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

This study has been completed.
Sponsor:
Collaborator:
Merck Serono S.P.A., Italy
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01075763
First received: February 24, 2010
Last updated: January 20, 2014
Last verified: January 2014
  Purpose

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.


Condition Intervention Phase
Alzheimer's Disease
Drug: Interferon beta-1a
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Pilot Trial of Interferon Beta-1a in Alzheimer's Disease

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score [ Time Frame: Baseline and Week 52 ] [ Designated as safety issue: No ]
    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:
  • Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score [ Time Frame: Week 12 and 28 ] [ Designated as safety issue: No ]
    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).

  • Mini Mental Status Examination (MMSE) Score [ Time Frame: Baseline, Week 12, 28 and 52 ] [ Designated as safety issue: No ]
    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).

  • Alzheimer's Disease Assessment Scale, Non-cognitive Subscale (ADAS-NonCog) Score [ Time Frame: Baseline, Week 12, 28 and 52 ] [ Designated as safety issue: No ]
    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).

  • Instrumental Activities of Daily Living (IADL) Score [ Time Frame: Baseline, Week 28 and 52 ] [ Designated as safety issue: No ]
    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).

  • Physical Self-Maintenance Scale (PSMS) Score [ Time Frame: Baseline, Week 28 and 52 ] [ Designated as safety issue: No ]
    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).

  • Clinician's Interview Based Impression of Change (CIBIC-PLUS) Score [ Time Frame: Week 28 and 52 ] [ Designated as safety issue: No ]
    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.

  • Geriatric Depression Scale (GDS) Score [ Time Frame: Baseline, Week 28 and 52 ] [ Designated as safety issue: No ]
    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'.

  • Global Deterioration Scale Score [ Time Frame: Baseline, Week 28 and 52 ] [ Designated as safety issue: No ]
    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).


Enrollment: 42
Study Start Date: November 2004
Study Completion Date: May 2008
Primary Completion Date: May 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment arm - Rebif®
Subjets in this arm received interferon beta-1a (Rebif® 22 mcg tiw)
Drug: Interferon beta-1a
Interferon (IFN) beta-1a [Rebif® 22 microgram (mcg), three times per week (tiw)] administered subcutaneously (sc)
Other Name: Rebif®
Placebo Comparator: Placebo arm
Subjects in this arm received placebo
Drug: Placebo
The inactive substance (placebo) looks the same as Interferon beta-1a (Rebif®), and is given the same way

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.

  Eligibility

Ages Eligible for Study:   50 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01075763

Locations
Italy
U.VA. Neurologia - Azienda Ospedaliera Garibaldi Nesina
Catania, CT, Italy, 95122
Sponsors and Collaborators
Merck KGaA
Merck Serono S.P.A., Italy
Investigators
Study Director: Andrea Paolillo, MD, PhD Merck Serono S.P.A., Italy
  More Information

No publications provided

Responsible Party: Merck KGaA
ClinicalTrials.gov Identifier: NCT01075763     History of Changes
Other Study ID Numbers: 24386
Study First Received: February 24, 2010
Results First Received: March 7, 2012
Last Updated: January 20, 2014
Health Authority: Italy: The Italian Medicines Agency

Keywords provided by Merck KGaA:
Alzheimer's
Dementia
Interferon beta-1a
Rebif

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Interferon-beta
Interferons
Interferon beta 1a
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Adjuvants, Immunologic

ClinicalTrials.gov processed this record on July 20, 2014