Efficacy, Safety, & Tolerability of AZD3480 Patients With Mild to Moderate Dementia of the Alzheimer's Type (AD)
AD is the most common form of dementia, affecting more than half of demented patients. It is the fourth leading cause of death among people 65 years of age or older (Sadik, 2003). In the US, the disease affects 6-10% of people between the ages of 65 and 85 years, and from 25 to 45% of those over the age of 85 (Evans et al., 1991; US General Accounting Office, 1998). It has been estimated that AD affects approximately 4.5 million people in the US (Hebert et al., 2003). The global prevalence of the disease will increase significantly as the population ages, unless preventative treatments can be identified and marketed.
AZD3480 is a selective partial agonist of the α4β2 subtype of NNRs with marked CNS selectivity. In a comparative non clinical study of visual memory (novel object recognition test) the AChEI donepezil showed substantially less effect compared to AZD3480 in enhancing cognition. Moreover, results from non clinical and clinical studies in healthy volunteers and patients with AAMI, MCI, and AD have demonstrated that AZD3480 has the potential to have a disease modifying effects in AD and could be very beneficial in improving cognition in these patients.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Double-Blind, Positive Comparator, Randomized, Parallel Study of Efficacy, Safety, and Tolerability of AZD3480 (TC-1734-226) as Monotherapy in Patients With Mild to Moderate Dementia of the Alzheimer's Type|
- ADAS-Cog [ Time Frame: 54 weeks ] [ Designated as safety issue: No ]The ADAS-Cog tests patients' abilities in memory, language, orientation, and praxis, where higher scores (sum of errors) indicate declining cognition. ADAS-Cog will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal.
- CIBIC-(+) [ Time Frame: 54 Weeks ] [ Designated as safety issue: No ]The Clinician Interview-Based Impression of Change carer interview (CIBIC-Plus) comprises Likert scales for disease severity and changes, and written accounts summarizing semistructured interviews evaluating behavior, cognition, and function. The CIBIC-(+) is a co-primary endpoint with the ADAS-Cog in the United States. It will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal and will be a co-primary outcome for the US.
- ADCS-ADL [ Time Frame: 54 Weeks ] [ Designated as safety issue: No ]Alzheimer's Disease Cooperative Study - Activities of Daily Living is a caregiver rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 implies full functioning with no impairment. It will be the co-primary outcome measure in Europe. The ADCS-ADL is the co-primary endpoint with the ADAS-Cog in Europe. ADCS-ADL will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal.
- NPI [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]Neuropsychiatric Inventory (NPI) at Day 1, Week 12, Week 24, and Week 52 or EW.
- ADCS-ADL (in United States) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]Alzheimer's Disease Cooperative Study - Activities of Daily Living is a caregiver rated questionnaire of 23 items, with possible scores over a range of 0-78, where 78 implies full functioning with no impairment. ADCS-ADL will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal.
- CIBIC-(+) [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]The Clinician Interview-Based Impression of Change carer interview (CIBIC-Plus) comprises Likert scales for disease severity and changes, and written accounts summarizing semistructured interviews evaluating behavior, cognition, and function. It will be collected at Week -3, Day 1, Weeks 4, 12, 24, 36, 52, and 54 or early withdrawal.
- MMSE [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]The MMSE (Folstein et al., 1975) consists of 11 tests of orientation, memory (recent and immediate), concentration, language, and praxis. Scores range from 0 to 30, with lower scores indicating greater cognitive impairment. The scale is completed by the investigator, based on the performance of the subject. The MMSE will be administered at Week -3 (Screen), Day 1 (Baseline), and Weeks 4, 12, 24, 36, and 52.
- Proportion of responders defined by improvement on ADAS-Cog [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]Proportion of responders on ADAS-Cog at Weeks 24 and 52 (defined as the proportion of subjects with >/= 1 point improvement from Baseline)
- Percent showing no deterioration in CIBIC-(+) or ADCS-ADL) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]Percent of subjects showing no deterioration in CIBIC-(+) or ADCS-ADL from baseline to Weeks 24 and 52
|Study Start Date:||October 2011|
|Estimated Study Completion Date:||July 2014|
|Estimated Primary Completion Date:||July 2014 (Final data collection date for primary outcome measure)|
AZD3480 is manufactured as hard gelatin capsules for oral administration. The capsule formulation is a blend of AZD3480 and excipients. The excipients are pregelatinized starch, magnesium stearate, and microcrystalline cellulose. Matching placebo will also be provided to maintain the blind.
Subjects taking 30mg AZD3480 will take a 30mg capsule of AZD3480 and a placebo for donepezil (to maintain blind) p.o. qd.
Other Name: TC-1734
Active Comparator: Donepezil
Donepezil drug product will be provided as one (1) tablet of an over-encapsulated commercially available 5 mg dose strength as a single capsule, or two (2) tablets of over-encapsulated commercially available 5mg dose strengths as a single capsule. The excipients are magnesium stearate and mannitol.
The hard gelatin capsules are grey opaque, using titanium dioxide as the opacifier and iron oxide black as the colorant. All components comply with the relevant Ph. Eur. And USP monographs. The matching placebo capsule for donepezil contains the excipients magnesium stearate, and microcrystalline cellulose.
Subjects taking Donepezil will take a 5mg capsule from Day 1 to Week 4, and a 10mg capsule from Week 4 to Week 52. Subjects who did not tolerate donepezil at 5mg or 10mg will be withdrawn from the study. Subjects taking donepezil will take a blinded capsule containing commercial donepezil and excipients and a placebo for AZD3480 p.o. qd.
Other Name: Aricept
A parallel group design allows the effects of AZD3480 to be compared directly to a positive comparator, donepezil, and the randomized nature of the design minimizes observer and subject bias. Donepezil was chosen as the positive comparator since it is widely used in the long-term treatment of AD, has an efficacy profile similar to other AChEIs and is better tolerated than other drugs in this class. The choice of a positive comparator such as donepezil rather than placebo allows the ethical use of a one-year treatment period. The assessment of the efficacy of AZD3480 versus donepezil will satisfy the regulatory requirements for an adequate and well-controlled study, if it is positive.
The dose of AZD3480 evaluated in this study, 30 mg free base (48mg as the p-hydroxybenzoic acid salt), reflects an appropriate dose for AZD3480 based upon extrapolations from earlier preclinical and clinical findings: (a) 30mg is expected to produce plasma concentrations of AZD3480 similar to or exceeding those leading to a cognitive enhancing effect in animal models; (b) it matches the exposure observed to enhance cognitive function in elderly patients with AAMI, MCI, and AD in earlier studies; and (c) it has 80% receptor occupancy at the α4β2 NNR based on a PET receptor occupancy study. (Donepezil is being used in doses as recommended in the data sheet which states that treatment should be initiated with 5 mg and then increased to a 10 mg daily dose).
Patients with an MMSE ranging from 12-22 have been specifically selected to enhance the likelihood of seeing a difference in the efficacy endpoints with AZD3480 vs. donepezil; instead of the mild group of AD patients who usually have an MMSE greater then 22.
|United States, Arizona|
|Banner Alzheimer Institute|
|Phoenix, Arizona, United States, 85006|
|United States, Florida|
|Brooksville, Florida, United States, 34601|
|Hallandale Beach, Florida, United States, 33009|
|Chocen, Czech Republic|
|Kladno, Czech Republic|
|Bialbi.s.r.o. Psychiatrické oddělení|
|Litoměřice, Czech Republic|
|Olomouc, Czech Republic|
|Vojenska Nemocnice Psychiatricke oddeleni|
|Olomouc, Czech Republic|
|Praha, Czech Republic|
|Praha, Czech Republic|
|Prerov, Czech Republic|
|Spitalul Judetean de Urgenta Arad, Clinica de Psihiatrie|
|Arad, Romania, 310022|
|Spitalul de Urgenta "SF. Pantelimon" Focsani|
|Focsani, Romania, 620165|
|Spitalul Clinic de Psihiatrie Socola Iasi|
|Crucea Alba - Dr. Oros si Asociatii - Societate Civila Medicala|
|Spitalul Clinic Judetean de Urgenta SIBIU|
|Spitalul de Psihiatrie Sibiu|
|Sibiu, Romania, 550012|
|Spitalul Clinic Judetean de Urgenta, Clinica Psihiatrie|
|Spitalul Clinic Judetean de Urgenta, Clinica Neurologie 2|
|Neurologicka Ambulancia, s.r.o.|
|Banska Bystrica, Slovakia|
|Univerzitna nemocnica Bratislava, Geronto-psychiatrické oddelenie|
|Dubnica nad Váhom, Slovakia|
|Dnipropetrovsk Regional Clinical Hospital|
|Dnipropetrovsk, Ukraine, 49005|
|Dnipropetrovsk Regional Clinical Hospital|
|Donetsk Regional Clinical Psychiatric Hospital|
|Central Clinical Hospital Ukrzaliznytsi|
|Department of Age Physiology and Pathology of Nervous System; Institute of Gerontology NAMS|
|Kyiv, Ukraine, 04114|
|Lugansk Regional Clinical Psychoneurological Hospital|
|Lviv National Medical University named after Galytskyy|
|Lviv, Ukraine, 79010|
|Odessa Regional Psychiatric Hospital # 2|
|Odessa Regional Psychoneurology Dispensary|
|Poltava Regional Clinical Psychiatric Hospital|
|Poltava, Ukraine, 36006|
|Department #3 of the Kherson Regional Psychiatric Hospital|
|Principal Investigator:||Pierre Tariot, MD||Banner Alzheimer Institute|