A Phase 3 Study Evaluating Safety and Effectiveness of Immune Globulin Intravenous (IGIV 10%) for the Treatment of Mild-to-Moderate Alzheimer´s Disease

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the efficacy and safety of 2 doses of Immune Globulin Intravenous (IGIV), 10% administered every 2 weeks as an intravenous (IV) infusion compared with placebo in participants with mild to moderate Alzheimer's disease (AD).

Detailed Description
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Study visits: Each participant will be tested at the investigational site, and if qualified, will be treated intravenously (through a vein) every two weeks for 70 weeks (approximately 18 months). The first three infusions must be done at the site, but if the infusions are well tolerated, subsequent infusions may be done by a qualified healthcare provider in the home or other suitable location. Each participant must return to the site every 3 months for evaluation of cognition as well as blood tests and scans of the brain.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Two Dose Arm, Parallel Study of the Safety and Effectiveness of Immune Globulin Intravenous (Human), 10% (IGIV, 10%) for the Treatment of Mild-to-Moderate Alzheimer´s Disease

Conditions
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Alzheimer´s Disease

Intervention / Treatment
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* Biological: Immune Globulin Intravenous (Human), 10% (IGIV, 10%) 400 mg/kg
* Biological: Immune Globulin Intravenous (Human), 10% (IGIV, 10%) 200 mg/kg
* Biological: Placebo solution: Human Albumin 0.25% - 4 mL/kg
* Biological: Placebo solution: Human Albumin 0.25% - 2 mL/kg


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Written informed consent - participant (or participant´s legally acceptable representative) and caregiver who are willing and able to participate for the duration of the study Diagnosis of probable Alzheimer´s Disease (AD) Dementia of mild to moderate severity defined as mini-mental state examination (MMSE) 16-26 inclusive at the time of screening Neuroimaging (computed tomography [CT] or MRI) performed after symptom onset consistent with AD diagnosis Ability to comply with testing and infusion regimen, including fluency in English or Spanish, adequate corrected visual acuity and hearing ability On stable doses of regulatory authority approved AD medication(s) for at least 3 months prior to screening. These medications must be continued throughout this study. If receiving psychoactive medications (e.g. antidepressants other than monoamine oxidase inhibitors (MAOIs) and most tricyclics, antipsychotics, anxiolytics, anticonvulsants, mood stabilizers, etc), must be on stable doses for at least 6 weeks prior to screening Main Exclusion Criteria (Reasons why it might not be appropriate to participate): Any other forms of dementia Medical issues that might increase the risk of treatment with IGIV, 10%, such as: Significant problems with blood pressure, heart disease, clotting disorders, strokes or recent heart attacks Evidence of current bleeding in the brain by MRI Serious problems with the liver or kidneys Allergies to blood products Medical issues that might interfere with the evaluation of the treatment of dementia or might make dementia worse, such as: Diabetes Recent treatment with chemotherapy or immune suppression The recent use of other investigational drugs, especially antibody therapy for AD Severe headaches or psychiatric problems

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IGIV, 10% 400mg/kg<br>Immune Globulin Intravenous (Human), 10% (IGIV, 10%) | Biological: Immune Globulin Intravenous (Human), 10% (IGIV, 10%) 400 mg/kg<br>* 400 mg/kg bodyweight every 2 weeks for 70 weeks<br>* Other names: KIOVIG;|
| Experimental: IGIV, 10% 200mg/kg<br>Immune Globulin Intravenous (Human), 10% (IGIV, 10%) | Biological: Immune Globulin Intravenous (Human), 10% (IGIV, 10%) 200 mg/kg<br>* 200 mg/kg bodyweight every 2 weeks for 70 weeks<br>* Other names: Gammagard Liquid;|
| Placebo Comparator: Human Albumin 0.25% Solution - 4 mL/kg<br>0.25% human albumin solution infused at 4 mL/kg/2weeks | Biological: Placebo solution: Human Albumin 0.25% - 4 mL/kg<br>* Placebo solution: 0.25% human albumin solution infused at 4 mL/kg/2weeks for 70 weeks<br>|
| Placebo Comparator: Human Albumin 0.25% Solution - 2 mL/kg<br>0.25% human albumin solution infused at 2 mL/kg/2weeks | Biological: Placebo solution: Human Albumin 0.25% - 2 mL/kg<br>* Placebo solution: 0.25% human albumin solution infused at 2 mL/kg/2weeks for 70 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at 18 Months in the Alzheimer´s Disease Assessment Scale- Cognitive Subscale (ADAS-Cog) | The ADAS-Cog is a validated psychometric instrument that evaluates memory (word recall, word recognition), attention, reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs). This test was administered by experienced raters certified by Alzheimer's Disease Cooperative Study (ADCS) at each site. Scores on the ADAS-Cog range from 0-70 with higher scores indicating greater impairment; hence increases from baseline reflect potential cognitive deterioration. | Baseline & 18 months | 
| Change From Baseline at 18 Months in Alzheimer´s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) | The ADCS-ADL scale is a validated tool to assess instrumental and basic activities of daily living based on a 23 item structured interview of the caregiver or qualified study partner. Scores on the ADCS-ADL range from 0-78 with lower scores indicating greater impairment; hence decreases from baseline reflect potential functional deterioration. | Baseline & 18 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline at 9 Months in the Alzheimer´s Disease Assessment Scale- Cognitive Subscale (ADAS-Cog) | The ADAS-Cog is a validated psychometric instrument that evaluates memory (word recall, word recognition), attention, reasoning (following commands), language (naming, comprehension), orientation, ideational praxis (placing letter in envelope) and constructional praxis (copying geometric designs). This test was administered by experienced raters certified by Alzheimer's Disease Cooperative Study (ADCS) at each site. Scores on the ADAS-Cog range from 0-70 with higher scores indicating greater impairment; hence increases from baseline reflect potential cognitive deterioration. | Baseline & 9 months | 
| Change From Baseline at 9 Months in Alzheimer´s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) | The ADCS-ADL scale is a validated tool to assess instrumental and basic activities of daily living based on a 23 item structured interview of the caregiver or qualified study partner. Scores on the ADCS-ADL range from 0-78 with lower scores indicating greater impairment; hence decreases from baseline reflect potential functional deterioration. | Baseline & 9 Months | 
| Change From Baseline at 9 Months in Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Assessment | The ADCS-CGIC is a validated categorical measure of change in a participant's clinical condition between baseline and follow-up visits; it is used to assess global clinical status. The ADCS CGIC score is based on direct examination of the participant and an interview of the caregiver. The rater should refer to the baseline ADCS-CGIC worksheets in making a rating. A skilled and experienced clinician who is blinded to treatment assignment rates the participant on a 7-point Likert scale, ranging from 1 (marked improvement) to 7 (marked worsening). 1= Very much better 2= Much better 3= A little better 4= Same 5= A little worse 6= Much worse 7= Very much worse | Baseline & 9 Months | 
| Change From Baseline at 18 Months in Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) Assessment | The ADCS-CGIC is a validated categorical measure of change in a participant's clinical condition between baseline and follow-up visits; it is used to assess global clinical status. The ADCS CGIC score is based on direct examination of the participant and an interview of the caregiver. The rater should refer to the baseline ADCS-CGIC worksheets in making a rating. A skilled and experienced clinician who is blinded to treatment assignment rates the participant on a 7-point Likert scale, ranging from 1 (marked improvement) to 7 (marked worsening). 1= Very much better 2= Much better 3= A little better 4= Same 5= A little worse 6= Much worse 7= Very much worse | Baseline & 18 Months | 
| Change From Baseline at 18 Months in the Modified Mini-Mental State Examination (3MS) Examination | The 3MS is a comprehensive validated instrument that provides a 100 point composite rating for spatial and temporal orientation, verbal recall, simple attention, working memory, naming, repetition, comprehension, writing and constructional abilities. Scores range from 0 to 100 with lower values indicating greater impairment. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Neuropsychiatric Inventory (NPI) Assessment | The NPI is a validated instrument used to assess behavioral psychopathology in AD; it evaluates the frequency and severity of 12 neuropsychiatric features including delusions, hallucinations, dysphoria, anxiety, agitation/aggression, euphoria, disinhibition, irritability/lability, apathy, aberrant motor activity, sleep and night-time behavior change, and appetite and eating change. The NPI total score ranged 0-144, with higher scores indicating greater impairment. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Logsdon Quality of Life in Alzheimer's Disease (QOL-AD) Assessment- Participant Response | The QOL AD is a validated, 13-item instrument developed specifically for individuals with dementia. The assessment rates the participant's quality of life for physical, emotional, interpersonal, and environmental domains. The QOL-AD total score ranged 13-52. Lower scores on the QOL AD are associated with a lower quality of life. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Logsdon Quality of Life in Alzheimer's Disease (QOL-AD) Assessment- Caregiver Response | The QOL AD is a validated, 13-item instrument developed specifically for individuals with dementia. The assessment rates the participant's quality of life for physical, emotional, interpersonal, and environmental domains. The QOL-AD total score ranged 13-52. Lower scores on the QOL AD are associated with a lower quality of life. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Adjunct Neuropsychological Testing: Wechsler Adult Intelligence Scale- Revised (WAIS-R) Digit Span Forward | This test assesses working memory and attention, the rater asks the participant to repeat single-digit number sequences of increasing length, which are read aloud by the rater (in forward or backward order). Two trials are presented for each sequence length, and the test is ended when the participant misses both trials at a given sequence length. The WAIS-R score ranged from 0-14. Results are presented as total number correct; therefore, lower numbers represent greater impairment. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Adjunct Neuropsychological Testing: Wechsler Adult Intelligence Scale- Revised (WAIS-R) Digit Span Backward | This test assesses working memory and attention, the rater asks the participant to repeat single-digit number sequences of increasing length, which are read aloud by the rater (in forward or backward order). Two trials are presented for each sequence length, and the test is ended when the participant misses both trials at a given sequence length. The WAIS-R score ranged from 0-14. Results are presented as total number correct; therefore, lower numbers represent greater impairment. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Adjunct Neuropsychological Testing: FAS Verbal Fluency | In the FAS assessment of phenomic verbal fluency, participants are given 1 minute each to name as many words as they can that begin with a specified letter (F, A, S). To receive credit, words must be verifiable in a dictionary, cannot be proper nouns, and cannot be the same word or variations of the same word (e.g., the same word with a different ending, such as 'acts,' 'acted,' 'acting'). Results are presented as total number correct; therefore, lower numbers indicate greater impairment. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Adjunct Neuropsychological Testing: Wechsler Adult Intelligence Scale- Revised (WAIS-R) Digit Symbol Substitution | WAIS-R digit symbol substitution test assesses attention, psychomotor speed, complex scanning, visual tracking, and immediate memory. This test consists of 4 rows each with 25 small blank squares; above each square is a number between 1 and 9. At the top is a 'key,' which pairs each number (1 through 9) with an unfamiliar symbol. The participant has 90 seconds to work as quickly as possible (left to right across the rows) to fill in each blank square with the appropriate symbol based on the number above the square. Results are presented as total number correct; therefore, lower numbers indicate greater impairment. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Adjunct Neuropsychological Testing: Animals Category Fluency | In this test, which assesses semantic verbal fluency, participants are given 1 minute to name as many items in the category animals as possible. To receive credit that word cannot be a mythical animal, but can be an animal species; breed; male, female, or infant name for a species (e.g., bull, cow, calf); in addition, names for birds, fish, reptiles, and insects receive credit. Results are presented as total number correct; therefore, lower numbers indicate greater impairment. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Adjunct Neuropsychological Testing: Trail-Making Test (TMT), Part A | This test, which has 2 parts, is used to assess processing speed, visuomotor and perceptual scanning skills, and executive function. In Part A, 25 circles each containing a number between 1 and 25 are randomly placed on a sheet of paper, and the participant is asked to draw a line as quickly as possible between each circle in ascending numerical order. In Part B, 25 circles are again randomly placed on a sheet of paper; however, in this test 13 of the circles contain the numbers 1 through 13, and the remaining 12 circles contain the letters A through L. In this test, the participant must draw a line as quickly as possible between the circles in alternating between numbers and letters in ascending order (e.g., 1 to A, A to 2, 2 to B,…). Total values for TMT Part A range between 0 and 150 seconds. Results are presented as time to complete; therefore, higher numbers indicate greater impairment. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Adjunct Neuropsychological Testing: Trail-Making Test (TMT), Part B | This test, which has 2 parts, is used to assess processing speed, visuomotor and perceptual scanning skills, and executive function. In Part A, 25 circles each containing a number between 1 and 25 are randomly placed on a sheet of paper, and the participant is asked to draw a line as quickly as possible between each circle in ascending numerical order. In Part B, 25 circles are again randomly placed on a sheet of paper; however, in this test 13 of the circles contain the numbers 1 through 13, and the remaining 12 circles contain the letters A through L. In this test, the participant must draw a line as quickly as possible between the circles in alternating between numbers and letters in ascending order (e.g., 1 to A, A to 2, 2 to B,…). Total values for TMT Part B range between 0 and 300 seconds. Results are presented as time to complete; therefore, higher numbers indicate greater impairment. | Baseline & 18 months | 
| Change From Baseline at 18 Months in the Adjunct Neuropsychological Testing: Clock Drawing Test | In this test, which assesses constructional ability, visuoperception, and executive functioning, the participant is given a blank sheet of paper and asked to draw the face of a clock showing the numbers and 2 hands set to 'ten after eleven.' Results are presented as score obtained (range 0 to 5, with 0 indicating the greatest impairment). | Baseline & 18 months | 
| Number of Participants Experiencing Study Product-related Non-serious Adverse Events (Non-SAEs), by System Organ Class |  | Throughout the study period, approximately 4 years | 
| Number of Participants Experiencing Study Product-related Serious Adverse Events (SAEs), by System Organ Class |  | Throughout the study period, approximately 4 years | 
| Number of Participants Experiencing Any Non-serious Adverse Events (Non-SAEs), by System Organ Class | Related and unrelated non-SAEs | Throughout the study period, approximately 4 years | 
| Number of Participants Experiencing Any Serious Adverse Events (SAEs), by System Organ Class | Related and unrelated SAEs | Throughout the study period, approximately 4 years | 
| Number of Infusions Temporally Associated With Non-serious Adverse Events (Non-SAEs) and/or Serious Adverse Events (SAEs) | Refers to non-SAEs and/or SAEs occurring during infusion or within 72 hours of completion of infusion (regardless of causality) | During or within 72 hours of completion of an infusion | 
| Number of Infusions With Causally Associated Non-serious Adverse Events (Non-SAEs) and/or Serious Adverse Events (SAEs) | Each adverse event (AE) that was considered related to investigational product (IP) was linked to the most recent infusion administered | Throughout the study period, approximately 4 years | 
| Number of Infusions Discontinued, Slowed, or Interrupted Due to an Adverse Event (AE) |  | Throughout each infusion period | 
| Number of Participants Experiencing a Clinically Significant Decrease in Hemoglobin (>1.5 g/dL) Between Consecutive Visits |  | Throughout the study period, approximately 4 years | 
| Number of Participants Experiencing a Clinically Significant Rash | Participants requiring systemic therapy or discontinuation from further treatment | Throughout the study period, approximately 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer´s, Dementia, Dementia of Alzheimer Type, Immunoglobulins, Gammaglobulins, Immune Globulin Intravenous (IGIV), Intravenous Immune Globulin (IVIG), Antibodies, Amyloid, Immunotherapy