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| Name | Class |
|---|---|
| Merck Serono S.P.A., Italy | INDUSTRY |
This was a 52-week, multicentric, phase II, pilot study conducted in 40 subjects with early-onset Alzheimer's disease (AD) to evaluate safety, tolerability and clinical efficacy of subcutaneous (sc) interferon (IFN) beta-1a [Rebif® 22 microgram (mcg), three times per week (tiw)] in the treatment of AD by comparing the neuropsychological performance changes into placebo and treatment arms from screening/baseline to 52 week.
Alzheimer's disease is characterized by progressive cognitive impairment resulting from neuronal loss. The primary pathological feature of the disease is the extracellular deposition of fibrillary amyloid and its compaction into senile plaques. The senile plaque is the focus of a complex cellular reaction involving the activation of both microglia and astrocytes adjacent to the amyloid plaque. In fact, microglias are the most abundant and prominent cellular components associated with these plaques. Plaque-associated microglia exhibits a reactive or activated phenotype. Through the acquisition of a reactive phenotype, microglia responds to various stimuli, as is evident by the increased expression of numerous cell-surface molecules, including major histocompatibility complex (MHC) class-II antigens and complement receptors.
Traditionally, multiple sclerosis (MS) has been considered a "demyelinating" disease. Recent immunocytochemical studies suggest that MS may be more than a demyelinating disorder, and that even in early stages of the disease, MS pathological scenario envisages axonal damage. Interferons, the modern therapeutic strategies for the treatment of MS, are cytokines - proteins which lead to a network of signals within different cells. In the immune system, IFNs act at different levels. For example, IFNs increase the expression of MHC class II antigens and, thereby, facilitate the antigen-presenting process and the activation of lymphocytes. T-lymphocytes are important targets of IFN immunomodulation. In MS, it is believed that IFN beta suppresses the production of proinflammatory cytokines such as IFN-γ and TNF-α, and increases the production of immunosuppressive cytokines such as interleukin-4 (IL-4) and IL-10. Since the activation of microglia and astrocytes is common to both AD and MS, IFN beta could have therapeutic applications in the treatment of AD. Furthermore, recent studies have also found that through astrocyte production, IFNs promote the activation of nerve-growth factor.
OBJECTIVES
In this study, subjects were randomized into two groups: the first group (treatment arm, n=20) received Rebif® 22 mcg tiw; the second group (placebo arm, n=20) received placebo. The treatment period was for 28 weeks and subjects were followed up to Week 52. Efficacy was determined by comparing neuropsychological performance changes into placebo and treatment arms from screening/baseline to Week 52.
On Day 1 of the study treatment period, subjects received injection training and were administered the first dose of Rebif under the supervision of the clinical personnel by subcutaneous injection tiw at approximately the same time each day preferably in the late afternoon or evening. All subjects received 28 weeks of therapy and after 24 weeks from the therapy conclusion, a termination visit was conducted.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment arm - Rebif® | Experimental | Subjets in this arm received interferon beta-1a (Rebif® 22 mcg tiw) |
|
| Placebo arm | Placebo Comparator | Subjects in this arm received placebo |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Interferon beta-1a | Drug | Interferon (IFN) beta-1a [Rebif® 22 microgram (mcg), three times per week (tiw)] administered subcutaneously (sc) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score | ADAS: global rating scale created to evaluate both cognitive and functional aspects linked with disease progression. ADAS-Cog: subscale of ADAS which consists in a series of short tests aimed to evaluate possible cognitive impairment due to disease progression. It includes 11 items, testing word-finding difficulty, following commands, naming: objects and fingers, orientation, word recognition, recall of test instructions, constructions, ideational praxis, spoken language ability, comprehension of spoken language and word recall. Scores range from 0 (no impairment) to 70 (serious deficit). | Baseline and Week 52 |
| Measure | Description | Time Frame |
|---|---|---|
| Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score | ADAS: global rating scale created to evaluate both cognitive and functional aspects linked with disease progression. ADAS-Cog: subscale of ADAS which consists in a series of short tests aimed to evaluate possible cognitive impairment due to disease progression. It includes 11 items, testing word-finding difficulty, following commands, naming: objects and fingers, orientation, word recognition, recall of test instructions, constructions, ideational praxis, spoken language ability, comprehension of spoken language and word recall. Scores range from 0 (no impairment) to 70 (serious deficit). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Andrea Paolillo, MD, PhD | Merck Serono S.P.A., Italy | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| U.VA. Neurologia - Azienda Ospedaliera Garibaldi Nesina | Catania | CT | 95122 | Italy |
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| ID | Title | Description |
|---|---|---|
| FG000 | Rebif 22 Mcg | Single dose of interferon beta-1a (Rebif) injection administered subcutaneously (sc) three times per week (tiw) at a dose of 4.4 microgram (mcg) for first 2 weeks followed by 11 mcg for next 2 weeks and finally 22 mcg for remaining 24 weeks (treatment period 28 weeks). |
| FG001 | Placebo | Single dose of matching placebo injection administered sc tiw at a dose of 4.4 mcg for first 2 weeks followed by 11 mcg for next 2 weeks and finally 22 mcg for remaining 24 weeks (treatment period of 28 weeks). |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Rebif 22 Mcg | Single dose of interferon beta-1a (Rebif) injection administered subcutaneously (sc) three times per week (tiw) at a dose of 4.4 microgram (mcg) for first 2 weeks followed by 11 mcg for next 2 weeks and finally 22 mcg for remaining 24 weeks (treatment period 28 weeks). |
| BG001 |
| 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 | Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score | ADAS: global rating scale created to evaluate both cognitive and functional aspects linked with disease progression. ADAS-Cog: subscale of ADAS which consists in a series of short tests aimed to evaluate possible cognitive impairment due to disease progression. It includes 11 items, testing word-finding difficulty, following commands, naming: objects and fingers, orientation, word recognition, recall of test instructions, constructions, ideational praxis, spoken language ability, comprehension of spoken language and word recall. Scores range from 0 (no impairment) to 70 (serious deficit). | Per protocol population included all participants who received treatments as scheduled and were followed up to week 52. | Posted | Mean | Standard Deviation | units on a scale | Baseline and Week 52 |
|
Baseline to Week 52
An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.
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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 | Rebif 22 Mcg | Single dose of interferon beta-1a (Rebif) injection administered subcutaneously (sc) three times per week (tiw) at a dose of 4.4 microgram (mcg) for first 2 weeks followed by 11 mcg for next 2 weeks and finally 22 mcg for remaining 24 weeks (treatment period 28 weeks). |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Articular Pain | Musculoskeletal and connective tissue disorders | MedDRA | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Merck KGaA Communication Center | Merck Serono, a division of Merck KGaA | +49-6151-72-5200 | service@merckgroup.com |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| D003704 | Dementia |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D024801 | Tauopathies |
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| ID | Term |
|---|---|
| D000068556 | Interferon beta-1a |
| ID | Term |
|---|---|
| D016899 | Interferon-beta |
| D007370 | Interferon Type I |
| D007372 | Interferons |
| D016207 | Cytokines |
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|
| Placebo | Drug | The inactive substance (placebo) looks the same as Interferon beta-1a (Rebif®), and is given the same way |
|
| Week 12 and 28 |
| Mini Mental Status Examination (MMSE) Score | MMSE is a tool for screening cognitive decline associated with dementia. It is a brief examination intended to evaluate an adult participant's level of cognitive functioning. The test is performed in following areas: orientation in time and place, learning and immediate recall, mental control and concentration, short-term recall, naming ability, language expression, verbal comprehension, writing comprehension, writing ability and visual-spatial coordination. Scores range between 0 (maximum cognitive deficit) and 30 (no cognitive deficit). | Baseline, Week 12, 28 and 52 |
| Alzheimer's Disease Assessment Scale, Non-cognitive Subscale (ADAS-NonCog) Score | ADAS-NonCog is a subscale of ADAS aimed to evaluate the non-cognitive features such as mood state and behavioral changes. It takes about 10 minutes to be performed and includes 10 items: testing tearful, depressed mood, concentration/distractibility, uncooperative to testing, delusions, hallucinations, pacing, motor activity increase, tremors and appetite change. Scores range between 0 (excellent performance) and 35 (worst performance). | Baseline, Week 12, 28 and 52 |
| Instrumental Activities of Daily Living (IADL) Score | IADL is used to evaluate participants with early-stage disease, both to assess level of disease and to determine participant's ability of self-care. IADL scale measures functional impact of emotional, cognitive, and physical impairments. It provides information about participants' compromising rate and care he might need. It includes 8 items: testing ability to use telephone, shopping, food preparation, housekeeping, laundry, mode of transportation, responsibility for own medication and ability to handle finances. Scores range between 0 (impairment) and 8 (full independence). | Baseline, Week 28 and 52 |
| Physical Self-Maintenance Scale (PSMS) Score | PSMS designed as a disability measure for use in planning and evaluating treatment in elderly participants living in community or in institutions, is Guttman scale containing 6 items of self-care. The scale is based on theory that human behavior can be ordered in a hierarchy of complexity, within each category, a further hierarchy of complexity runs from basic to complex activities. It includes 6 items, testing the following areas: toilet use, eating, dressing, physical appearance, deambulation and bath. Scores range between 0 (excellent performance) and 30 (worst performance). | Baseline, Week 28 and 52 |
| Clinician's Interview Based Impression of Change (CIBIC-PLUS) Score | CIBIC-PLUS: structured instrument based on comprehensive evaluation of 3 domains: participant cognition, behavior and functioning, including assessment of daily living activities. It includes 15 items and represents assessment of skilled clinician using validated scales based on the observation at interviews conducted separately with participant and caregiver familiar with behavior of participant. According to comparison between baseline and follow-up assessments, scores can range between 1 (markedly improved) and 7 (markedly worsened), with 4 indicating no change observed between two visits. | Week 28 and 52 |
| Geriatric Depression Scale (GDS) Score | The GDS consists of 30 'yes' or 'no' items aimed to assess depression. One point is assigned to each answer and the cumulative score is rated on a scoring grid. Scores are grouped as follows: 0-9 'normal', 10-19 'mildly depressed', and 20-30 'severely depressed'. | Baseline, Week 28 and 52 |
| Global Deterioration Scale Score | Global deterioration scale includes seven different diagnostic stages ranging between "no cognitive deterioration" and "very serious cognitive deterioration". It investigates the cognitive impairment. Scores range between 1 (no cognitive deterioration) and 7 (very severe cognitive decline). | Baseline, Week 28 and 52 |
| Withdrawal by Subject |
|
| Placebo |
Single dose of matching placebo injection administered sc tiw at a dose of 4.4 mcg for first 2 weeks followed by 11 mcg for next 2 weeks and finally 22 mcg for remaining 24 weeks (treatment period of 28 weeks). |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
Single dose of interferon beta-1a (Rebif®) injection administered subcutaneously (sc) three times per week (tiw) at a dose of 4.4 microgram (mcg) for first 2 weeks followed by 11 mcg for next 2 weeks and finally 22 mcg for remaining 24 weeks (treatment period 28 weeks).
| OG001 | Placebo | Single dose of matching placebo injection administered sc tiw at a dose of 4.4 mcg for first 2 weeks followed by 11 mcg for next 2 weeks and finally 22 mcg for remaining 24 weeks (treatment period of 28 weeks). |
|
|
|
| Secondary | Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score | ADAS: global rating scale created to evaluate both cognitive and functional aspects linked with disease progression. ADAS-Cog: subscale of ADAS which consists in a series of short tests aimed to evaluate possible cognitive impairment due to disease progression. It includes 11 items, testing word-finding difficulty, following commands, naming: objects and fingers, orientation, word recognition, recall of test instructions, constructions, ideational praxis, spoken language ability, comprehension of spoken language and word recall. Scores range from 0 (no impairment) to 70 (serious deficit). | Per protocol population included all participants who received treatments as scheduled and were followed up to week 52. | Posted | Mean | Standard Deviation | units on a scale | Week 12 and 28 |
|
|
|
|
| Secondary | Mini Mental Status Examination (MMSE) Score | MMSE is a tool for screening cognitive decline associated with dementia. It is a brief examination intended to evaluate an adult participant's level of cognitive functioning. The test is performed in following areas: orientation in time and place, learning and immediate recall, mental control and concentration, short-term recall, naming ability, language expression, verbal comprehension, writing comprehension, writing ability and visual-spatial coordination. Scores range between 0 (maximum cognitive deficit) and 30 (no cognitive deficit). | Per protocol population included all participants who received treatments as scheduled and were followed up to week 52. | Posted | Mean | Standard Deviation | units on a scale | Baseline, Week 12, 28 and 52 |
|
|
|
|
| Secondary | Alzheimer's Disease Assessment Scale, Non-cognitive Subscale (ADAS-NonCog) Score | ADAS-NonCog is a subscale of ADAS aimed to evaluate the non-cognitive features such as mood state and behavioral changes. It takes about 10 minutes to be performed and includes 10 items: testing tearful, depressed mood, concentration/distractibility, uncooperative to testing, delusions, hallucinations, pacing, motor activity increase, tremors and appetite change. Scores range between 0 (excellent performance) and 35 (worst performance). | Per protocol population included all participants who received treatments as scheduled and were followed up to week 52. | Posted | Mean | Standard Deviation | units on a scale | Baseline, Week 12, 28 and 52 |
|
|
|
|
| Secondary | Instrumental Activities of Daily Living (IADL) Score | IADL is used to evaluate participants with early-stage disease, both to assess level of disease and to determine participant's ability of self-care. IADL scale measures functional impact of emotional, cognitive, and physical impairments. It provides information about participants' compromising rate and care he might need. It includes 8 items: testing ability to use telephone, shopping, food preparation, housekeeping, laundry, mode of transportation, responsibility for own medication and ability to handle finances. Scores range between 0 (impairment) and 8 (full independence). | Per protocol population included all participants who received treatments as scheduled and were followed up to week 52. | Posted | Mean | Standard Deviation | units on a scale | Baseline, Week 28 and 52 |
|
|
|
|
| Secondary | Physical Self-Maintenance Scale (PSMS) Score | PSMS designed as a disability measure for use in planning and evaluating treatment in elderly participants living in community or in institutions, is Guttman scale containing 6 items of self-care. The scale is based on theory that human behavior can be ordered in a hierarchy of complexity, within each category, a further hierarchy of complexity runs from basic to complex activities. It includes 6 items, testing the following areas: toilet use, eating, dressing, physical appearance, deambulation and bath. Scores range between 0 (excellent performance) and 30 (worst performance). | Per protocol population included all participants who received treatments as scheduled and were followed up to week 52. | Posted | Mean | Standard Deviation | units on a scale | Baseline, Week 28 and 52 |
|
|
|
|
| Secondary | Clinician's Interview Based Impression of Change (CIBIC-PLUS) Score | CIBIC-PLUS: structured instrument based on comprehensive evaluation of 3 domains: participant cognition, behavior and functioning, including assessment of daily living activities. It includes 15 items and represents assessment of skilled clinician using validated scales based on the observation at interviews conducted separately with participant and caregiver familiar with behavior of participant. According to comparison between baseline and follow-up assessments, scores can range between 1 (markedly improved) and 7 (markedly worsened), with 4 indicating no change observed between two visits. | Per protocol population included all participants who received treatments as scheduled and were followed up to week 52. | Posted | Number | participants | Week 28 and 52 |
|
|
|
| Secondary | Geriatric Depression Scale (GDS) Score | The GDS consists of 30 'yes' or 'no' items aimed to assess depression. One point is assigned to each answer and the cumulative score is rated on a scoring grid. Scores are grouped as follows: 0-9 'normal', 10-19 'mildly depressed', and 20-30 'severely depressed'. | Per protocol population included all participants who received treatments as scheduled and were followed up to week 52. | Posted | Mean | Standard Deviation | units on a scale | Baseline, Week 28 and 52 |
|
|
|
|
| Secondary | Global Deterioration Scale Score | Global deterioration scale includes seven different diagnostic stages ranging between "no cognitive deterioration" and "very serious cognitive deterioration". It investigates the cognitive impairment. Scores range between 1 (no cognitive deterioration) and 7 (very severe cognitive decline). | Per protocol population included all participants who received treatments as scheduled and were followed up to week 52. | Posted | Mean | Standard Deviation | units on a scale | Baseline, Week 28 and 52 |
|
|
|
|
| 0 |
| 23 |
| 5 |
| 23 |
| EG001 | Placebo | Single dose of matching placebo injection administered sc tiw at a dose of 4.4 mcg for first 2 weeks followed by 11 mcg for next 2 weeks and finally 22 mcg for remaining 24 weeks (treatment period of 28 weeks). | 0 | 19 | 5 | 19 |
| Fever | General disorders | MedDRA | Non-systematic Assessment |
|
| High Cholesterol | Investigations | MedDRA | Non-systematic Assessment |
|
| High level of alanine transaminase (ALT) and aspartate aminotransferase (AST) | Investigations | MedDRA | Non-systematic Assessment |
|
| High level of aspartate aminotransferase (AST) - alanine transaminase (ALT) | Investigations | MedDRA | Non-systematic Assessment |
|
| High pseudocholinesterase | Investigations | MedDRA | Non-systematic Assessment |
|
| High triglycerides | Investigations | MedDRA | Non-systematic Assessment |
|
| High thyroid stimulating hormone | Investigations | MedDRA | Non-systematic Assessment |
|
| Low blood pressure | Vascular disorders | MedDRA | Non-systematic Assessment |
|
| Repolarization ventricular anomaly | Investigations | MedDRA | Non-systematic Assessment |
|
| Right ear buzzing | Ear and labyrinth disorders | MedDRA | Non-systematic Assessment |
|
| Flu-like syndrome | General disorders | MedDRA | Non-systematic Assessment |
|
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| D019636 |
| Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D036341 |
| Intercellular Signaling Peptides and Proteins |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011506 | Proteins |
| D001685 | Biological Factors |
| t-test, 2 sided |
| 0.74 |
| 95 |
| No |
| Superiority or Other |
| Week 28 |
|
| Week 52 |
|
| t-test, 2 sided |
| 0.88 |
| 95 |
| No |
| Superiority or Other |
| For Week 28: the difference between the two groups was analyzed using t-test. | t-test, 2 sided | 0.68 | 95 | No | Superiority or Other |
| For Week 52: the difference between the two groups was analyzed using t-test. | t-test, 2 sided | 0.81 | 95 | No | Superiority or Other |
| Week 28 |
|
| Week 52 |
|
| t-test, 2 sided |
| 0.36 |
| 95 |
| No |
| Superiority or Other |
| For Week 28: the difference between the two groups was analyzed using t-test. | t-test, 2 sided | 0.68 | 95 | No | Superiority or Other |
| For Week 52: the difference between the two groups was analyzed using t-test. | t-test, 2 sided | 0.41 | 95 | No | Superiority or Other |
| Week 52 |
|
| t-test, 2 sided |
| 0.62 |
| 95 |
| No |
| Superiority or Other |
| For Week 52: the difference between the two groups was analyzed using t-test. | t-test, 2 sided | 0.21 | 95 | No | Superiority or Other |
| Week 52 |
|
| t-test, 2 sided |
| 0.73 |
| 95 |
| No |
| Superiority or Other |
| For Week 52: the difference between the two groups was analyzed using t-test. | t-test, 2 sided | 0.30 | 95 | No | Superiority or Other |
| Week 28: CIBIC-PLUS Score 3 |
|
| Week 28: CIBIC-PLUS Score 4 |
|
| Week 28: CIBIC-PLUS Score 5 |
|
| Week 28: CIBIC-PLUS Score 6 |
|
| Week 28: CIBIC-PLUS Score 7 |
|
| Week 52: CIBIC-PLUS Score 1 |
|
| Week 52: CIBIC-PLUS Score 2 |
|
| Week 52: CIBIC-PLUS Score 3 |
|
| Week 52: CIBIC-PLUS Score 4 |
|
| Week 52: CIBIC-PLUS Score 5 |
|
| Week 52: CIBIC-PLUS Score 6 |
|
| Week 52: CIBIC-PLUS Score 7 |
|
| Week 52 |
|
| t-test, 2 sided |
| 0.74 |
| 95 |
| No |
| Superiority or Other |
| For Week 52: the difference between the two groups was analyzed using t-test. | t-test, 2 sided | 0.12 | 95 | No | Superiority or Other |
| Week 52 |
|
| t-test, 2 sided |
| 0.85 |
| 95 |
| No |
| Superiority or Other |
| For Week 52: the difference between the two groups was analyzed using t-test. | t-test, 2 sided | 0.85 | 95 | No | Superiority or Other |