Clinical trial NCT01075763: A Pilot Trial of Interferon Beta-1a in Alzheimer's Disease
Official title: Pilot Trial of Interferon Beta-1a in Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Keywords: Alzheimer's
Dementia
Interferon beta-1a
Rebif
Lead sponsor: Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
Collaborators: name: Merck Serono S.P.A., Italy
First posted: 2010-02-25
Enrollment: 42
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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

Primary outcomes:
measure: Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score
timeFrame: Baseline and Week 52
Secondary outcomes:
measure: Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) Score
timeFrame: Week 12 and 28
measure: Mini Mental Status Examination (MMSE) Score
timeFrame: Baseline, Week 12, 28 and 52
measure: Alzheimer's Disease Assessment Scale, Non-cognitive Subscale (ADAS-NonCog) Score
timeFrame: Baseline, Week 12, 28 and 52
measure: Instrumental Activities of Daily Living (IADL) Score
timeFrame: Baseline, Week 28 and 52
measure: Physical Self-Maintenance Scale (PSMS) Score
timeFrame: Baseline, Week 28 and 52
measure: Clinician's Interview Based Impression of Change (CIBIC-PLUS) Score
timeFrame: Week 28 and 52
measure: Geriatric Depression Scale (GDS) Score
timeFrame: Baseline, Week 28 and 52
measure: Global Deterioration Scale Score
timeFrame: Baseline, Week 28 and 52
Other outcomes:
Locations:
city: Catania
country: Italy
facility: U.VA. Neurologia - Azienda Ospedaliera Garibaldi Nesina
state: CT
Study officials:
affiliation: Merck Serono S.P.A., Italy
name: Andrea Paolillo, MD, PhD
role: STUDY_DIRECTOR
References: