according to the GRADE approach.

Results

Among the four published clinical studies none met the inclusion criteria. Missing publication was documented for two completed RCTs in subjects with mild-to-moderate AD. One of the two studies {NCT00818662}, a phase 3 double-blind, placebo-controlled, two dose arm RCT, aiming at testing the safety and effectiveness of IVIG for patients with mild-to-moderate AD, had its results posted on a clinical trial register in October 23rd 2014, after completion of this report. The authors and the sponsor had been previously contacted (May 2014) but did not provide any data. As this study, according to decision of Editorial Team, met inclusion criteria, release of this report was postponed in order to include it in the analysis. Available data do not permit an evaluation of the methodology and conduction of the study due to the absence of information posted. Manufacturer was not contacted again to provide more data. The confidence in effect estimate for overall evidence on all considered outcomes is very low, according to GRADE approach. Participants were 383 patients (completing the study: 302) that were randomized to one of two doses of IVIG (Gammagard Liquid 10%, 400 mg/kg bodyweight or 200 mg/kg bodyweight, every two weeks) or one of two doses of placebo (0.25% human albumin solution infused at 4mL/kg or at 2 mL/kg, every two weeks) for 70 weeks. Any important clinical outcomes such as cognitive functions (ADAS-Cog, ADCSC-GIC), activity of daily living (ADCS-ADL) and quality of life (both in patients and caregivers according to QOLAD) did not differ between IVIG and placebo groups.

Two additonal ongoing RCTs have been identified: one including subjects with MCI, and one including subjects with mild-to-moderate AD. These trials are reported to and expected to end in November 2014 and December 2016, respectively. Patients with moderate-to-severe AD are not considered by any study.

Conclusion

We found limited evidence of very low quality suggesting lack of effectiveness of IVIG in adults with mild-to-moderate AD and no evidence for adults with MCI or moderate-to-severe AD. Conclusive evidence from unpublished and ongoing studies are necessary before setting up RCTs on long term effectiveness of IVIG in patients with MCI, mild-to-moderate and moderate-to-severe AD.

Introduction

Background

The Clinical Effectiveness Domains describes the range and size of beneficial health effects expected through the use of the technology {HTA Core Model Handbook Online, Version 1.5}. The two key elements are that effective interventions should be directly compared and studied in patients who are typical of day-to-day health care settings {HTA Core Model Application for Pharmaceuticals, 2.0}.

AD is a chronic neurodegenerative disorder strongly associated with the formation and accumulation of extracellular plaques of amyloid-beta (Aβ) protein in the brain that is followed by synaptic dysfunction, inflammation and eventually neuronal death (Ballard 2011; Silvergleid 2013). It is suggested that IVIG might have beneficial effects on the pathogenic processes of AD (Dodel 2013) and even at the stage of MCI, by interfering positively with metabolism of amyloid β that seems to be reduced in subjects at risk for AD.

The causal chain suggesting a clinical benefit from the use of IVIG for MCI and AD appears as follows:

- amyloid β (Aβ) is the metabolic product of the amyloid precursor protein, an element placed in the normal cell membrane (Ballard 2011; National Institute on Aging 2011);

- abnormal increase of amyloid β in the brain - as beta-amyloid plaques - is probably the first expression of the pathological process that damages neurons in AD (Ballard 2011; National Institute on Aging 2011);

- biomarkers of the metabolism of Amyloid Precursor Protein are amyloid β40, amyloid β42, Anti-Aβ autoantibodies (Ballard 2011; Du 2002); all these products can be measured in cerebrospinal fluid and serum (Buchhave 2012; Dodel 2013; Du 2002; Jack 2013);

- amyloid β metabolism seems to be reduced in patients with AD; in particular it is reported that cerebrospinal fluid and serum amyloid β40 and amyloid β42 could be lower than normal in patients with MCI and AD, and that cerebrospinal fluid and plasma titers of anti–Aβ antibodies are lower in AD patients compared with controls (Jack 2013; Relkin 2009);

- natural polyclonal anti-Aβ autoantibodies are present in normal human blood (Dodel 2002; Weksler 2002);

- it is hypothesised that an immune-mediated amyloid-β degrading pathway may be physiologically present and its actions clinically significant in humans;

- early observations report that after IVIG treatment a significant increase in total anti-Aβ autoantibodies concentration can be produced in the plasma of patients with AD (Dodel 2002; Relkin 2009); peripherally administered antibodies against Aβ can induce a shift of Aβ from the CSF to the blood, thereby reducing the cerebral Aβ burden (the “peripheral sink hypothesis”) and with increased plasma concentration and decreased CSF concentration of Aβ;

- it is hypothesised that IVIG use for passive immunotherapy in AD could slow the disease progression (Dodel 2002; Dodel 2013; Loeffler 2013; Relkin 2009) and use in patients with MCI could avoid or delay the onset of AD.

Objectives

Primary objectives:

1. To assess the effectiveness of IVIG in adults with MCI.
2. To assess the effectiveness of IVIG (alone or in combination with other treatments) in adults with mild-to-moderate AD.
3. To assess the effectiveness of IVIG (alone or in combination with other treatments) in adults with moderate-to-severe AD.

Secondary objectives:

• to map available evidence against the technology’s evidence profile, i.e. the body of evidence needed to demonstrate its effectiveness in the above reported target conditions
• to identify research gaps.

Methodology

Frame

The collection scope is used in this domain.

Technology	Immunoglobulins (IGG) Description Naturally occurring proteins produced by the body’s immune system to combat foreign antigens
Intended use of the technology	Treatment Treatment of Alzheimer’s disease Target condition Alzheimer’s disease Target condition description Alzheimer's disease (AD) or Alzheimer disease, is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death. Target population Target population sex: Any. Target population age: elderly. Target population group: Patients who have the target condition. Target population description AD is diagnosed mostly in people over 65 years of age, although there is an early-onset form that can occur much earlier. According to Wikipedia in 2006, there were 26.6 million sufferers worldwide.
Comparison	placebo, not doing anything or Usual supportive care Description There is no MA for IGGs for AD yet and there is no other intervention licensed for use in AD so the comparison would have to be against placebo or best supportive care
Outcomes	Description of aims of technology (TECH) Regulatory status (CUR) Cognitive function (EFF) Harms (SAF) Cost effectiveness compared to alternatives (ECO) Potential impact on plasma derivative market (ORG/Medico-legal) Impact on family and carers (SOC) Appropriateness of use in relation to solidity of evidence(ETH)

Assessment elements

	Topic	Issue	Relevant	Research questions or rationale for irrelevance
D0006	Morbidity	How does the technology affect the progression (or recurrence) of the target condition?	yes	Are IVIG effective in slowing or avoiding progression from Mild Cognitive Impairment to Alzheimer’s disease when compared to placebo? Are IVIG effective in improving biomarkers of progression from Mild Cognitive Impairment to Alzheimer’s disease when compared to placebo? Are IVIG effective in improving imaging markers of progression from Mild Cognitive Impairment to Alzheimer’s disease when compared to placebo? Are IVIG effective in slowing disease progression from mild-to-moderate to moderate-to-severe Alzheimer’s disease (measured with MMSE) when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving biomarkers of progression in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving imaging markers of progression in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving biomarkers of progression in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine? Are IVIG effective in improving imaging markers of progression in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0005	Morbidity	How does the technology affect symptoms and findings (severity, frequency) of the target condition?	yes	Are IVIG effective in improving neuropsychiatric symptoms in patients Mild Cognitive Impairment when compared to placebo? Are IVIG effective in improving behavioural symptoms in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving behavioural symptoms in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0001	Mortality	What is the expected beneficial effect of the intervention on overall mortality?	yes	Are IVIG effective in reducing overall mortality in patients with Mild Cognitive Impairment when compared to placebo? Are IVIG effective in reducing overall mortality in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in reducing overall mortality in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0002	Mortality	What is the expected beneficial effect on the disease-specific mortality?	no	Disease-specific mortality is not a plausible outcome for Alzheimer Disease as death in these patients is expected due to complications and not to Alzheimer's disease itself.
D0003	Mortality	What is the effect of the technology on the mortality due to causes other than the target disease?	no	More relevant for the SAF domain
D0011	Function	What is the effect of the technology on patients’ body functions	yes	Are IVIG effective in improving cognitive functions of patients with Mild Cognitive Impairment when compared to placebo? Are IVIG effective in improving cognitive functions of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving cognitive functions of patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0016	Function	How does use of the technology affect activities of daily living?	yes	Are IVIG effective in improving activities of daily living of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving activities of daily living of patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0014	Function	What is the effect of the technology on work ability?	no	Already covered by the assessment of daily activities.
D0015	Function	What is the effect of the technology on return to previous living conditions?	no	This issue is important for diseases with acute or relapsing course. Alzheimer disease has a progressive course.
D0012	Health-related Quality of life	What is the effect of the technology on generic health-related quality of life?	yes	Are IVIG effective in improving generic health-related quality of life of patients with Mild Cognitive Impairment when compared to placebo? Are IVIG effective in improving generic health-related quality of life of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving generic health-related quality of life of caregivers of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving generic health-related quality of life of caregivers of patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0013	Health-related Quality of life	What is the effect of the technology on disease specific quality of life?	yes	Are IVIG effective in improving disease specific health-related quality of life of patients with mild-to- moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving disease specific health-related quality of life of caregivers of patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Are IVIG effective in improving disease specific health-related quality of life of caregivers of patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0010	Change-in management	How does the technology modify the need for hospitalization?	yes	Does IVIG impact on the need for hospitalization in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Does IVIG impact on the need for institutionalization in patients with mild-to-moderate Alzheimer’s disease when compared to placebo or acetyl cholinesterase inhibitors? Does IVIG impact on the need for hospitalization in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine? Does IVIG impact on the need for institutionalization in patients with moderate-to-severe Alzheimer’s disease when compared to placebo or memantine?
D0023	Change-in management	How does the technology modify the need for other technologies and use of resources?	no	More relevant for the ORG domain
D0029	Benefit-harm balance	What are the overall benefits and harms of the technology in health outcomes?	yes	What are the overall benefits and harms of IVIG in health outcomes of patients with Mild Cognitive Impairment? What are the overall benefits and harms of IVIG in health outcomes of patients with mild-to-moderate Alzheimer’s disease? What are the overall benefits and harms of IVIG in health outcomes of patients with moderate-to-severe Alzheimer’s disease?
D0017	Patient satisfaction	Was the use of the technology worthwhile?	no	Not important

Methodology description

Criteria for considering studies

Types of studies

All published or unpublished full report of randomised controlled trials (RCTs) were considered for inclusion. For unpublished studies we accepted results from publicly available controlled trials’ registers (decision made by Editorial Team). Report on animal models, pre-clinical and biological studies, narrative reviews, editorials, opinions, were excluded.

To establish stage of development of research of the technology, RCTs as well as interventional prospective controlled and uncontrolled studies were searched for.

Types of participants (target population)

Adult (18+ years) patients of any sex who have one of the target conditions:

1. MCI (ICD-9-CM Diagnosis Code 331.83; ICD-10-CM G31.84) as defined by validated criteria.
2. Mild-to-moderate AD (ICD-9-CM Diagnosis Code 331.0; ICD-10-CM G30.9), as defined by validated criteria and with MMSE score between 15 and 26.
3. Moderate-to-severe AD (ICD-9-CM Diagnosis Code 331.0; ICD-10-CM G30.9), as defined by validated criteria and with MMSE score less than or equal to 14.

Types of interventions

IVIG any dose, any regimen, any product, alone or in combination with non-pharmacological interventions, and/or with approved drugs (acetyl cholinesterase inhibitors, memantine).

Types of control treatments

• MCI: placebo, non-pharmacological treatments or no treatment
• Treatment naïve patients with mild-to-moderate AD: placebo, acetyl cholinesterase inhibitors, non-pharmacological treatments or no treatment
• Patients with mild-to-moderate AD treated with acetyl cholinesterase inhibitors: placebo plus acetyl cholinesterase inhibitors or acetyl cholinesterase inhibitors
• Patients with mild-to-moderate AD intolerant to acetyl cholinesterase: placebo and/or non-pharmacological treatment or no treatment.
• Patients with moderate-to-severe AD treated with memantine: placebo plus memantine, non-pharmacological treatments plus memantine, or memantine
• Patients with moderate-to-severe AD intolerant to memantine: placebo and/or non-pharmacological treatment or no treatment.

Types of outcomes and outcome measures

MCI

Primary outcomes (timeframe: 3 years)

• Progression to AD (timeframe: within 3 years) according to available AD validated criteria (NINCDS-ADRDA, ICD, DSM) [Issue domain Morbidity D0006]

Secondary outcomes

• Overall mortality [Issue domain Mortality D0001];
• Cognition improvement (Cognitive functions measured by ADAS-Cog, MMSE, Clinical Dementia Rating, and Global Change scales measured by Clinical Global Impression of Change (CGI-C), Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus), Global Deterioration Scale (GDS)) [Issue domain Function D0011];
• Neuropsychiatric symptoms measured by scales (Neuropsychiatric Inventory – NPI - or other validated scales in the target population) [Issue domain Morbidity D0005];
• Generic health related quality of life measured by common scales (SF-36; EQ-5D) [Issue domain Health-related Quality of life D0012].

Other outcomes

• Variation of biomarkers (change of cerebrospinal fluid Aβ1-42; change of serum anti-Aβ autoantibodies) [Issue domain Morbidity D0006];
• Variation of imaging signs (change in standardized uptake value (SUVR) at PIB-PET; change in ventricular volumetric as measured by MRI) [Issue domain Morbidity D0006].

Mild-to-moderate AD

Primary outcomes (timeframe: at least 1 year)

• Progression to moderate-to-severe AD according to MMSE [Issue domain Morbidity D0006];
• Cognitive outcomes changes (Cognitive functions measured by ADAS-Cog or CDR-GS [Issue domain Function D0011];
• Functional ability changes (Activities of daily living measured by DAD, ADCS-ADL or other validated scales in the target population [Issue domain Function D0016];
• Behavioural changes (Neuropsychiatric Inventory - NPI, the Behavioural Pathology in AD Rating Scale  - BEHAVE-AD, and the Behavioural Rating Scale for Dementia -BRSD) (GPC 2013) [Issue domain Morbidity D0005].

Secondary outcomes (timeframe: at least 1 year)

• Overall mortality [Issue domain Mortality D0001];
• Generic health related quality of life measured by common scales (SF-36; EQ-5D) both in patients and caregivers [Issue domain Health-related Quality of life D0012];
• Disease specific health related quality of life scales both in patients (ADRQL, CBS, DCM, DQoL PWB-CIP, QUALID Scale, QOL-AD, QOLAS, DEMQOL) and caregivers (DEMQOL-Proxy-U; Zarit Burden Interview) [Issue domain Health-related Quality of life D0013];
• Hospitalization [Issue domain Change in management D0010];
• Delay on institutionalization [Issue domain Change in management D0010].

Other outcomes

• Variation of biomarkers (change of cerebrospinal fluid Aβ1-42; change of serum anti-Aβ autoantibodies) [Issue domain Morbidity D0006];
• Variation of imaging signs (change in standard uptake value ratio - SUVR) at PIB-PET; change in ventricular volumetric as measured by MRI) [Issue domain Morbidity D0006].

Moderate-to-severe AD

Primary outcomes (timeframe: at least 1 year)

• Cognitive outcomes changes (Cognitive functions measured by SIB, ADAS-Cog, MMSE[Issue domain Function D0011];
• Functional ability changes (Activities of daily living measured by DAD, ADCS-ADL or other validated scales in the target population [Issue domain Function D0016].
• Behavioural changes (Neuropsychiatric Inventory - NPI, the Behavioural Pathology in AD Rating Scale  - BEHAVE-AD, and the Behavioural Rating Scale for Dementia -BRSD) (GPC 2013) [Issue domain Morbidity D0005].

Secondary outcomes (timeframe: at least 1 year)

• Overall mortality [Issue domain Mortality D0001];
• Generic health related quality of life measured by common scales (SF-36; EQ-5D) in caregivers [Issue domain Health-related Quality of life D0012];
• Disease specific health related quality of life scales both in caregivers (DEMQOL-Proxy-U; Zarit Burden Interview) [Issue domain Health-related Quality of life D0013];
• Hospitalization [Issue domain Change in management D0010];
• Delay of institutionalization [Issue domain Change in management D0010].

Other outcomes

• Variation of biomarkers (change of cerebrospinal fluid Aβ1-42; change of serum anti-Aβ autoantibodies) [Issue domain Morbidity D0006];
• Variation of imaging signs (change in SUVR at PIB-PET; change in ventricular volumetric as measured by MRI) [Issue domain Morbidity D0006].

 

Search methods for identification of studies

Electronic searches

The following databases and clinical trials registers were searched:

Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, LILACS, ALOIS (the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group) and national and international trials registers (Australian New Zealand Clinical Trials Register (ANZCTR), http://www.anzctr.org.au/; metaRegister of Controlled Trials (mRCT), http://www.controlled-trials.com/mrct/; ClinicalTrials.gov. www.clinicaltrials.gov/; NIH Clinical Research Studies, http://clinicalstudies.info.nih.gov/; EU Clinical Trials Register, https://www.clinicaltrialsregister.eu/; International Clinical Trials Register Platform (ICTRP), http://www.who.int/ictrp/en/).

Initial search was carried out on February 24^th 2014 and an update was carried out close to the release of the report on December 16^th 2014.

See Appendix 6 for detailed search strategies. The strategy for MEDLINE was adapted to other databases. No language or date of publication restrictions were applied.

Searching other resources. In addition we checked conference proceedings for relevant abstracts, and contact individual researchers working in this field, organizations and pharmaceutical companies to identify additional RCTs, especially those unpublished. We also checked the reference lists of all studies identified by the above methods.

 

Data collection and analysis

Selection of studies

The titles and abstracts of all studies identified by the search were screened independently by two investigators (ASSR). Full text was retrieved of all studies which any investigator considered potentially relevant. Two investigators then identified studies for inclusion or exclusion independently (ASSR). Different selection results were discussed in order to achieve consensus. A third person was involved to resolve discrepancies (AAZ and SBU).

Data extraction and management

A data extraction form was developed and piloted specifically for this review. For each study, data were extracted on: participants (including inclusion and exclusion criteria, baseline investigations, co-treatments); interventions; outcomes; study design; results. For eligible studies, when data on outcomes of interest were missing or incompletely reported investigators contacted the Authors for additional information. For dichotomous outcomes, data extracted were the number of participants with the outcome of interest in each group at each time point. For continuous outcomes, data extracted were the mean and standard deviation (SD) in each group at each time point. If only change-from-baseline data were available, those were extracted.

Assessment of risk of bias of included studies and of overall quality of evidence

To assess risk of bias of included RCTs the risk of bias system proposed by the Cochrane Handbook for Systematic Reviews of Interventions {Higgins et al. 2011} was used. Overall quality of evidence for each outcome was assessed and synthesised according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach {Guyatt 2011a; Balshem 2011; Guyatt 2011b; Guyatt 2011c; Guyatt 2011d; Guyatt 2011e; Guyatt 2011f; Guyatt 2011g; Guyatt 2013}, and presented in table. This approach specifies four levels of quality:

• High: further research is very unlikely to change our confidence in the estimate of effect;
• Moderate: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimates;
• Low: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate;
• Very low: we are very uncertain about the estimate.

Data synthesis

Quantitative results were expressed as point estimates together with associated 95% confidence intervals (95% CI) and p-values. We had planned, if possible, to carry out a meta-analysis with graphical display of results and assessment of heterogeneity, according to the Cochrane Handbook for Systematic Reviews of Interventions {Higgins et al. 2011}.

Studies used to map available evidence against the technology’s evidence profile, i.e. the body of evidence needed to demonstrate its effectiveness in the above reported target conditions were grouped by target conditions included in this protocol. A descriptive summary of these studies with details about study design, numbers and characteristics of enrolled patients, intervention/s and comparator/s, outcomes, outcomes’ measures and results is provided in tables and plain text format. In order to map available evidence against the technology’s evidence profile, for each research question the results from available evidence and upcoming evidence were charted in order to describe stage of development and to highlight research gaps. Available evidence refer to published or unpublished studies with available data and upcoming evidence refer to unpublished without available data and ongoing studies..

 

Description of studies

Results of the search

The first electronic searches strategy (February 24^th 2014), yielded 515 citations, after removal of duplicates. Of these, 388 were directly excluded, because judged not relevant. Of the remaining 127 citations, none meet our inclusion criteria and were excluded from relative effectiveness assessment (primary objectives). Checking periodically the registers of ongoing trials, the results of one of the RCT {NCT00818662}, tracked on clinical trial registries, were posted on ClinicalTrials.gov by the study sponsor in October 23rd 2014. Thus this study was included (decision by Editorial Team) and remaining the 126 citations excluded. The second electronic search strategy (December 16^th 2014) yielded 71 citations, after removal of duplicates; 70 were excluded, because judged not relevant, and 1 excluded after evaluation of the full text. From the final periodic check of registers of ongoing trials (December 16^th 2014) there was no further status change for included ongoing trials.

See PRISMA study flow diagram in Appendix 1 {Figure A1}.

Excluded studies

The reasons for exclusion of the 128 records were as follows: in vitro /animal studies (n=13); other treatments (n=22); review papers (n=31); comments/editorials/news (n=14); other topics (n=4); studies on the current use of IVIG (n=2); case control studies (n=2); study without data on outcomes (n=1); interventional studies not fulfilling design inclusion criteria (38 citations corresponding to 16 studies). The latter group of 16 studies were found eligible for the evidence mapping against the technology’s evidence profile: 7 studies resulted as completed and unpublished {Hara 2011, Kondo 2011, Kountouris 2000, Papatriantafyllou 2006, Rovira 2011, NCT00299988, Relkin 2012 }, 2 studies are ongoing {NCT01300728, NCT01561053}, 2 studies had been planned but they were terminated prematurely {NCT01524887, NCT01736579}, and 5 studies were published {Arai 2014, Devi 2008, Dodel 2004, Dodel 2013, Relkin 2009}.

Included studies

No studies fitting our inclusion criteria were found.

Included unpublished studies with results posted in clinical trials registers (Editorial Team decision)

The following information refers to data posted by the study sponsor on one trial register (ClinicalTrials.gov) in October 23rd 2014. The Authors and the sponsor were previously contacted (May 2014). They responded but did not provide results. The Authors and the Sponsor were not contacted again. The included RCT {NCT00818662} was a phase 3 double-blind, placebo-controlled, two dose arm study aiming at testing the safety and effectiveness of IVIG for patients with mild-to-moderate AD. Participants were 383 patients (patients completing the study: 302; intention-to-treat population not declared) with probable AD (criteria not reported), with a mini-mental state examination score of 16–26 and age 50–89 years at baseline. Included patients had been taking a stable dose of an approved Alzheimers disease drug for at least 3 months before screening (not reported number of patients on treatment). Participants were randomized to one of two doses of IVIG (Gammagard Liquid 10%, 400 mg/kg bodyweight every two weeks, or 200 mg/kg bodyweight every two weeks) or one of two doses of placebo (0.25% human albumin solution infused at 4 mL/kg every two weeks or at 2 mL/kg every two weeks), for 70 weeks. The randomization ratio was 2:2:1:1. Co-primary outcomes were change from baseline at 18 months in the Alzheimer´s Disease Assessment Scale Cognitive Subscale (ADAS-Cog) and change from baseline at 18 months in the Alzheimer´s Disease Cooperative Study Activities of Daily Living (ADCS-ADL). Other patients important outcomes considered in the study were: change at 9 months in ADAS-Cog, change at 9 months in ADCS-ADL, change at 9 and 18 months in Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCSC-GIC), change at 18 months in the Neuropsychiatric Inventory (NPI), change at 18 months in the Logsdon Quality of Life in Alzheimer's Disease (QOLAD) of patients and caregivers. Other outcomes assessed in the study but not considered in this review were: Modified MiniMental State Examination (3MS), Wechsler Adult Intelligence Scale Revised Digit Span, FAS Verbal Fluency, Animals Category Fluency, Trail Making Test Part A and Part B, Clock Drawing Test. The study - funded by Baxter Healthcare Corporation and conducted in USA and Canada – started in December 2008 and ended in December 2012.

Characteristics of published, unpublished and ongoing studies used for mapping available evidence against the technology’s evidence profile

Published studies

Five studies (interventional n=4; observational, n=1) were found and summarised in Appendices 3 and 4.

The second RCT by Arai et al. {Arai 2014} was an exploratory multiple dose double-blind, randomised, placebo-controlled study aiming at testing the safety and tolerability of treatment with IVIG for patients with mild-to-moderate AD. Participants were 16 subjects (intention-to-treat and per protocol population: 16) with probable AD (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria), with a mini-mental state examination score 16–26 and age 50–89 years at baseline. Patients could have been taking a stable dose of an approved AD drug (cholinesterase inhibitors, memantine) for at least 120 days prior baseline. However no data were reported about the use of these drugs. Participants were randomized to one of two doses of IVIG (0.2 g/kg, 0.4 g/kg every 2 weeks) or to placebo (50 mL 0.25% human albumin solution every 2 weeks). Treatment duration was 12 weeks and follow up lasted up to 26 weeks. The outcome measures were safety and tolerability. Moreover MMSE score change 14 weeks after the end of treatment (week 26 of follow up) was considered. The study was conducted in 5 centres of Japan. No information was provided about funding. The study does not report a Study Registration number.

The RCT by Dodel et al. {Dodel 2013} was an exploratory phase 2 dose finding double-blind, block-randomised, placebo-controlled study aiming at testing the safety, effective dose, and infusion interval of treatment with IVIG for patients with mild-to-moderate AD. Participants were 58 subjects (modified intention-to-treat population: 57; per protocol population: 45) with probable AD (National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association criteria), with a mini-mental state examination score 16–26 and age 50–85 years at baseline. Patients had to have been taking a stable dose of an approved Alzheimers disease drug for at least 3 months before screening; 36 out of 41 patients in IVIG (88%) used acetylcholinesterase inhibitor or memantine as well as 11 out of 14 (79%) patients in Placebo group. Participants were randomized to one of six doses of IVIG (0.2 g/kg, 0.5 g/kg or 0.8 g/kg every 4 weeks; 0.1 g/kg, 0.25 g/kg, or 0.4 g/kg every 2 weeks) or to placebo (0.9% isotonic sodium chloride every 4 weeks or every 2 weeks). Treatment duration was 24 weeks. Primary outcome was the difference of the median area under the curve (AUC) of plasma concentration of Aβ1–40 between placebo groups and the six intervention groups, measured from last infusion to final visit. Other surrogate outcomes were the difference of AUC for plasma concentration of Aβ1–42 and of anti-Aβ autoantibodies; the difference of plasma concentration of Aβ1–40, Aβ1–42 and anti-Aβ autoantibodies at week 24 compared with baseline; the change in CSF concentration of Aβ1–40, Aβ1–42, anti -Aβ autoantibodies and p-tau181, 24 h after last infusion compared with baseline; the difference between baseline and week 24 of change in whole brain volume, hippocampus volume; glucose metabolism. Moreover some patient important outcomes were considered: difference in scores at baseline and at week 24 on the AD assessment scale-cognitive part (ADAS-cog), the clinical dementia rating scale-sum of boxes, the AD Cooperative Study-activities of daily living scale, the mini-mental state examination; adverse events. The study - funded by Octapharma AG – was conducted in hospitals, research centres and private clinics of Germany and USA.

The other three studies {Devi 2008, retrospective observational study; Dodel 2004 and Relkin 2009, interventional prospective non-controlled studies} applied to small samples (n = 5 to 10) of subjects with AD (National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association criteria) and tested the safety and the clinical effect of various schemes of IVIg administration (0.4 g/kg every 2 weeks; 0.4 g/kg on three consecutive days every 4 weeks; 0.4 g/kg every week; 1 g/kg every 2 weeks; 2 g/kg every 4 weeks) for 3-6 months of duration. The outcomes considered were difference between baseline and end of treatment of cognitive functions according to various scales/tools (Wechsler Adult Intelligence Scale; Wechsler Memory Scale; Boston Naming Test; ADAS-cog; CDR-GS; MMSE; Visual construction abilities), immunologic surrogate outcomes (changes before and after infusion of serum or CSF anti-Abeta antibody, changes of CSF Abeta 40 and Abeta42), adverse events. Two studies {Dodel 2004, Relkin 2009} received both public and manufacturer’s funding; in the third study {Devi 2008} the source of funding was not reported.

Unpublished studies

Seven more studies - summarised in Appendix 3 - were carried out but not published as full papers, resulting as protocols in ClinicalTrial.gov {NCT00299988 } or abstracts at congress {Hara 2011, Kondo 2011, Kountouris 2000, Papatriantafyllou 2006, Relkin 2012, Rovira 2011}. None of them had results posted in clinical trials registers.

The NCT00299988 study {NCT00299988} was a phase 2 randomized, placebo-controlled trial, conducted in USA. Participants were 24 subjects with mild-to-moderate AD. Four schemes of intravenous immunoglobulin (ranging from 0.2 g/kg every 2 weeks to 0.8 g/kg every months) were compared to placebo. Treatment duration was 6 months. Primary outcome were ADAS-Cog and ADCS-CGIC. Other outcomes were cognitive functions measured by other scales/tools (MMSE; ADCS-ADL; NPI; GDS), quality of life (scales not reported), immunologic surrogate outcomes (plasma and CSF anti-amyloid antibody titers and beta amyloid levels), imaging surrogate outcomes (Positron Emission Tomography: FDG Cerebral Glucose Utilization, PIB Cerebral Amyloid Distribution, PK11195 Microglial Activation), adverse events. The study - funded by Weill Medical College of Cornell University Collaborators and by Baxter BioScience – was completed in April 2010 but results are still unpublished. For this study an open label extension of three years was carried out in 16 subjects in order to assess the long-term safety the IVIg infusion, but results are similarly unpublished as full paper (available only an abstract, Relkin 2012). Authors of the study were contacted in May 2014, and although they responded, they did not provide results.

Other four studies {Hara 2011, Kondo 2011, Papatriantafyllou 2006, Rovira 2011} applied a before-and-after design to small samples (n = 4 to 10) of subjects with AD testing the safety and effectiveness of various schemes of IVIg administration for 3-62 months of duration. The outcomes considered were difference between baseline and end of treatment of cognitive functions according to various scales/tools, surrogate outcomes, adverse events. These studies are still unpublished as full paper (available only as abstracts). The Authors of the these studies were contacted. Two of them responded without providing results, stating that the studies will be probably published.

Finally, one study {Kountouris 2000} applied a non-randomized controlled design to 16 subjects with AD comparing the effectiveness of IVIg infusion together with piracetam versus the administration of piracetam only, for 12 months of duration. The outcome considered was the cognitive function assessed by the MMSE. This study is unpublished as full paper (available only as abstract). The Author of the this study was contacted, without response.

Terminated studies

Two other studies - summarised in Appendix 3– are terminated {NCT01736579, NCT01524887}, that is stopped prematurely.

An open label extension of three years of one of the above reported RCTs {NCT00818662} was planned {NCT01736579} in order to assess the long-term safety of the IVIg infusion. The study was terminated in 2013 after enrollment of 6 patients because the preceding phase 3 study did not demonstrate efficacy on the co-primary endpoints.

The NCT01524887 study {NCT01524887} was a phase 3 randomized, placebo-controlled trial planned to include subjects with mild-to-moderate AD in order to test two unspecified schemes of intravenous immunoglobulin versus placebo for a treatment duration of 18 months. Primary outcome considered were ADAS-Cog and ADCS-ADL. The study - devised by Baxter Healthcare Corporation – was terminated in 2013 without enrollment of any patients because the first phase 3 study {NCT00818662} did not demonstrate efficacy on the co-primary endpoints.

Ongoing studies

Two more studies - summarised in Appendix 3 – are still ongoing {NCT01300728, NCT01561053}.

The NCT01300728 study {NCT01300728} is a phase 2 randomized, placebo-controlled trial, that is ongoing in USA. Participants are 50 subjects with MCI, amnestic type (single or multi domain) according to Petersen criteria (Petersen 1999) and supported by a CDR score of 0.5. IVIg infusion (0.4 g/kg every 14 days for a total of five infusions in two months) will be compared to placebo. Primary outcome is change in ventricular volumetric as measured by MRI (time frame: baseline and 24 month). Other outcomes are conversion from amnestic MCI to AD, cognitive functions measured by other scales/tools (ADAS-cog; MMSE; Clinical Dementia Rating and Sum of Boxes), other imaging surrogate outcomes, adverse events. The study - funded by Sutter Health – will be completed in October 2014.

The NCT01561053 study {NCT01561053} is a phase 2/3 randomized, placebo-controlled trial, that is ongoing in USA and Spain. Participants are 350 subjects with mild-to-moderate Alzheimer Disease (National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association criteria). IVIg (Flebogamma DIF) infusion (at unspecified high and low dose) together with plasmapheresis or plasmapheresis alone will be compared to a sham procedure. Primary outcome is increase in cognitive scores as measured by ADAS-Cog (time frame 14 months). Other outcomes are change in: cognitive, functional and neuropsychiatric scores (measured by MMSE, NPS battery, ADCS-ADL, NPICDR-Sb, ADCS-CGIC, CSDD, C-SSRS), surrogate immunological outcomes (levels of AB1-40 and AB1-42, T-tau and P-tau in CSF; levels of AB1-40 and AB1-42 in plasma), surrogate imaging outcomes (structural changes in volume of the hippocampus, posterior cingulate area, and other associated areas at MRI; brain functional changes through FDG-PET), adverse events. The study - funded by Grifols Biologicals Inc. – will be completed in December 2016.

 

Risk of bias in included studies

The included RCT {NCT00818662} was a phase 3 double-blind, placebo-controlled, two dose arm study. Available data (posted on ClinicalTrials.gov, last access December 5 2014) do not permit an evaluation of the methodology and conduction of the study due to the absence of information posted. Authors and Manufacturer were not contacted again and risk of bias was assessed by Principal Investigators. A risk of attrition bias was present (81 out of 383 randomized patients did not complete the study). The study was industry sponsored. The overall risk of bias of this study was judged to be “high”. For details on study’s risk of bias please see Table 1.

Table 1. Risk of bias table for NCT00818662 trial

Bias	Judgement	Support for judgement Cochrane Risk of Bias; Criteria from EUnetHTA guideline, Internal validity of randomized controlled trials
Random sequence generation adequate (selection bias)	Unclear	No details on random generation.
Allocation concealment adequate (selection bias)	Unclear	No details on allocation concealment.
Blinding of patients (performance bias)	Unclear	No details on blinding.
Blinding of treating personnel (performance bias)	Unclear	No details on blinding.
Blinding of outcome assessment (detection bias)	Unclear	No details on blinding.
Incomplete outcome assessment unlikely (attrition bias)	High risk	383 patients were randomized: 127 IVIG 400mg/kg; 135 IVIG 200mg/kg; 58 Placebo 4mL/kg; 63 Placebo 2mL/kg. 82 (21.4%) patients did not complet the trial: 23 (18.1%) IVIG 400mg/kg; 33 (24.4%) IVIG 200mg/kg; 9 (15.5%) Placebo 4mL/kg; 16 (25.4%) Placebo 2mL/kg
ITT principle appropriately implemented (attrition bias)	Unclear risk	No details on ITT analysis.
Selective outcome reporting unlikely (reporting bias)	Low risk	No main discrepancies between the protocol and the reported results are present.
Other bias	High risk	Sponsored study Two Study  Directors are reported Study Director: Norman Relkin, MD, PhD Alzheimer's Disease Cooperative Study (ADCS) Study Director: David Gelmont, MD Baxter Healthcare Corporation Role of the funding source “Restriction Description: Agreements with PIs may vary per requirements of individual PI, but contain common elements. For this study, PIs are restricted from independently publishing results until the earlier of the primary multicenter publication (by USCD) or 12 months after study completion. Baxter requires a review of results communications (e.g., for confidential information) ≥45 days prior to submission or communication. Baxter may request an additional delay of ≤45 days(e.g., for intellectual property protection)”

 

Result cards

Morbidity

Mortality

Function

Health-related Quality of life

Change-in management

Benefit-harm balance

Discussion

There is limited evidence on IVIG in adults with mild-to-moderate AD and no evidence for adults with MCI or moderate-to-severe AD.

The systematic search of electronic databases retrieved 5 published studies: 2 RCTs {Arai 2014, Dodel 2013}, 2 prospective interventional non-controlled studies {Dodel 2004, Relkin 2009}, and 1 observational study {Devi 2008} – including patients with mild-to-moderate AD. They were not eligible for inclusion and were used to illustrate the state of development of research. No studies were found for MCI and moderate-to-severe AD.

During the periodical check of registers of ongoing trials, a previously tracked completed but not published RCT {NCT00818662} had final results posted by the study sponsor in October 23rd 2014. Inclusion of this study in the assessment was decided by Editorial Team. Authors and sponsor were previously contacted (May 2014) but they did not provide any data. No further contacts were sought. The included RCT is a phase 3 double-blind, placebo-controlled study, including 383 patients with mild-to-moderate AD. Data show that any important clinical outcomes such as cognitive functions (according to ADAS-Cog and ADCSC-GIC), activity of daily living (ADCS-ADL) and quality of life (both in patients and caregivers according to QOLAD) did not differ between IVIG groups (400 mg/kg or 200 mg/kg) versus placebo groups after 70 weeks of treatment. The confidence in effect estimate for overall evidence on all considered outcomes is very low, according to GRADE method, due to high risk of bias.

We have documented the missing publication of another RCT {NCT00299988} and of other six interventional non-controlled studies. All these studies included subjects with mild-to-moderate AD.

Other two ongoing RCTs have been recorded: one phase 2, dose-finding, including 50 subjects with MCI {NCT01300728}, and one phase 2/3, including 350 subjects with mild-to-moderate AD {NCT01561053}. Trials are reported to or expected to end in November 2014 and December 2016, respectively.

The published studies were conducted in hospitals, research centres and private clinics in Germany and USA. The tested therapeutic schemes and the duration of treatment varied substantially. The IVIGs used in published studies were Gammagard by Baxter Healthcare Corporation and Octagam by Octapharma AG. The unpublished study {NCT00818662} – by Baxter Healthcare Corporation - used Gammagard Liquid (200 mg or 400 mg/kg every 2 weeks). The ongoing RCTs are testing Flebogamma by Grifols S.A. and NewGam by Sutter Health. The latter study tests IVIG (high dose or low dose – no other details provided) together with plasmapheresis against plasmapheresis alone or against infusion of 20% albumin.

Implications for practice

At present there is limited evidence on lack of effectiveness of IVIG in adults with mild-to-moderate AD, and no evidence for adults with MCI and moderate-to-severe AD.

Implications for research

Publication bias was identified in the evidence base of subjects with mild-to-moderate AD. Two RCTs have been recently completed but not published {NCT00299988, NCT00818662}. One of them had its results recently posted on a clinical trial register. Another RCT including 350 patients will be ended within the next two years {NCT01561053}. Future complete access to all these data might provide valuable evidence to assess effectiveness of IVIG for these patients. No further trials would be advised before full publication of these studies. One small study on subjects with MCI {NCT01300728} is awaiting completion. It would produce only preliminary short term data on surrogate outcomes. Other studies – if suitable – will have to be devised to assess patient important outcomes in the long term. The category of moderate-to-severe AD is not considered for future study, probably because the rationale of IVIG’s use for advanced AD is weak or absent.

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Appendices

Appendix 1

Figure A1.1. Flow chart of study selection for the effectiveness domain.

From: {Moher 2009}.

Appendix 2

Included Studies

Table A2.1. Characteristics of included studies (see Appendix 5 for more details).

Reference	Last update	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
NCT00818662	October 23th 2014 (Clinicaltrials.gov)	phase 3 RCT	383 patients () with mild-to-moderate AD	IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (70 weeks)	Placebo: Human Albumin 0.25% 4 mL/kg or 2 mL/kg; every 2weeks (70 weeks)	Function D0011	Cognitive functions changes measured by ADAS-Cog at 9 and 18 months	Baxter Healthcare Corporation
						Function D0016	Activities of daily living changes measured by ADCS-ADL at 9 and 18 months
						Function D0011	Cognitive functions changes measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCSC-GIC) at 9 and 18 months
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI) at 18 months
						Health-related Quality of life D0013	Disease specific health related quality of life changes in patients measured by Logsdon Quality of Life in Alzheimer's Disease (QOLAD) at 18 months
						Health-related Quality of life D0013	Disease specific health related quality of life changes in caregivers measured by Logsdon Quality of Life in Alzheimer's Disease (QOLAD) at 18 months

Table A2.2. GRADE Evidence profile on effectiveness of IVIG in mild-to-moderate AD, at overall and study level.

Cognitive functions: ADAS-Cog mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

7.4 ± 7.95 (105)

8.9 ± 8.20 (100)

8.4 ± 9.37 (95)

-0.8 (-3.1 to 1.5); P = 0.476^

0.7 (-1.6 to 3.0); P = 0.530^

No difference between groups

Very low

Cognitive functions: ADAS-Cog mean score change (± SD) from baseline to 9 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

2.7 ± 5.20 (114)

4.5 ± 6.16 (114)

3.5 ± 6.44 (106)

-0.7 (-2.3 to 0.8); P = 0.368^

0.8 (-0.8 to 2.4); P = 0.319^

No difference between groups

Very low

Cognitive functions: ADCSC-GIC change (units: patients) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

Very much better: 0 Much better: 1 A little better: 6 Same: 15 A little worse: 44 Much worse: 32 Very much worse: 7 (105)

Very much better: 0 Much better: 2 A little better: 1 Same: 15 A little worse: 43 Much worse: 33 Very much worse: 7 (101)

Very much better: 0 Much better: 1 A little better: 3 Same: 16 A little worse: 36 Much worse 32 Very much worse: 4 (92)

-0.1 (-0.3 to 0.2); P = 0.660#

0.0 (-0.2 to 0.3); P = 0.766#

No difference between groups

Very low

Cognitive functions: ADCSC-GIC change (units: patients) from baseline to 9 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

Very much better: 0 Much better: 2 A little better: 7 Same: 33 A little worse: 52 Much worse: 19 Very much worse: 1 (114)

Very much better: 0 Much better: 1 A little better: 3 Same: 33 A little worse: 56 Much worse: 18 Very much worse: 3 (114)

Very much better: 0 Much better: 1 A little better: 7 Same: 36 A little worse: 48 Much worse 12 Very much worse: 0 (104)

0.1 (-0.1 to 0.3); P = 0.306#

0.3 (0.0 to 0.5 ); P = 0.028#

No difference between IVIG 400mg/kg group and Placebo group Difference between 200mg/kg group and Placebo group, in favour of Placebo group

Very low

Activities of daily living: ADCS-ADL mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

-11.4 ± 10.49 (104)

-12.4 ± 11.41 (102)

-11.4 ± 12.19 (95)

0.4 (-2.9 to 3.7); P = 0.812^

-0.9 (-4.3 to 2.5); P = 0.602^

No difference between groups

Very low

Activities of daily living: ADCS-ADL mean score change (± SD) from baseline to 9 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

-5.4 ± 7.03 (111)

-6.1 ± 8.13 (116)

-5.8 ± 8.32 (107)

0.3 (-1.8 to 2.4); P = 0.778^

-0.2 (-2.3 to 1.9); P = 0.851^

No difference between groups

Very low

Behaviour: NPI mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

3.7 ± 12.93 (104)

4.9 ± 13.30 (102)

2.4 ± 10.77 (94)

0.7 (-2.1 to 3.4); P = 0.640^

2.5 (-0.3 to 5.3); P = 0.075^

No difference between groups

Very low

Disease specific health related quality of life in patients: QOLAD mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

-0.5 ± 5.34 (99)

-0.7 ± 4.40 (99)

-1.5 ± 5.20 (86)

1.1 (-0.2 to 2.3); P = 0.094^

1.1 (-0.2 to 2.3); P = 0.094^

No difference between groups

Very low

Disease specific health related quality of life in caregivers: QOLAD mean score change (± SD) from baseline to 18 months

1/383

RCT NCT00818662

High§ -2

No indirectness

No inconsistency (only 1 trial)

No serious imprecision

Limitations* - 1

-3.0 ± 4.97 (99)

-2.5 ± 5.17 (99)

-1.6 ± 5.12 (92)

-1.1 (-2.3 to 0.2); P = 0.096^

-1.0 (-2.2 to 0.3); P = 0.123^

No difference between groups

Very low

§ Not available details for assessing the major sources of bias; presence of risk of attrition bias * Industry funded; detection of publication bias ^Method of analysis: ANCOVA (as reported in clinicaltrial.gov: results combined from 100 imputations from estimates & standard errors from 100 ANCOVA results for fixed effect of treatment, E4 allele of apolipoprotein E carrier status, & continuous covariates age at baseline, baseline ADASCog & education level) # Method of analysis: Mixed Models Analysis.

 

Appendix 3

Excluded studies

Table A3.1: Characteristics of published studies (see Appendix 5 for more details).

Reference	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
Arai 2014	multiple dose, placebo controlled, RCT	16 patients (12 experimental group; 4 control group) with mild-to-moderate Alzheimer Disease	one of two doses of intravenous immunoglobulin (0·2 g/kg, 0·4 g/kg) every 2 weeks (12 weeks)	placebo (50-mL 0.25% human albumin solution) every 2 weeks	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured MMSE	Not reported
Devi 2008	Observational-retrospective study	10 patients with AD	IVIG 0.4 g/kg every 2 weeks (3-6 months)	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by WAIS, WMS, Boston	Not reported
Dodel 2004	Interventional prospective non-controlled study	5 patients with AD (4 mild-to-moderate; 1 moderate-to-severe)	IVIG (OctagamH) 0.4 g/kg on three consecutive days every 4 weeks (6 months)	None	Function D0011	Cognitive functions measured by ADAS-Cog Other: MMSE, CERAD neuropsychological test battery	Public Octapharma (Lagenfeld, Germany) provided IVIG
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)
Dodel 2013	phase 2, dose-finding; placebo controlled, RCT	58 patients (42 experimental group; 14 control group) with mild-to-moderate AD	one of three doses of intravenous immunoglobulin (0·2 g/kg, 0·5 g/kg, or 0·8 g/kg) every 4 weeks, or half of that dose (0·1 g/kg, 0·25 g/kg, or 0·4 g/kg) every 2 weeks (24 weeks)	placebo (0·9% isotonic sodium chloride) every 4 weeks or every 2 weeks	Function D0011	Cognitive functions measured by ADAS-Cog, CDR-GS Other: MMSE	Octapharma AG
					Function D0016	Activities of daily living measured by ADCS-ADL
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)
					Morbidity D0006	Variation of imaging signs (change in ventricular volumetric as measured by MRI)
Relkin 2009	Interventional prospective  dose finding study	8 patients with mild-to-moderate AD	one of four IVIG (Gammagard S/D) doses (0.4 g/kg/2 weeks, 0.4 g/kg/week, 1 g/kg/2 weeks and 2 g/kg/4 weeks) (6 months + 9 months)	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by MMSE	Public and Baxter Bioscience Corporation
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)

 

 

Table A3.2: Characteristics of unpublished studies, randomized controlled studies (see Appendix 5 for more details).

Reference	Last update	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
NCT00299988	2010	phase 2 RCT	24 patients with mild-to-moderate AD	one of four doses of IVIG (from 0·2 g/kg every 2 weeks to 0·8 g/kg every month) (6 months)	Placebo	Function D0011	Cognitive functions measured by ADAS-Cog Other: ADCS-CGIC	Public, Baxter BioScience
						Function D0016	Activities of daily living measured by ADCS-ADL
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI)
						Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)
						Morbidity D0006	Variation of imaging signs (change in SUVR at PIB-PET)
						Health-related Quality of life D0012	Generic health related quality of life
						Health-related Quality of life D0013	Disease specific health related quality of life
						Function D0016	Activities of daily living measured by ADCS-ADL
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI)
						Health-related Quality of life D0012	Generic health related quality of life
						Health-related Quality of life D0013	Disease specific health related quality of life

 

Table A3.3: Characteristics of unpublished studies, other designs (see Appendix 5 for more details).

Reference	Last update	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
Kountouris 2000	2000	Open label, non-randomized controlled trial	16 patients with AD	IVIG (Octagam) 0,2 g/Kg + piracetam (12 months)	Piracetam	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by MMSE	Not reported
Papatriantafyllou 2006	2006	uncontrolled longitudinal study	6 patients with mild-to-moderate AD	total dose of 0.4g/Kg IVIG in three consecutive days every 4 weeks (6 months)	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by MMSE	Not reported
						Function D0016	Activities of daily living measured by ADCS-ADL
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI)
Hara 2011	2011	Uncontrolled longitudinal study	10 patients with AD	IVIG (5.5-62.3 months)	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by Memory Performance Index, and the Functional Assessment Staging test	Not reported
Kondo 2011	2011	Uncontrolled longitudinal study	4 patients with AD	0.4 g/kg of IVIGfor 3 consecutive days every month for 3 months	None	Function D0011	None of the prespecified ADAS-Cog, CDR-GS Cognitive functions measured by MMSE	Not reported
						Morbidity D0006	Variation of imaging signs (change in SUVR at PIB-PET)
Rovira 2011	2011	open label pilot uncontrolled longitudinal study	4 patients with mild-to-moderate AD	0.5 g/kg of IVIG (Flebogamma DIF, Grifols) every 2 weeks (6 months)	None	Function D0011	Cognitive functions measured by ADAS-Cog, CDR-GS Other: MMSE	Not reported
						Morbidity D0006	Variation of imaging signs (change in ventricular volumetric as measured by MRI)
Relkin 2012 (open extension of NCT00299988)	2012	12 month open label extension of a Phase II, double blind placebo controlled study	16 patients with mild-to-moderate AD	IVIG (Gammagard, Baxter) 0.4g/ kg/2 weeks (36 months)	None	Function D0011	Cognitive functions measured by ADAS-Cog Other: ADCS-CGIC	Not reported
						Function D0016	Activities of daily living measured by ADCS-ADL
						Morbidity D0005	Behavioural changes measured by Neuropsychiatric Inventory (NPI)
						Health-related Quality of life D0012	Generic health related quality of life
						Health-related Quality of life D0013	Disease specific health related quality of life

Table A3.4: Characteristics of terminated studies (see Appendix 5 for more details)

Reference	Last update	Study design	Participants	Intervention (duration)	Control	Funding
NCT01524887	2013 The study was terminated without enrol any patient because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints	phase 3 RCT	patients with mild-to-moderate AD	Experimental: IVIG, 10% at Dose A (high dose) or Dose B (low dose) (18 months)	Placebo	Baxter Healthcare Corporation
NCT01736579	2013 The study was terminated after enrolment of 8 patients  because the first Phase 3 did not demonstrate efficacy on the co-primary endpoints	open label extension previous study (NCT00818662)	patients with mild-to-moderate AD	IVIG (Gammagard Liquid) 200 mg or 400 mg/kg every 2 weeks (3 years)	None	Baxter Healthcare Corporation

Table A3.5: Characteristics of ongoing studies

Reference	Study design	Participants	Intervention (duration)	Control	EFF issues	EFF outcome measure	Funding
NCT01300728 (estimated completion November 2014)	phase 2 RCT	50 patients with MCI	IVIG (NewGam) at 0.4 g/kg every 14 days for a total of five infusions (two months)	Placebo	Morbidity D0006	Rate of progression or frequency of patients progressed to AD according to according to available AD validated criteria (NINCDS-ADRDA, ICD, DSM) at 24 months	Sutter Health
					Function D0011	Cognitive functions measured by ADAS-Cog, CDR-GS at 24 months Other: MMSE
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42) at 24 months
					Morbidity D0006	Variation of imaging signs (change in ventricular volumetric as measured by MRI) at 24 months
NCT01561053 (estimated completion December 2016)	phase 2/3 RCT	350 patients with mild-to-moderate AD	Plasmapheresis alone or with infusion of 20% albumin and IVIG high dose or low dose (14 months)	Sham procedure	Function D0011	Cognitive functions measured by ADAS-Cog Other: MMSE	Instituto Grifols, S.A.
					Function D0016	Activities of daily living measured by ADCS-ADL
					Morbidity D0005	Behavioural changes (Neuropsychiatric Inventory – NPI)
					Morbidity D0006	Variation of biomarkers (decrease of cerebrospinal fluid Aβ1-40/Aβ1-42; increase of serum Aβ1-40/Aβ1-42)
					Morbidity D0006	Variation of imaging signs (change in ventricular volumetric as measured by MRI)

 

Appendix 4

Stage of development of research

To describe the stage of development of current and future research on effectiveness on IVIG for MCI and AD we tabled the studies against the evidence profile.

MCI

Available evidence

No evidence is available on effectiveness of IVIG for patients with MCI.

Upcoming evidence

One ongoing phase 2 RCT will be able to provide preliminary data on some important clinical outcomes (frequency of patients progressed to AD and cognitive functions, however in a short time frame (24 months of follow up).

 

Table A4.1: Stage of development of research on effectiveness on IVIG for MCI.

IVIG for MCI
Issue	Outcome	MCI
		Available evidence	Upcoming evidence
Morbidity [D0006]	Rate of progression or frequency of patients progressed	None	1 phase 2 RCT (50 pts)
Mortality [D0001]	Overall mortality rate	None	None
Function [D0011]	Cognitive functions	None	1 phase 2 RCT (50 pts)
Morbidity [D0005]	Neuropsychiatric symptoms/Behavioural changes	None	None
Health-related Quality of life [D0012]	Generic health related quality of life	None	None
Morbidity [D0006]	Variation of biomarkers	None	1 phase 2 RCT (50 pts)
Morbidity [D0006]	Variation of imaging signs	None	1 phase 2 RCT (50 pts)

 

Mild-to-moderate AD

Available evidence

Comparative data about cognitive functions and activity of daily living are available from one phase 2 RCT on 58 patients (see Table A4.2) and and one phase 3 RCT (383 patients), the latter included in the present study. These studies were preceded by three small non-controlled studies investigating mainly effect of IVIG on surrogate outcomes.

Table A4.2: Synopsis of results of the phase 2, dose-finding, RCT by Dodel et al. {Dodel 2013}.

Issues and outcome measures at 24 weeks

IVIg Dose/4 weeks (No. of pts) 0.2 g/kg (6) 0.5 g/kg (8) 0.8 g/kg (7)

Placebo 4 weeks (No. pts =7)

Difference (95% CI) Placebo vs IVIg 4 weeks 0.2 g/kg 0.5 g/kg 0.8 g/kg

Interpretation

IVIg Dose/2 weeks (No. pts) 0.1 g/kg (6) 0.25 g/kg (7) 0.4 g/kg (7)

Placebo 2 weeks (No. pts =7)

Difference (95% CI) Placebo vs IVIg 2 weeks 0.1 g/kg 0.25 g/kg 0.4 g/kg

Interpretation

Function D0011 - Cognitive functions ADAS-cog median change from baseline (range) Higher scores worse

5.3 (–4.7 to 8.7) 1.8 (–8.0 to 24.0) –1.5 (–4.3 to 18.3)

0.3 (–3.3 to 5.0)

–3.8 (–9.3 to 4.0) –0.3 (7.0 to 5.7) 0.8 (–13.3 to 7.3)

No statistically significant difference between groups

2.5 (–3.7 to 6.0) –1.3 (–7.3 to 4.0) 4.5 (–4.0 to 8.3)

–0.3 (–5.3 to 5.0)

–3.0 (–7.0 to 1.7) 2.0 (–4.0 to 7.0) –4.3 (–10.7 to 2.3)

No statistically significant difference between groups

Function D0011 - Cognitive functions CDR-sum of boxes median change from baseline (range) Higher scores worse

0.5 (–1.0 to 3.0) 0.0 (–1.0 to 5.0) 0.3 (–1.5 to 3.0)

–0.5 (–6.0 to 0.0)

–1.5 (–6.5 to 0.0) –0.5 (–6.0 to 0.0) –1.3 (–5.5 to 0.5)

No statistically significant difference between groups

0.0 (–1.0 to 5.0) 0.5 (–2.0 to 2.0) 0.8 (–1.5 to 4.0)

0.0 (–2.5 to 1.5)

–1.3 (–3.5 to 0.5) –0.5 (–2.5 to 1.0) –2.5 (–3.5 to 0.0)

No statistically significant difference between groups

Function D0016 - Activities of daily living ADCS-ADL median change from baseline (range) Higher scores better

–3.0 (–31.0 to 11.0) 0.0 (–15.0 to 11.0) –1.5 (–5.0 to 3.0)

–3.0 (–8.0 to 7.0)

–19.0 (–13.0 to –25.0) –4.5 (–14.0 to 7.0) –1.5 (–8.0 to 6.0)

No statistically significant difference between groups

–0.5 (–11.0 to 4.0) –3.0 (–17.0 to 3.0) –4.0 (–25.0 to 2.0)

2.0 (–6.0 to 10.0)

3.0 (–3.0 to 10.0) 5.0 (–1.0 to 13.0) 6.5 (0.0 to 18.0)

No statistically significant difference between groups

Morbidity D0006 – median change in AUC of plasma Aβ1-40 (range)

–18.0 (–1347.0 to 1068.5) –364.3 (–5834.5 to 1953.5) –351.8 (–1084.0 to 936.5)

–116.3 (–1379.0 to 5266.0)

–32.5 (–1358.0 to 4197.5) 195.3 (–1005.5 to 5302.0) 235.5 (–984.5 to 4329.5)

No statistically significant difference between groups

–13.8 (–1729.0 to 307.0) –32.5 (–1102.5 to 451.5) 47.0 (–341.0 to 72.5)

159.5 (51.5 to 303.0)

159.8 (–124.5 to 1838.5) 200.5 (–51.0 to 474.5) 134.5 (4.5 to 500.5)

Statistically significant difference in the group of 0.4 g/kg: the effect was favoring placebo

Morbidity D0006 - median change in AUC of plasma Aβ1-42 (range)

–41.8 (–244.4 to 336.6) –119.3 (–1220.6to 375.0) –107.5 (–173.5 to 231.0)

–20.5 (–183.7 to 489.0)

30.3 (–234.6 to 346.4) 114.8 (–64.5 to 622.0) 87.00 (–95.7 to 275.5)

No statistically significant difference between groups

3.0 (–109.5 to 74.5) –33.5 (–190.6 to –16.5) –9.5 (–57.0 to 5.0)

24.0 (2.0 to 125.5)

26.5 (–45.0 to 133.5) 63.0 (40.0 to 178.0) 39.0 (–11.5 to –135.0)

Statistically significant difference in the groups of 0.25 and 0.4 g/kg: the effect was favoring placebo. C.I for the latter group are probably misprinted in the paper

Morbidity D0006 – mean (SD) change from baseline normalized whole brain volume (cm3) at MRI

–1.4 (1.8) –1.1 (1.0) –1.6 (1.1)

–0.9 (0.8)

0.5 (–1.7 to 2.7) 0.2 (–1.1 to 1.5) 0.7 (–0.7 to 2.2)

No statistically significant difference between groups

–2.0 (0.8) –1.5 (0.7) –1.4 (1.7)

–1.4 (1.0)

0.6 (–0.8 to 2.0) 0.1 (–1.1 to 1.3) 0.0 (–2.3 to 2.2)

No statistically significant difference between groups

Differences between treatment groups were assessed by t test (two-sided, α=0·05) for biomarkers and MRI results and by calculating Hodges-Lehmann estimates and non-parametric 95% CIs, compared with Wilcoxon rank sum test (normal approximation, two-sided, α=0·05) for the cognitive and functional scales. 

Upcoming evidence

One completed unpublished RCT and one ongoing phase 2/3 RCT will be able to add comparative data on some important outcomes (cognitive functions, activity daily living, behavioural changes) of IVIG – according to different dosing and administration schemes – for some hundreds of patients and on long term (14 months). In the last decade four non-controlled studies result to be completed and unpublished. They will be able to add only very few data on efficacy outcomes.

Table A4.3: Stage of development of research on effectiveness on IVIG for mild-to-moderate AD.

IVIG for mild-to-moderate AD
Issue	Outcome	Mild-to-moderate AD
		Available evidence	Upcoming evidence
Morbidity [D0006]	Rate of progression or frequency of patients progressed	None	None
Mortality [D0001]	Overall mortality rate	None	None
Function [D0011]	Cognitive functions	1 interventional prospective non-controlled study study (5 pts), 1 phase 2 RCT (58 pts), 1 phase 3 RCT (383 pts)	2 uncontrolled longitudinal studies (20 pts), 2 RCTs (764 pts)
Function [D0011]	Activities of daily living	1 phase 2 RCT (58 pts), 1 phase 3 RCT (383 pts)	2 uncontrolled longitudinal studies (22 pts), 2 RCTs (374 pts)
Morbidity [D0005]	Neuropsychiatric symptoms/Behavioural changes	1 phase 3 RCT (383 pts)	2 uncontrolled longitudinal studies (22 pts), 2 RCTs (374 pts)
Health-related Quality of life [D0012]	Generic health related quality of life	None	1 uncontrolled longitudinal studies (16 pts), 1 RCT (24 pts)
Health-related Quality of life [D0013]	Disease specific health related quality of life	1 phase 3 RCT (383 pts)	1 uncontrolled longitudinal study (16 pts), 1 RCT (24 pts)
Change in management [D0010]	Hospitalization	None	None
Change in management [D0010]	Institutionalization	None	None
Morbidity [D0006]	Variation of biomarkers	2 interventional prospective non-controlled studies (13 pts), 1 phase 2 RCT (58 pts)	3 RCTs (764 pts)
Morbidity [D0006]	Variation of imaging signs	1 phase 2 RCT (58 pts)	2 uncontrolled longitudinal studies  studies (20 pts), 2 RCTs (374 pts)

 

Moderate-to-severe AD

Available evidence

No evidence is available on effectiveness of IVIG for patients with moderate-to-severe AD.

Upcoming evidence

No evidence is foreseen to be available on effectiveness of IVIG for patients with moderate-to-severe AD.

Table A4.4: Stage of development of research on effectiveness on IVIG for moderate-to-severe AD.

IVIG for moderate-to-severe AD
Issue	Outcome	Moderate-to-severe AD
.		Available evidence	Upcoming evidence
Mortality [D0001]	Overall mortality rate	None	None
Function [D0011]	Cognitive functions	None	None
Function [D0011]	Activities of daily living	None	None
Morbidity [D0005]	Neuropsychiatric symptoms/Behavioural changes	None	None
Health-related Quality of life [D0012]	Generic health related quality of life	None	None
Health-related Quality of life [D0013]	Disease specific health related quality of life	None	None
Change in management [D0010]	Hospitalization	None	None
Change in management [D0010]	Institutionalization	None	None
Morbidity [D0006]	Variation of biomarkers	None	None
Morbidity [D0006]	Variation of imaging signs	None	None

 

Appendix 5

                                                                                                

Appendix 6

Search strategy

Database: Pubmed

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014*
1	"Immunoglobulins, Intravenous"[Mesh]	9526
2	venimmun OR "modified immune globulin" OR "ivig" OR "endobulin" OR "alpha globin" OR venoglobulin OR sandoglobulin OR "intraglobin" OR "globulin n" OR "privigen" OR "gamunex" OR "gammagard" OR "gamimmune" OR "gamimune" OR "flebogamma dif" OR "intravenous ig" OR "iveegam" OR "immunoglobulins iv" OR "immunoglobulins ivig" OR "immunoglobulins ivigs" OR "iv immunoglobulin" OR "iv immunoglobulins"[All Fields]	15230
3	1 OR 2	15230
4	"Mild Cognitive Impairment"[Mesh]	1647
5	"Alzheimer Disease"[Mesh]	64256
6	“Mild Cognitive Impairment"[title/abstract] OR dementia*[Title/Abstract] OR Alzheimer*[Title/Abstract] OR MCI[Abstract/Title]	137580
7	4 OR 5 OR 6	144293
8	3 AND 7	82	24

* search re-run with the same date limit in February 18 2015, in order to capture references previously not indexed  with Mesh terms.

 

Database: EMBASE

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	‘immunoglobulin'/exp/dd_iv	22907
2	'endobulin':ab,ti OR 'ivig':ab,ti OR 'alpha globin':ab,ti OR venoglobulin:ab,ti OR sandoglobulin:ab,ti OR 'intraglobin':ab,ti OR 'globulin n':ab,ti OR 'privigen':ab,ti OR 'gamunex':ab,ti OR 'gammagard':ab,ti OR 'gamimmune':ab,ti OR 'gamimune':ab,ti OR 'flebogamma dif':ab,ti OR 'intravenous ig':ab,ti OR 'iveegam':ab,ti OR 'immunoglobulins iv':ab,ti OR 'immunoglobulins ivig':ab,ti OR 'immunoglobulins ivigs':ab,ti OR 'iv immunoglobulin':ab,ti OR 'iv immunoglobulins':ab,ti OR 'intravenous antibodies':ab,ti OR 'intravenous antibody':ab,ti OR 'intravenous immunoglobulin':ab,ti OR 'intravenous immunoglobulins':ab,ti AND [embase]/lim	14395
3	1 OR 2	31178
4	'dementia'/de OR 'alzheimer disease'/exp OR 'mild cognitive impairment'/exp	173965
5	3 OR 4	359	42

 

Database: Cochrane Central Register of Controlled Trials

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	MeSH descriptor: [Immunoglobulins, Intravenous] explode all trees	616
2	('endobulin':ab,ti or 'ivig':ab,ti or 'alpha globin':ab,ti or venoglobulin:ab,ti or sandoglobulin:ab,ti or 'intraglobin':ab,ti or 'globulin n':ab,ti or 'privigen':ab,ti or 'gamunex':ab,ti or 'gammagard':ab,ti or 'gamimmune':ab,ti or 'gamimune':ab,ti or 'flebogamma dif':ab,ti or 'intravenous ig':ab,ti or 'iveegam':ab,ti or 'immunoglobulins iv':ab,ti or 'immunoglobulins ivig':ab,ti or 'immunoglobulins ivigs':ab,ti or 'iv immunoglobulin':ab,ti or 'iv immunoglobulins':ab,ti or 'intravenous antibodies':ab,ti or 'intravenous antibody':ab,ti or 'intravenous immunoglobulin':ab,ti or 'intravenous immunoglobulins':ab,ti)	2379
3	1 OR 2	2467
4	MeSH descriptor: [Alzheimer Disease] explode all trees	2065
5	MeSH descriptor: [Mild Cognitive Impairment] explode all trees	65
6	Alzheimer or "mild cognitive impairment" or "mild cognitive impairments"	5163
7	4 OR 5 OR 6	5198
8	3 AND 7	10	5

 

Database: Lilacs, Ibec, Medcarib

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	tw: immunoglobulin* AND (alzheimer* OR dementia OR ”mild cognitive impairment”)	11	0

 

Database: Isi web of Knowledge

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	Topic=(Venimmun OR "modified immune globulin" OR "ivig" OR "endobulin" OR "alpha globin" OR venoglobulin OR sandoglobulin  OR "intraglobin" OR "globulin n" OR "privigen" OR "gamunex" OR "gammagard" OR "gamimmune") OR "gamimune" OR "flebogamma dif" OR "intravenous ig" OR "iveegam" OR "immunoglobulins iv" OR "immunoglobulins ivig" OR "immunoglobulins ivigs" OR "iv immunoglobulin" OR "iv immunoglobulins" OR "intravenous antibodies" OR "intravenous antibody" OR "intravenous immunoglobulin" OR "intravenous immunoglobulin" OR "intravenous immunoglobulins")
2	Topic=(mci[title/abstract] OR "Mild Cognitive Impairments"[title/abstract] OR "Mild Cognitive Impairment"[title/abstract] OR dementia*[Title/Abstract] OR alzheimer*[Title/Abstract])
3	1 AND 2	138	30

 

Clinical Registers

ALOIS: a comprehensive register of dementia studies

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunlobulin*	7	0

 

metaRegister of Controlled Trials (mRCT), including ISRCTN (International Standard Randomised Controlled Trial Number Register)

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	(immunoglobulin*) and (Alzheimer or dementia or “mild cognitive impairment”)	2	0

 

ClinicalTrials.gov

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	(alzheimer* OR dementia* OR "mild cognitive impairment") AND ( immunoglobulin*)	51	21

 

NIH Clinical research studies

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunoglobulin* and Alzheimer	0	0

 

EU Clinical Trials Register website

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunoglobulin* and Alzheimer	4	0

 

International Clinical Trials Register Platform (ICTRP)

#	Searches	Results Search Date: 24/02/2014	Update 16/12/2014
1	immunoglobulin* and Alzheimer	4	0

Appendix 7

Use of Intravenous immunoglobulins for Mild Cognitive Impairment and Alzeheimer’s disease - PROTOCOL

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