Study of Octagam (Intravenous Immunoglobulin [IVIG]) 10% on the Treatment of Mild to Moderate Alzheimer's Disease

Study Overview
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Brief Summary
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This study evaluated the effect of 6 or 12 infusions of different doses of octagam (intravenous immunoglobulin [IVIG]) 10% on the reduction of amyloid beta peptide (Aβ) in cerebral spinal fluid (CSF) and on the increase of Aβ in blood plasma in patients with mild to moderate Alzheimer's disease.

Detailed Description
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Participants received 12 infusions of 0.1 g/kg, 0.25 g/kg, or 0.4 g/kg body weight octagam 10% at 2-week intervals (±3 days) or 6 infusions of 0.2 g/kg, 0.5 g/kg, or 0.8 g/kg body weight octagam 10% at 4-week intervals (±5 days). The effect of the infusions on the reduction of Aβ peptide in CSF and the increase of Aβ peptide in blood plasma was evaluated.

Official Title
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Prospective 24-week, Double-blind, Randomised, Placebo-controlled, Multicenter Study Evaluating Safety and Change in Efficacy-related Surrogate Parameters in Patients With Dementia of the Alzheimer's Type Under Treatment With Increasing Dosages of Intravenous Immunoglobulin (Octagam 10%)

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Placebo
* Biological: octagam 10%


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Probable Alzheimer's Disease (AD) according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Age of 50 to 85. Mini-mental State Examination (MMSE) score of 16 to 26. Sufficient language skills for testing. Sufficient vision and hearing for testing. Modified Hachinski-Rosen Score < 5. Magnetic resonance imaging (MRI) of the head consistent with the diagnosis of AD. Caregiver available with contact at least 4 days per week for greater than 1 hour. Outpatient status or assisted living. Post-menopause (women) as evidenced by lack of menstruation for at least 12 consecutive months or by having bilateral oophorectomy. Stable doses of approved AD medication(s) for at least 3 months prior to screening (eg, acetylcholine esterase (AChE) inhibitors, memantine). Normal vital signs or clinically insignificant, if outside normal limits. Laboratory findings within normal limits or clinically insignificant, if outside normal limits. Normal electrocardiogram (ECG) or clinically not significant, if outside normal limits. Exclusion Criteria: Other causes of dementia (eg, vascular dementia, Lewy-body dementia, fronto-temporal dementia, Creutzfeldt-Jacob disease, Huntington's disease, Parkinson's disease). History of or present significant other diseases of the central nervous system (eg, brain tumor, normal pressure hydrocephalus, Parkinson's Disease, stroke, severe brain trauma, brain surgery, epilepsy, encephalitis). Geriatric depression scale score > 7 (short form with scale from 0 to 15). Present significant psychiatric disorder (eg, major depression). History of psychosis or hallucinations. Mental retardation. Unstable medical disease in the opinion of the investigator. Insulin dependent diabetes mellitus. Acute infectious disease. Vitamin B12 deficiency unless on stable replacement therapy for at least 3 months is acceptable. Unstable thyroid dysfunction. Uncontrolled hypertension. Severe liver or kidney disease. Major surgery within 3 months prior to screening. Prohibited medications: Antiepileptic drugs, antipsychotics (but allowed for treatment of acute episodes), antiparkinson agents, anticholinergic drugs, selegiline, monoamine oxidase inhibitors (MAOI), tricyclics, immunosuppressive medications, anti-histamines (unless on a stable dose for at least 3 months or used for treatment of acute episodes), benzodiazepines (but allowed for treatment of acute episodes), and lithium. Antidepressants are permitted, if on a stable dose for at least 3 months and without significant anticholinergic side-effects. Peripheral venous conditions which impair establishing regular venous access for infusions. Potential reasons that patient may become non-evaluable during the study (eg, planned moving into a nursing home, but assisted living is acceptable). Peripheral venous conditions, which impair establishing regular venous access for infusions. Known IgA deficiency with antibodies to IgA. History of hypersensitivity to blood or plasma derived products, or any component of octagam 10%, such as maltose. Medical conditions which interfere with protein catabolism (eg, nephrotic syndrome). Known blood hyperviscosity or other hypercoagulable states. Deep vein thrombosis within preceding 4 years. Symptomatic stroke. Transient ischemic attack (TIA) within preceding 2 years. Participation in another drug trial within the previous 3 months before screening. Participation in immunological treatment studies of AD other than with intravenous immunoglobulin (IGIV) within the previous 6 months before screening. IGIV use in the previous 6 months. Live viral vaccination within the last month before study entry. Not eligible for lumbar puncture (anticoagulant therapy, coagulation disorders, severe spinal alterations). Patients with a past or present history of drug abuse or alcohol abuse within the preceding 5 years. Patients with any condition that would make the patient, in the opinion of the Investigator, unsuitable for the study.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo every 2 weeks<br>Participants received placebo intravenously every 2 weeks for 24 weeks (total of 12 infusions). | Drug: Placebo<br>* Commercially available 0.9% isotonic sodium chloride solution.<br>|
| Experimental: 0.1 g/kg octagam 10% every 2 weeks<br>Participants received 0.1 g/kg octagam 10% intravenously every 2 weeks for 24 weeks (total of 12 infusions). | Biological: octagam 10%<br>* octagam 10% was supplied as ready-to-use solutions of human immunoglobulin.<br>* Other names: IVIG;|
| Experimental: 0.25 g/kg octagam 10% every 2 weeks<br>Participants received 0.25 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). | Biological: octagam 10%<br>* octagam 10% was supplied as ready-to-use solutions of human immunoglobulin.<br>* Other names: IVIG;|
| Experimental: 0.4 g/kg octagam 10% every 2 weeks<br>Participants received of 0.4 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). | Biological: octagam 10%<br>* octagam 10% was supplied as ready-to-use solutions of human immunoglobulin.<br>* Other names: IVIG;|
| Placebo Comparator: Placebo every 4 weeks<br>Participants received placebo intravenously every 4 weeks for 20 weeks (total of 6 infusions). | Drug: Placebo<br>* Commercially available 0.9% isotonic sodium chloride solution.<br>|
| Experimental: 0.2 g/kg octagam 10% every 4 weeks<br>Participants received 0.2 g/kg octagam 10% intravenously every 4 weeks for 20 weeks (total of 6 infusions). | Biological: octagam 10%<br>* octagam 10% was supplied as ready-to-use solutions of human immunoglobulin.<br>* Other names: IVIG;|
| Experimental: 0.5 g/kg octagam 10% every 4 weeks<br>Participants received 0.5 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). | Biological: octagam 10%<br>* octagam 10% was supplied as ready-to-use solutions of human immunoglobulin.<br>* Other names: IVIG;|
| Experimental: 0.8 g/kg octagam 10% every 4 weeks<br>Participants received of 0.8 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). | Biological: octagam 10%<br>* octagam 10% was supplied as ready-to-use solutions of human immunoglobulin.<br>* Other names: IVIG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the Area Under the Curve of Plasma Aβ1-40 in the 2 or 4 Weeks After the Last Treatment Infusion From the Trough Level Prior to the Last Treatment Infusion | For participants who received infusions every 2 weeks, plasma samples were collected at the trough level at Week 22 and on Days 1, 4, 7, and 14 after Week 22. For participants who received infusions every 4 weeks, plasma samples were collected at the trough level at Week 20 and on Days 1, 4, 7, 14, 21, and 28 after Week 20. Samples for determining Aβ1-40 in blood plasma were processed at a central laboratory using a commercially available kit from Innogenetics NV (INNO-BIA plasma Aβ forms; Gent, Belgium). | Week 22 to Week 24 for participants who received infusions every 2 weeks and Week 20 to Week 24 participants who received infusions every 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Plasma Concentration of Aβ1-40 and Aβ1-42 From Baseline to the End of the Study (Week 24) | Samples for determining Aβ1-40 and Aβ1-42 in blood plasma were processed at a central laboratory using a commercially available kit from Innogenetics NV (INNO-BIA plasma Aβ forms; Gent, Belgium). | Baseline to Week 24 | 
| Change in Plasma Concentration of Anti-Aβ Autoantibodies From Baseline to the End of the Study (Week 24) | Samples for determining anti-Aβ autoantibodies in blood plasma were processed at a central laboratory using a commercially available kit from DRG Instruments GmbH, (EIA-5099; Marburg, Germany) using methods established at the Department of Neurology, Philipps-University, Marburg, Germany (Professor Dr. med. Richard Dodel). The kit includes 6 standard concentrations of anti-Aβ antibody against which the results of the assay are compared. The standards contain 1, 5, 15, 30, 60, and 120 Relative Units (RTU) which contain 0.03, 0.17, 0.5, 1, 2, and 4 mg IgG/mL, respectively. | Baseline to Week 24 | 
| Change in the Area Under the Curve of Plasma Aβ1-42 in the 2 or 4 Weeks After the Last Treatment Infusion From the Trough Level Prior to the Last Treatment Infusion | For participants who received infusions every 2 weeks, plasma samples were collected at the trough level at Week 22 and on Days 1, 4, 7, and 14 after Week 22. For participants who received infusions every 4 weeks, plasma samples were collected at the trough level at Week 20 and on Days 1, 4, 7, 14, 21, and 28 after Week 20. Samples for determining Aβ1-42 in blood plasma were processed at a central laboratory using a commercially available kit from Innogenetics NV (INNO-BIA plasma Aβ forms; Gent, Belgium). | Week 22 to Week 24 for participants who received infusions every 2 weeks and Week 20 to Week 24 participants who received infusions every 4 weeks | 
| Change in the Area Under the Curve of Plasma Anti-Aβ Autoantibodies in the 2 or 4 Weeks After the Last Treatment Infusion From the Trough Level Prior to the Last Treatment Infusion | For participants who received infusions every 2 weeks, plasma samples were collected at the trough level at Week 22 and on Days 1, 4, 7, and 14 after Week 22. For participants who received infusions every 4 weeks, plasma samples were collected at the trough level at Week 20 and on Days 1, 4, 7, 14, 21, and 28 after Week 20. Samples for determining anti-Aβ autoantibodies in blood plasma were processed at a central laboratory using a commercially available kit from DRG Instruments GmbH, (EIA-5099; Marburg, Germany) using methods established at the Department of Neurology, Philipps-University, Marburg, Germany (Professor Dr. med. Richard Dodel). The kit includes 6 standard concentrations of anti-Aβ antibody against which the results of the assay are compared. The standards contain 1, 5, 15, 30, 60, and 120 Relative Units (RTU) which contain 0.03, 0.17, 0.5, 1, 2, and 4 mg IgG/mL, respectively. | Week 22 to Week 24 for participants who received infusions every 2 weeks and Week 20 to Week 24 participants who received infusions every 4 weeks | 
| Change From Baseline in Aβ1-40 and Aβ1-42 in Cerebral Spinal Fluid 24-48 Hours After the Last Infusion | Samples for determining Aβ1-40 and Aβ1-42 in cerebral spinal fluid were processed at a central laboratory using a commercially available kit from Meso Scale Discovery (MSD 96-Well Multi-Spot Human/Rodent (4G8) Abeta Triplex Ultra-Sensitive Assay; Rockville, MD, USA). | Baseline to Week 23 Day 2 for participants who received infusions every 2 weeks and Baseline to Week 21 Day 2 for participants who received infusions every 4 weeks | 
| Change From Baseline in Anti-Aβ Autoantibodies in Cerebral Spinal Fluid 24-48 Hours After the Last Infusion | Samples for determining anti-Aβ autoantibodies in blood plasma were processed at a central laboratory using a commercially available kit from DRG Instruments GmbH, (EIA-5099; Marburg, Germany) using methods established at the Department of Neurology, Philipps-University, Marburg, Germany (Professor Dr. med. Richard Dodel). The kit includes 6 standard concentrations of anti-Aβ antibody against which the results of the assay are compared. The standards contain 1, 5, 15, 30, 60, and 120 Relative Units (RTU) which contain 0.03, 0.17, 0.5, 1, 2, and 4 mg IgG/mL, respectively. | Baseline to Week 23 Day 2 for participants who received infusions every 2 weeks and Baseline to Week 21 Day 2 for participants who received infusions every 4 weeks | 
| Change From Baseline in Tau and Phosphorylated Tau in Cerebral Spinal Fluid 24-48 Hours After the Last Infusion | Samples for determining tau and phosphorylated tau in cerebral spinal fluid were processed at a central laboratory using commercially available kits from Innogenetics NV (INNOTEST® hTau Ag, INNOTEST PHOSPHO-TAU (181P); Gent, Belgium). To measure phosphorylated tau, tau phosphorylated at threonine 181 (pTau181) was determined. | Baseline to Week 23 Day 2 for participants who received infusions every 2 weeks and Baseline to Week 21 Day 2 for participants who received infusions every 4 weeks | 
| Change From Baseline in the Mini Mental Status Examination (MMSE) Score at Week 12 and Week 24 | The MMSE test contains 30 questions that assess 8 cognitive domains (orientation to time, orientation to place, registration, attention and calculation, recall, language, repetition, and complex commands). The test is administered by a neuropsychologist, psychometrician, or certified study coordinator. The total score ranges from 0 (severe impairment) to 30 (no impairment), with a higher score indicating a better mental status. A positive change score indicates improvement. | Baseline to Week 24 | 
| Change From Baseline in the Alzheimer's Disease Assessment Scale, Cognitive Part (ADAS Cog) Score at Week 12 and Week 24 | The ADAS cog consists of 11 items that assess cognitive areas that are often impaired in Alzheimer's disease, specifically learning (word list), naming (objects), following commands (1 to 5 elements), ideational praxis (mail a letter), constructional praxis (copy 4 figures), orientation (person, time and place), recognition memory (from a second word list), and remembering test instructions (from the recognition subtest). The test includes 3 additional subjective scales that assess spoken language ability, word finding difficulty, and comprehension. The test is administered by a neuropsychologist, psychometrician, or certified study coordinator. The total score ranges from 0 to 70 with a higher score indicating greater cognitive impairment. A negative change score indicates improvement. | Baseline to Week 24 | 
| Change From Baseline in the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADAS-ADL) Score at Week 12 and Week 24 | The ADAS-ADL consists of 23 questions that measure the ability of a person to perform basic activities of daily living, such as eating, walking, bathing, grooming, and dressing. The test is administered by a neuropsychologist, psychometrician, or certified study coordinator. The total score ranges from 0 to 78 with a lower score indicating more impaired ability. A positive change score indicates improvement. | Baseline to Week 24 | 
| Change From Baseline in the Clinical Dementia Ratio, Sum of Boxes (CDR-SOB) Score at Week 12 and Week 24 | A semi-structured interview was conducted by a physician, neuropsychologist, psychometrician, or certified study coordinator with the patient and a caregiver. Based on the results of the interview, the patient was rated on 6 domains of cognition and function: Memory, orientation, judgment/problem solving, community activities, home and hobbies, and personal care. Each domain is rated from 0 = no dementia; 0.5 = questionable dementia, mild cognitive impairment; 1 = mild dementia; 2 = moderate dementia; 3 = severe dementia. The total score ranges from 0 to 18 with a higher score indicating more dementia. A negative change score indicates improvement. | Baseline to Week 24 | 
| Change From Screening in Whole Brain and Hippocampal Volume at Week 12 and Week 24 | The volume of the whole brain and of the left and right hippocampus was measured using high-resolution structural coronal 3D heavily T1-weighted gradient-echo sequence magnetic resonance imaging. All evaluations were done centrally by Professor Frederik Barkhof at the Image Analysis Centre, VU Medical Center, Amsterdam, Netherlands. A negative change score indicates loss of brain volume. | Screening to Week 24 | 
| Left and Right Hippocampal Cerebral Glucose Metabolism at Baseline and at Week 24 | Cerebral glucose metabolism was measured in validated 3 dimensional statistic surface projection analysis (Cortex ID®, GE Healthcare), transversal/coronal/sagittal-slice analysis (HERMES BRASS), and voxel-wise whole brain analysis (SPM5) using [18F]fluorodeoxyglucose positron emission tomography. | Baseline to Week 24 |