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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Placebo every 2 weeks | Placebo Comparator | Participants received placebo intravenously every 2 weeks for 24 weeks (total of 12 infusions). |
|
| 0.1 g/kg octagam 10% every 2 weeks | Experimental | Participants received 0.1 g/kg octagam 10% intravenously every 2 weeks for 24 weeks (total of 12 infusions). |
|
| 0.25 g/kg octagam 10% every 2 weeks | Experimental | Participants received 0.25 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). |
|
| 0.4 g/kg octagam 10% every 2 weeks | Experimental | Participants received of 0.4 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). |
|
| Placebo every 4 weeks | Placebo Comparator | Participants received placebo intravenously every 4 weeks for 20 weeks (total of 6 infusions). |
|
| 0.2 g/kg octagam 10% every 4 weeks |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Placebo | Drug | Commercially available 0.9% isotonic sodium chloride solution. |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Wolfgang Frenzel, MD | Octapharma Pharmazeutika Produktionsges.m.b.H., Vienna, Austria | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Octapharma USA | Hoboken | New Jersey | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 23375965 | Derived | Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K, Forster S, Winter Y, Bach JP, Popp J, Alferink J, Wiltfang J, Buerger K, Otto M, Antuono P, Jacoby M, Richter R, Stevens J, Melamed I, Goldstein J, Haag S, Wietek S, Farlow M, Jessen F. Intravenous immunoglobulin for treatment of mild-to-moderate Alzheimer's disease: a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial. Lancet Neurol. 2013 Mar;12(3):233-43. doi: 10.1016/S1474-4422(13)70014-0. Epub 2013 Jan 31. |
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Qualified patients meeting all inclusion exclusion criteria and providing informed consent were enrolled into the trial.
The first patient was enrolled February 2, 2009. The last patient study visit was September 21, 2010. Patients were enrolled in this study from a variety of settings including private practice clinics and hospitals. There were 12 study sites, 5 in Germany and 7 in the United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo Every 2 Weeks | Participants received placebo intravenously every 2 weeks for 24 weeks (total of 12 infusions). |
| FG001 | 0.1 g/kg Octagam 10% Every 2 Weeks | Participants received 0.1 g/kg octagam 10% intravenously every 2 weeks for 24 weeks (total of 12 infusions). |
| FG002 | 0.25 g/kg Octagam 10% Every 2 Weeks | Participants received 0.25 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). |
| FG003 | 0.4 g/kg Octagam 10% Every 2 Weeks | Participants received of 0.4 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). |
| FG004 | Placebo Every 4 Weeks | Participants received placebo intravenously every 4 weeks for 20 weeks (total of 6 infusions). |
| FG005 | 0.2 g/kg Octagam 10% Every 4 Weeks | Participants received 0.2 g/kg octagam 10% intravenously every 4 weeks for 20 weeks (total of 6 infusions). |
| FG006 | 0.5 g/kg Octagam 10% Every 4 Weeks | Participants received 0.5 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). |
| FG007 | 0.8 g/kg Octagam 10% Every 4 Weeks | Participants received of 0.8 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Full analysis set: All randomized patients who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo Every 2 Weeks | Participants received placebo intravenously every 2 weeks for 24 weeks (total of 12 infusions). |
| BG001 | 0.1 g/kg Octagam 10% Every 2 Weeks | Participants received 0.1 g/kg octagam 10% intravenously every 2 weeks for 24 weeks (total of 12 infusions). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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). | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | (pg/mL)*days | 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 |
|
Adverse events were monitored throughout the entire study period, starting from the baseline visit until the final study visit.
Safety set: All randomized participants who received at least 1 infusion of study medication.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Placebo Every 2 Weeks | Participants received placebo intravenously every 2 weeks for 24 weeks (total of 12 infusions). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastral antral vascular ectasia | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | MedDRA 12.0 | Systematic Assessment |
Small numbers of patients per treatment group (between 5 and 8) and variable total Aβ levels over time.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Michael Eppolito, Director, Clinical Operations Immunology and ICU Medicine | Octapharma USA | 201-604-1155 | michael.eppolito@octapharma.com |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D016756 | Immunoglobulins, Intravenous |
| ID | Term |
|---|---|
| D007074 | Immunoglobulin G |
| D007132 | Immunoglobulin Isotypes |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| Experimental |
Participants received 0.2 g/kg octagam 10% intravenously every 4 weeks for 20 weeks (total of 6 infusions). |
|
| 0.5 g/kg octagam 10% every 4 weeks | Experimental | Participants received 0.5 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). |
|
| 0.8 g/kg octagam 10% every 4 weeks | Experimental | Participants received of 0.8 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). |
|
| octagam 10% | Biological | octagam 10% was supplied as ready-to-use solutions of human immunoglobulin. |
|
|
| 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 |
| Adverse Event |
|
| Did Not Come to Study Visit |
|
| Withdrawal of Consent |
|
| Reason Not Specified |
|
| BG002 | 0.25 g/kg Octagam 10% Every 2 Weeks | Participants received 0.25 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). |
| BG003 | 0.4 g/kg Octagam 10% Every 2 Weeks | Participants received of 0.4 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). |
| BG004 | Placebo Every 4 Weeks | Participants received placebo intravenously every 4 weeks for 20 weeks (total of 6 infusions). |
| BG005 | 0.2 g/kg Octagam 10% Every 4 Weeks | Participants received 0.2 g/kg octagam 10% intravenously every 4 weeks for 20 weeks (total of 6 infusions). |
| BG006 | 0.5 g/kg Octagam 10% Every 4 Weeks | Participants received 0.5 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). |
| BG007 | 0.8 g/kg Octagam 10% Every 4 Weeks | Participants received of 0.8 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). |
| BG008 | Total | Total of all reporting groups |
| Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| OG000 | Placebo Every 2 Weeks | Participants received placebo intravenously every 2 weeks for 24 weeks (total of 12 infusions). |
| OG001 | 0.1 g/kg Octagam 10% Every 2 Weeks | Participants received 0.1 g/kg octagam 10% intravenously every 2 weeks for 24 weeks (total of 12 infusions). |
| OG002 | 0.25 g/kg Octagam 10% Every 2 Weeks | Participants received 0.25 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). |
| OG003 | 0.4 g/kg Octagam 10% Every 2 Weeks | Participants received of 0.4 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). |
| OG004 | Placebo Every 4 Weeks | Participants received placebo intravenously every 4 weeks for 20 weeks (total of 6 infusions). |
| OG005 | 0.2 g/kg Octagam 10% Every 4 Weeks | Participants received 0.2 g/kg octagam 10% intravenously every 4 weeks for 20 weeks (total of 6 infusions). |
| OG006 | 0.5 g/kg Octagam 10% Every 4 Weeks | Participants received 0.5 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). |
| OG007 | 0.8 g/kg Octagam 10% Every 4 Weeks | Participants received of 0.8 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). |
|
|
| Secondary | 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). | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | pg/mL | Baseline to Week 24 |
|
|
|
| Secondary | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | RTU | Baseline to Week 24 |
|
|
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| Secondary | 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). | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | (pg/mL)*days | 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 | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | RTU*days | 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 | 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). | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | pg/mL | 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 |
|
|
|
| Secondary | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | RTU | 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 |
|
|
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| Secondary | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | pg/mL | 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 |
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| Secondary | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | Units on a scale | Baseline to Week 24 |
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| Secondary | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | Units on a scale | Baseline to Week 24 |
|
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| Secondary | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | Units on a scale | Baseline to Week 24 |
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|
| Secondary | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | Units on a scale | Baseline to Week 24 |
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|
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| Secondary | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | cm^3 | Screening to Week 24 |
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| Secondary | 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. | Full analysis set: All randomized participants who received at least 1 infusion of the study medication and had at least 1 post-baseline efficacy assessment. Only participants with available data were included in the analysis. | Posted | Mean | Standard Deviation | µCi/mL | Baseline to Week 24 |
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|
|
| 2 |
| 7 |
| 5 |
| 7 |
| EG001 | 0.1 g/kg Octagam 10% Every 2 Weeks | Participants received 0.1 g/kg octagam 10% intravenously every 2 weeks for 24 weeks (total of 12 infusions). | 1 | 6 | 4 | 6 |
| EG002 | 0.25 g/kg Octagam 10% Every 2 Weeks | Participants received 0.25 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). | 0 | 7 | 5 | 7 |
| EG003 | 0.4 g/kg Octagam 10% Every 2 Weeks | Participants received of 0.4 g/kg octagam 10% every 2 weeks for 24 weeks (total of 12 infusions). | 2 | 7 | 3 | 7 |
| EG004 | Placebo Every 4 Weeks | Participants received placebo intravenously every 4 weeks for 20 weeks (total of 6 infusions). | 2 | 7 | 3 | 7 |
| EG005 | 0.2 g/kg Octagam 10% Every 4 Weeks | Participants received 0.2 g/kg octagam 10% intravenously every 4 weeks for 20 weeks (total of 6 infusions). | 0 | 7 | 4 | 7 |
| EG006 | 0.5 g/kg Octagam 10% Every 4 Weeks | Participants received 0.5 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). | 1 | 8 | 4 | 8 |
| EG007 | 0.8 g/kg Octagam 10% Every 4 Weeks | Participants received of 0.8 g/kg octagam 10% every 4 weeks for 20 weeks (total of 6 infusions). | 0 | 7 | 4 | 7 |
| Nausea | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
|
| Knee arthroplasty | Surgical and medical procedures | MedDRA 12.0 | Systematic Assessment |
|
| Spinal laminectomy | Surgical and medical procedures | MedDRA 12.0 | Systematic Assessment |
|
| Cerebral infarction | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
|
| Delirium | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
|
| Convulsion | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
|
| Dementia Alzheimer's Type | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
|
| Aggression | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
|
| Iron deficiency anemia | Blood and lymphatic system disorders | MedDRA 12.0 | Systematic Assessment |
|
| Lymphadenopathy | Blood and lymphatic system disorders | MedDRA 12.0 | Systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | MedDRA 12.0 | Systematic Assessment |
|
| Hearing impaired | Ear and labyrinth disorders | MedDRA 12.0 | Systematic Assessment |
|
| Glaucoma | Eye disorders | MedDRA 12.0 | Systematic Assessment |
|
| Colitis microscopic | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
|
| Colonic polyp | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
|
| Gastrointestinal pain | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
|
| Hiatus hernia | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 12.0 | Systematic Assessment |
|
| Chills | General disorders | MedDRA 12.0 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 12.0 | Systematic Assessment |
|
| Influenza like illness | General disorders | MedDRA 12.0 | Systematic Assessment |
|
| Infusion site extravasation | General disorders | MedDRA 12.0 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 12.0 | Systematic Assessment |
|
| Submandibular mass | General disorders | MedDRA 12.0 | Systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA 12.0 | Systematic Assessment |
|
| Gastroenteritis | Infections and infestations | MedDRA 12.0 | Systematic Assessment |
|
| Tooth abscess | Infections and infestations | MedDRA 12.0 | Systematic Assessment |
|
| Tooth infection | Infections and infestations | MedDRA 12.0 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 12.0 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 12.0 | Systematic Assessment |
|
| Anxiety postoperative | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Periorbital haematoma | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Post lumbar puncture syndrome | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Post procedural constipation | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Post procedural haemorrhage | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Procedural headache | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Procedural hypertension | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Procedural pain | Injury, poisoning and procedural complications | MedDRA 12.0 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 12.0 | Systematic Assessment |
|
| Blood creatine phosphokinase increased | Investigations | MedDRA 12.0 | Systematic Assessment |
|
| Blood iron decreased | Investigations | MedDRA 12.0 | Systematic Assessment |
|
| Blood lactate dehydrogenase increased | Investigations | MedDRA 12.0 | Systematic Assessment |
|
| Blood magnesium decreased | Investigations | MedDRA 12.0 | Systematic Assessment |
|
| Blood potassium decreased | Investigations | MedDRA 12.0 | Systematic Assessment |
|
| Blood pressure decreased | Investigations | MedDRA 12.0 | Systematic Assessment |
|
| CSF white blood cell count positive | Investigations | MedDRA 12.0 | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA 12.0 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 12.0 | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 12.0 | Systematic Assessment |
|
| Rotator cuff syndrome | Musculoskeletal and connective tissue disorders | MedDRA 12.0 | Systematic Assessment |
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| Cerebral haemorrhage | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
|
| Essential tremor | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
|
| Hypertonia | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
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| Hyporeflexia | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
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| Paraesthesia | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
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| Tremor | Nervous system disorders | MedDRA 12.0 | Systematic Assessment |
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| Agitation | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
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| Confusional state | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
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| Depression | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 12.0 | Systematic Assessment |
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| Haematuria | Renal and urinary disorders | MedDRA 12.0 | Systematic Assessment |
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| Respiratory tract congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 12.0 | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA 12.0 | Systematic Assessment |
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| Actinic keratosis | Skin and subcutaneous tissue disorders | MedDRA 12.0 | Systematic Assessment |
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| Dermatitis contact | Skin and subcutaneous tissue disorders | MedDRA 12.0 | Systematic Assessment |
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| Ecchymosis | Skin and subcutaneous tissue disorders | MedDRA 12.0 | Systematic Assessment |
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| Hyperkeratosis | Skin and subcutaneous tissue disorders | MedDRA 12.0 | Systematic Assessment |
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| Pruritis | Skin and subcutaneous tissue disorders | MedDRA 12.0 | Systematic Assessment |
|
| Blood pressure fluctuation | Vascular disorders | MedDRA 12.0 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 12.0 | Systematic Assessment |
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| Hypotension | Vascular disorders | MedDRA 12.0 | Systematic Assessment |
|
| Vasoconstriction | Vascular disorders | MedDRA 12.0 | Systematic Assessment |
|
Not provided
Not provided
| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| Aβ1-42 |
|
| Aβ1-42 |
|
| Phosphorylated tau |
|
| Week 24 (n=7,6,7,6,6,6,8,6) |
|
| Week 24 (n=7,6,7,6,5,6,8,6) |
|
| Week 24 (n=7,6,7,6,5,6,8,6) |
|
| Week 24 (n=7,6,7,6,5,6,8,6) |
|
| Left hippocampus - Week 12 (n=5,6,7,5,7,6,7,7) |
|
| Right hippocampus - Week 12 (n=5,6,7,5,7,6,7,7) |
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| Whole brain - Week 24 (n=4,5,6,5,4,6,8,6) |
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| Left hippocampus - Week 24 (n=4,6,6,5,5,6,8,6) |
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| Right hippocampus - Week 24 (n=4,6,6,5,5,6,8,6) |
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| Right hippocampus - Week 24 (n=6,6,6,5,3,6,8,6) |
|
| Left hippocampus - Baseline |
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| Left hippocampus - Week 24 (n=6,6,6,5,3,6,8,6) |
|