A Pilot Trial of Interferon Beta-1a in Alzheimer's Disease

Phase 2

Completed

Conditions: Alzheimer's Disease

Interventions: Drug: Interferon beta-1a
Drug: Placebo

Registration Number: NCT01075763

Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary: 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.

Detailed Description: 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

* To evaluate safety, tolerability and clinical efficacy of IFN beta-1a (Rebif® 22 mcg, tiw) in the treatment of AD

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 42

Inclusion Criteria

Subjects aged between 50 and 75 years
Subjects diagnosed with AD, according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)
Subjects with MMSE score of 20 to 26 (inclusive)
Subjects supervised by a caregiver
Subjects who have been given informed written consent and approval of the Local Ethical Committee

Exclusion Criteria

Subjects with constant use in the 3 months prior study enrolment of other drugs that can modify the course of the disease (e.g. statins, nonsteroidal anti-inflammatory drugs [NSAIDs] and steroids) or symptomatic cognitive treatments (e.g. cholinesterase inhibitors)
Subjects with modified Hachinski Ischemic Score ≥ 4
Subjects who are unable to undergo neuropsychological evaluation (including analphabetism)
Subjects with significant liver (aspartate aminotransferase, alanine aminotransferase , alkaline phosphatase > 2.0 times the upper limit of normal [ULN] of the local laboratory, or total bilirubin > 1.5 times the ULN of the local laboratory), thyroid (according to clinical judgment) or hematological dysfunctions (e.g. leucocytes ≤ 2.0 * 109/Liter [L]; platelets ≤ 100 * 109/L; hemoglobin ≤ 12 gram/deciliter [g/dL] for women and ≤ 13 g/dL for men, serum albumin ≤ 3 g/dL)
Subjects with history (past or recurrent) of depression unresponsive to medication or past medical history of suicidal ideation
Subjects with severe cardiac disease (angina, congestive heart failure class 3-4 New York Heart Association [NYHA] Functional Classification , or severe arrhythmia)
Subjects with epilepsy
Subjects with concomitant use of hypnotic, anxiolytic, antidepressant, antipsychotic, anticholinergic
Subjects with known allergic reactions against IFNs or other components of the applied drug

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment arm - Rebif®	Interferon beta-1a	Subjets in this arm received interferon beta-1a (Rebif® 22 mcg tiw)
Placebo arm	Placebo	Subjects in this arm received placebo

Primary Outcome Measures

Name	Time	Method
Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score	Baseline and Week 52	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).

Secondary Outcome Measures

Name	Time	Method
Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score	Week 12 and 28	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).
Alzheimer's Disease Assessment Scale, Non-cognitive Subscale (ADAS-NonCog) Score	Baseline, Week 12, 28 and 52	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).
Physical Self-Maintenance Scale (PSMS) Score	Baseline, Week 28 and 52	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).
Geriatric Depression Scale (GDS) Score	Baseline, Week 28 and 52	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'.
Mini Mental Status Examination (MMSE) Score	Baseline, Week 12, 28 and 52	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).
Clinician's Interview Based Impression of Change (CIBIC-PLUS) Score	Week 28 and 52	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.
Global Deterioration Scale Score	Baseline, Week 28 and 52	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).
Instrumental Activities of Daily Living (IADL) Score	Baseline, Week 28 and 52	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).