Disclaimer
This information collection is a core HTA, i.e. an extensive analysis of one or more health technologies using all nine domains of the HTA Core Model. The core HTA is intended to be used as an information base for local (e.g. national or regional) HTAs.

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

Immunoglobulins (IGG) compared to placebo, not doing anything or Usual supportive care in the treatment of Alzheimer’s disease in elderly 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.

(See detailed scope below)

HTA Core Model Application for Pharmaceuticals (2.0)
Core HTA
Published
Tom Jefferson (Agenas - Italy), Marina Cerbo (Agenas - Italy), Nicola Vicari (Agenas - Italy)
Alessandra Lo Scalzo (Agenas), Anna-Theresa Renner (GOG), Antonio Migliore (Agenas), Ingrid Wilbacher (HVB), Luca Vignatelli (ASSR RER), Luciana Ballini (ASSR RER), Nadine Berndt (CEM), Nicola Vicari (Agenas), Plamen Dimitrov (NCPHA), Susanna Maltoni (ASSR RER), Ricardo Ramos (INFARMED), Tom Jefferson (Agenas)
Agenas - Agenzia nazionale per i servizi sanitari regionali
AAZ (Croatia), ASSR RER (Italy), Avalia-t (Spain), CEM (Luxembourg), GÖG (Austria), HAS (France), HVB (Austria), IER (Slovenia), INFARMED (Portugal), ISC III (Spain), NCPHA (Bulgaria), NIPH (Slovenia), NSPH (Greece), NSPH MD (Romania), SBU (Sweden), SNHTA (Switzerland), THL (Finland), UTA (Estonia).
13.1.2014 12.32.00
30.11.2015 11.18.00
Jefferson T, Cerbo M, Vicari N [eds.]. Use of Intravenous immunoglobulins for Alzeheimer’s disease including Mild Cognitive Impairment [Core HTA], Agenas - Agenzia nazionale per i servizi sanitari regionali ; 2015. [cited 9 May 2021]. Available from: http://corehta.info/ViewCover.aspx?id=267

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

<< Collection summaryDescription and technical characteristics of technology >>

Health Problem and Current Use of the Technology

Authors: Antonio Migliore, Tapani Keranen, Sinikka Sihvo

Summary

Target Condition

Dementia is an overall term for a decline in mental ability severe enough to reduce a person's ability to perform everyday activities. Alzheimer's disease is the most common type of dementia, which accounts for 60 to 80 percent of cases. Alzheimer's is a progressive disease, where dementia symptoms gradually worsen over time. According to DSM-IV criteria for Alzheimer’s disease, memory deficit must be objectively demonstrated plus at least one other cognitive deficit: aphasia (abnormal speech), executive function impairment (difficulty with planning, judgment, mental flexibility, abstraction, problem-solving, etc.), agnosia (impaired recognition of people or objects), or apraxia (impaired performance of learned motor skills). These cognitive deficits must result in impairment in performance of daily activities. The diagnosis is confirmed by post mortem evidence of neurofibrillary tangles and neuritic plaques in excess of those found in normal ageing of the brain (ICD-10). Those with Alzheimer's live an average of 3.6 to 6.6 years after the diagnosis, depending on age and other health conditions. In the newest Diagnostic and Statistical Manual of Mental Disorders (DSM-5) “dementia” is replaced by “major neurocognitive disorder”. Mild cognitive impairment (MCI) describes a transitional state between normal aging and pathological decline. Many terms and definitions have been used to describe mild forms of cognitive impairment. According to Petersen et al. mild cognitive impairment is classified as 1) MCI that primarily affects memory is known as “amnestic MCI”, aMCI, and 2) MCI that affects thinking skills other than memory is known as “nonamnestic MCI”. A person with MCI is at an increased risk of developing Alzheimer's disease and other dementias, however, many individuals revert to normal or do not progress. The conversion rate from MCI to Alzheimer's is low, about 7 % in community based samples and 15% in specialized care samples. Therefore, MCI diagnosis alone cannot be equaled with a pre-dementia stage. In order to allow treatments like medication, MCI diagnosis should be supplemented with predictors of a rapid cognitive decline, such as older age, vascular risk factors, neurological symptoms, apoE ɛ4 genotype, etc.). In the DSM-5 a term “mild neurocognitive disorder” is used instead of mild cognitive impairment. Intravenous immunoglobulins (IVIG) are expected to have potentially beneficial effects on the pathogenetic process of Alzheimer’s disease by stabilizing cognitive functioning in patients with mild-to-moderate Alzheimer’s disease. The neuroprotective mechanisms of IVIG are not well known. If MCI would be identified early this would allow earlier treatment to slow progression of AD or even prevent it. Early interventions are likely to be more effective than if the disease is already advantaged. Slowing the progression of AD with IVIG or other therapies could have major impact on the need for care and burden of the disease.

Target Population

Target populations for IVIG therapy are: i) Patients with Mild Cognitive Impairment; ii) Patients with mild-to-moderate Alzheimer’s disease, as defined by validated criteria and with MMSE score between 15 and 26; iii) Patients with moderate-to-severe Alzheimer’s disease, as defined by validated criteria and with MMSE score less than or equal to 14. The worldwide prevalence estimates are given usually for dementia than for Alzheimer’s disease since the possibilities to make correct diagnosis can vary. In addition, estimates vary between studies. The age-standardised prevalence of dementia among populations > 60 years is 5-7%. In 2010 it was estimated that there are over 35 million people worldwide living with dementia. These numbers are expected to double every 20 years to 65.7 million in 2030 and to 115.4 million in 2050. According to worldwide meta-analysis of studies between 1984-2008, the prevalence of Mild Cognitive Impairment was 24.6% but varied between 21.5-71.5%. For people > 65 years the MCI incidence varied between 21.5-71.3/1000 person years.

Current Management of the Condition

There are no established treatments for MCI. In contrast to MCI, there are several pharmacological possibilities for the treatment of AD. Currently available drug treatments for AD are considered symptomatic. It is recommended that patients with AD and mild to moderate dementia are initially treated with one of the cholinesterase inhibitors (ChEIs), i.e. donepezil, galantamine, or rivastigmine. These drugs have been shown as having efficacy on cognitive function, global outcome, and ADL functions. ChEIs can be used also in the severe form of AD either alone or in combination with the glutamate antagonist memantine. Memantine can also be used alone in patients with severe AD and in patients who have contraindications or who are intolerant to ChEIs.

Utilisation

IVIG are not used for Alzheimer’s disease including Mild Cognitive Impairment in any of the EUnetHTA partners answered the survey. However, while some partners explicitly excluded the use of IVIG for the mentioned indications, some others stated that, given the characteristics of the internal monitoring and reimbursement system, it’s impossible exclude the off-label use of IVIG.

Regulatory Status

IVIG are currently used as first line therapy for various condition. However, some new indications are emerging and extensions in the indications could be proposed. At time of writing, no manufacturers have submitted requests to EMA for the market approval of the IVIG for Alzheimer’s disease including Mild Cognitive Impairment.

Introduction

This domain aims to give a broad overview on Alzheimer’s disease (AD) including Mild Cognitive Impairment (MCI) in terms of definition, diagnosis, current management, burden, as well as utilization and regulatory status of the IVIG.

Methodology

Frame

The collection scope is used in this domain.

TechnologyImmunoglobulins (IGG)
Description

Naturally occurring proteins produced by the body’s immune system to combat foreign antigens

Intended use of the technologyTreatment

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. 

Comparisonplacebo, 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

TopicIssue RelevantResearch questions or rationale for irrelevance
A0002Target ConditionWhat is the disease or health condition in the scope of this assessment?yesWhat is the disease in the scope of this assessment?
A0003Target ConditionWhat are the known risk factors for the disease or health condition?yesWhat are the known risk factors for the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI)?
A0004Target ConditionWhat is the natural course of the disease or health condition?yesWhat is the natural course of the Alzheimer’s disease (AD) and the Mild Cognitive Impairment (MCI)?
A0005Target ConditionWhat are the symptoms and burden of disease for the patient at different stages of the disease?yesWhat are the symptoms and burden of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) for the patient at different stages of the disease?
A0006Target ConditionWhat are the consequences of the disease or the health condition for the society (i.e. the burden of the disease)?yesWhat are the consequences of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) for the society (i.e. the burden of the disease)?
A0009Target ConditionWhat aspects of the consequences / burden of disease are targeted by the technology?yesWhat aspects of the consequences / burden of disease are targeted by the intravenous immunoglobulin (IVIG) therapy?
A0007Target PopulationWhat is the target population in this current assessment of the technology?yesWhat is the target population in this current assessment of intravenous immunoglobulin (IVIG) therapy?
A0023Target PopulationHow many people belong to the target population?yesHow many people belong to the target population?
A0017Current Management of the ConditionWhat are the differences in the management for different stages of the disease or health condition?yesWhat are the differences in the management for the different stages of the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI)?
A0018Current Management of the ConditionWhat are the other typical or common  alternatives to the current technology?yesWhat are the other typical or common alternatives to intravenous immunoglobulin (IVIG) therapy?
A0024Current Management of the ConditionHow is the disease or health condition currently diagnosed according to published guidelines and in practice?yesHow are Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) currently diagnosed according to published guidelines and in practice?
A0025Current Management of the ConditionHow is the disease or health condition currently managed according to published guidelines and in practice?yesHow are the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) currently managed according to published guidelines and in practice?
A0001UtilisationFor which health conditions and for what purposes is the technology used?yesFor which health conditions and for what purposes are intravenous immunoglobulins (IVIG) used?
A0011UtilisationHow much is the technology utilised currently and in the future?yesHow much are intravenous immunoglobulins (IVIG) utilised currently and in the future?
A0012UtilisationWhat kind of variations in use are there across countries/regions/settings?yesWhat kind of variations in the use of intravenous immunoglobulins (IVIG) are there across countries/regions/settings?
G0009UtilisationWho decides which people are eligible for the technology and on what basis?yesWho decides which people are eligible for intravenous immunoglobulin (IVIG) therapy and on what basis?
B0003UtilisationWhat is the phase of development and implementation of the technology and the comparator(s)?yesWhat is the phase of development and implementation of intravenous immunoglobulins (IVIG)?
F0001UtilisationIs the technology a new, innovative mode of care, an add-on to or modification of a standard mode of care or replacement of a standard mode of care?yesIs intravenous immunoglobulin (IVIG) therapy a new, innovative mode of care, an add-on to or modification of a standard mode of care or replacement of a standard mode of care?
A0020Regulatory StatusWhat is the marketing authorisation status of the technology?yesWhat is the marketing authorisation status of intravenous immunoglobulins (IVIG)?
A0021Regulatory StatusWhat is the reimbursement status of the technology across countries?yesWhat is the reimbursement status of intravenous immunoglobulins (IVIG) across countries?

Methodology description

Domain frame

The project scope is applied in this domain.

Information sources

The result cards CUR1, CUR2, CUR3, CUR4, CUR5, CUR6, CUR8, CUR9, CUR10, CUR11, CUR12, CUR14, and CUR18 have been produced using the results from the basic searches (done for the whole project) and additional, unsystematic literature searches performed by the authors {Appendix CUR-1}. Secondary studies were the main additional information sources considered. The result cards CUR7 and CUR13 have been produced using the findings reported in the document named “Use of Intravenous immunoglobulins for Mild Cognitive Impairment and Alzeheimer’s disease – Protocol” prepared by authors teams from SAF and EFF domains and presented in {Appendix SAF-7}. The result cards CUR15, CUR16, CUR17, CUR19, and CUR 20 have been produced using the results from the surveys carried out among the WP4 stakeholder advisory group (WP4 SAG) and EUnetHTA partners. The surveys are described in details in {Appendix CUR-3}.

Quality assessment tools or criteria

This domain presents descriptive information and rigorous quality assessment was believed not necessary by the domain’s authors. Quality assessment has not been performed for any of the considered citations.

Analysis and synthesis

Descriptive analysis was performed on different information sources. Results have been presented in narrative form. No numerical data analysis has been performed.

Result cards

Target Condition

Result card for CUR1: "What is the disease in the scope of this assessment?"

View full card
CUR1: What is the disease in the scope of this assessment?
Result

Importance: Critical

Transferability: Completely

Result card for CUR2: "What are the known risk factors for the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI)?"

View full card
CUR2: What are the known risk factors for the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI)?
Result

Importance: Important

Transferability: Completely

Result card for CUR3: "What is the natural course of the Alzheimer’s disease (AD) and the Mild Cognitive Impairment (MCI)?"

View full card
CUR3: What is the natural course of the Alzheimer’s disease (AD) and the Mild Cognitive Impairment (MCI)?
Result

Importance: Important

Transferability: Completely

Result card for CUR4: "What are the symptoms and burden of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) for the patient at different stages of the disease?"

View full card
CUR4: What are the symptoms and burden of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) for the patient at different stages of the disease?
Result

Importance: Important

Transferability: Completely

Result card for CUR5: "What are the consequences of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) for the society (i.e. the burden of the disease)?"

View full card
CUR5: What are the consequences of Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) for the society (i.e. the burden of the disease)?
Result

Importance: Critical

Transferability: Partially

Result card for CUR6: "What aspects of the consequences / burden of disease are targeted by the intravenous immunoglobulin (IVIG) therapy?"

View full card
CUR6: What aspects of the consequences / burden of disease are targeted by the intravenous immunoglobulin (IVIG) therapy?
Result

Importance: Critical

Transferability: Completely

Target Population

Result card for CUR7: "What is the target population in this current assessment of intravenous immunoglobulin (IVIG) therapy?"

View full card
CUR7: What is the target population in this current assessment of intravenous immunoglobulin (IVIG) therapy?
Result

Importance: Critical

Transferability: Completely

Result card for CUR8: "How many people belong to the target population?"

View full card
CUR8: How many people belong to the target population?
Result

Importance: Critical

Transferability: Completely

Current Management of the Condition

Result card for CUR9: "What are the differences in the management for the different stages of the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI)?"

View full card
CUR9: What are the differences in the management for the different stages of the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI)?
Result

Importance: Important

Transferability: Completely

Result card for CUR10: "What are the other typical or common alternatives to intravenous immunoglobulin (IVIG) therapy?"

View full card
CUR10: What are the other typical or common alternatives to intravenous immunoglobulin (IVIG) therapy?
Result

Importance: Critical

Transferability: Completely

Result card for CUR11: "How are Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) currently diagnosed according to published guidelines and in practice?"

View full card
CUR11: How are Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) currently diagnosed according to published guidelines and in practice?
Result

Importance: Critical

Transferability: Completely

Result card for CUR12: "How are the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) currently managed according to published guidelines and in practice?"

View full card
CUR12: How are the Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI) currently managed according to published guidelines and in practice?
Result

Importance: Important

Transferability: Completely

Utilisation

Result card for CUR13: "For which health conditions and for what purposes are intravenous immunoglobulins (IVIG) used?"

View full card
CUR13: For which health conditions and for what purposes are intravenous immunoglobulins (IVIG) used?
Result

Importance: Critical

Transferability: Completely

Result card for CUR14: "How much are intravenous immunoglobulins (IVIG) utilised currently and in the future?"

View full card
CUR14: How much are intravenous immunoglobulins (IVIG) utilised currently and in the future?
Result

Importance: Critical

Transferability: Completely

Result card for CUR15: "What kind of variations in the use of intravenous immunoglobulins (IVIG) are there across countries/regions/settings?"

View full card
CUR15: What kind of variations in the use of intravenous immunoglobulins (IVIG) are there across countries/regions/settings?
Result

Importance: Critical

Transferability: Completely

Result card for CUR16 / ORG12: "Who decides which people are eligible for intravenous immunoglobulin (IVIG) therapy and on what basis?"

View full card
CUR16 / ORG12: Who decides which people are eligible for intravenous immunoglobulin (IVIG) therapy and on what basis?
Result

Importance: Important

Transferability: Completely

Result card for CUR17 / TEC3: "What is the phase of development and implementation of intravenous immunoglobulins (IVIG)?"

View full card
CUR17 / TEC3: What is the phase of development and implementation of intravenous immunoglobulins (IVIG)?
Result

Importance: Critical

Transferability: Completely

Result card for CUR18: "Is intravenous immunoglobulin (IVIG) therapy a new, innovative mode of care, an add-on to or modification of a standard mode of care or replacement of a standard mode of care?"

View full card
CUR18: Is intravenous immunoglobulin (IVIG) therapy a new, innovative mode of care, an add-on to or modification of a standard mode of care or replacement of a standard mode of care?
Result

Importance: Critical

Transferability: Completely

Regulatory Status

Result card for CUR19: "What is the marketing authorisation status of intravenous immunoglobulins (IVIG)?"

View full card
CUR19: What is the marketing authorisation status of intravenous immunoglobulins (IVIG)?
Result

Importance: Critical

Transferability: Completely

Result card for CUR20: "What is the reimbursement status of intravenous immunoglobulins (IVIG) across countries?"

View full card
CUR20: What is the reimbursement status of intravenous immunoglobulins (IVIG) across countries?
Result

Importance: Critical

Transferability: Completely

Discussion

According to the information available at the time of writing, IVIG are not used for Alzheimer’s disease including Mild Cognitive Impairment in any of the EUnetHTA partners who answered the survey. However, while some partners explicitly excluded the use of IVIG for the mentioned indications, some others stated that, given the characteristics of the internal monitoring and reimbursement system, it’s impossible to exclude the off-label use of IVIG {Appendix CUR-3}. No manufacturers have submitted requests to EMA for the market approval of the IVIG for Alzheimer’s disease including Mild Cognitive Impairment {Appendix CUR-3}.

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Appendices

Appendix CUR-1 (strategy of the additional, unsystematic literature searches performed by the authors of this domain).

CUR Appendix 1

Appendix SAF-7 (document named “Use of Intravenous immunoglobulins for Mild Cognitive Impairment and Alzeheimer’s disease – Protocol” prepared by the authors team from SAF domain).

SAF Appendix 7

Appendix CUR-3 (surveys carried out by the WP4 Leader among the stakeholder advisory group, SAG, and EUnetHTA partners).

CUR-3 Appendix 3

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