Clinical trial NCT01677754: A Study of RO4602522 in Participants With Moderate Severity Alzheimer Disease on Background Alzheimer Disease Therapy
Official title: A Phase II, Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Investigate the Efficacy and Safety of RO4602522 Added to Background Alzheimer's Disease Therapy in Patients With Moderate Severity Alzheimer's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer's Disease
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2012-09-03
Enrollment: 542
Sex: ALL
Minimum age (years): 50
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This Phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled study will evaluate the efficacy and safety of RO4602522 in participants with moderate severity Alzheimer's disease. Participants who are taking background therapy of acetylcholinesterase inhibitors (AChEI) alone or in combination with memantine for at least 4 months before screening will be randomized to receive either one of two doses of RO4602522 or placebo for 12 months.


Eligibility criteria: Inclusion Criteria:

* Probable Alzheimer disease, based on the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS)/Alzheimer's Disease and Related Disorders Association (ADRDA) and Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (DSM-IV-TR) criteria
* Mini-Mental State Exam (MMSE) score at screening between 13 and 20, inclusive
* Body mass index (BMI) between 18 and 36 kilograms per square meter (kg/m\^2) (inclusive) at screening
* Modified Hachinski Ischemia Score of less than or equal to (\</=) 4
* Participants with Cornell Scale for Depression in Dementia (CSDD) scores \</= 13 at screening
* Receiving treatment with donepezil, rivastigmine, galantamine or any AChEIs in combination with memantine for at least 4 months before screening, with their dose and formulation stabilized at least 3 months before screening. All formulation and dosages are allowed except donezepil 23 mg (alone or in combination)
* Females of childbearing potential must have a negative pregnancy test and must agree to use effective contraception
* Generally healthy and ambulatory or ambulatory-aided (i.e., walker or cane)
* Have a reliable caregiver or some other identified responsible person who has frequent contact with the participant

Exclusion Criteria:

* Any neurological or psychiatric condition that may occur currently or during the course of the study that can impair cognition or functioning that is not associated with Alzheimer's disease
* Background of mental retardation
* Uncontrolled behavioral symptoms incompatible with compliance or evaluability
* Alcohol and/or substance abuse or dependence (DSM-IV-TR) in the past 2 years, except nicotine use which is allowed. However, smokers treated with nicotine replacement therapy or bupropion are excluded
* Unstable or poorly controlled hypertension as assessed by the investigator regardless of whether or not the participant is taking antihypertensive medications
* Unstable or clinically significant cardiovascular disease that could be expected to progress, recur, or change during study period to such an extent that it could bias the assessment of the clinical or mental status of the participant
* Inadequate hepatic, renal or thyroid function
* Positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV) infection
* Poorly controlled diabetes (glycosylated hemoglobin \[HbA1c\] greater than or equal to \[\>/=\] 9 percent at screening)
* Requiring nursing home care. Participants living in assisted living facilities are allowed if a reliable caregiver is available (see inclusion criteria)
* Current treatment for Alzheimer's disease other than those listed in inclusion criteria
* Participation at any time in an active Alzheimer's disease vaccine study
* Participation in a passive Alzheimer's disease immunization study less than 1 year before screening except for a) participants where documented medical history indicate that they were randomized to the placebo group in these studies, b) participants treated with bapineuzumab where a 6-month exclusion period applies
* Recent (\</= 12 weeks) or concomitant use of other Monoamine oxidase inhibitors (selective or not) including selegiline or rasagiline
* Antidepressant treatments are not allowed except for citalopram up to 20 mg daily, escitalopram up to 10 mg daily, paroxetine up to 30 mg daily, sertraline up to 100 mg daily and trazodone up to 100 mg daily. If treated with one of these antidepressants, the treatment should be present for at least 6 weeks at screening. All other antidepressants including other SSRIs, tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), St. John's wort and bupropion are excluded
* Anti-psychotic use within 4 weeks before screening is not permitted except risperidone up to 1.5 mg/day, quetiapine up to 100 milligrams per day (mg/day), olanzapine up to 5 mg/day, and aripiprazole up to 10 mg daily
* Anxiolytics/ hypnotics use is not permitted except for benzodiazepines of short or intermediate half-life for anxiety/sleeping disorders. Zolpidem (up to 5 mg/day), zopiclone (up to 7.5 mg/day), eszopiclone (up to 2 mg/day), trazodone (up to 50 mg/day, at bedtime) or zaleplon (up to 5 mg/day) is permitted for insomnia
* Anti-Parkinson's agents within 2 weeks before screening are not permitted
* Recent (less than 4 weeks prior to screening) or concomitant use of anticonvulsants
* Anticholinergics/ antihistaminics within 2 weeks before screening are not permitted, except i) if used episodically more than 3 days before the screening cognitive measurement, ii) non-sedating antihistaminic medications (without anticholinergic effects such as cetirizine) or peripheral anticholinergics without central anticholinergic effects (such as, trospium for the treatment of hyperactive bladder), which are permitted
* Recent (less than 1 week prior to screening) or concomitant use of opioid drugs (tramadol, methadone, propoxyphene, or meperidine), cyclobenzaprine and dextromethorphan
* Concomitant use of sympathomimetic drugs, including sympathomimetics in local anesthetics and ephedra supplements

Primary outcomes:
measure: Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Behavior Subscale (ADAS-Cog-11) Score at Month 12
timeFrame: Baseline, Month 12
Secondary outcomes:
measure: Percentage of Participants Achieving Response, Defined as an Increase From Baseline of Less Than or Equal to (<=) 4 Points in ADAS-Cog-11
timeFrame: Baseline, Month 12
measure: Change From Baseline in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Scale Score at Month 12
timeFrame: Baseline, Month 12
measure: Change From Baseline in Behavioral Pathology in Alzheimer's Disease Frequency-Weighted Severity Scale (BEHAVE-AD-FW) Score at Month 12
timeFrame: Baseline, Month 12
measure: Percentage of Participants With Worsening in BEHAVE-AD-FW Score
timeFrame: Baseline to Month 12
measure: Change From Baseline in Apathy Evaluation Scale (AES) Score at 12 months
timeFrame: Baseline, Month 12
measure: Change From Baseline in Alzheimer's Disease Cooperative Study Clinician Global Impression of Change (ADCS-CGIC) Scale Score at 12 months
timeFrame: Baseline, Month 12
measure: Percentage of Participants With Worsening in ADCS-CGIC Score
timeFrame: Baseline to Month 12
measure: Change From Baseline in Global Deterioration Scale (GDS) Score at 12 months
timeFrame: Baseline, Month 12
measure: Change From Baseline in Columbia Suicide Severity Rating Scale (C-SSRS) Score at 12 months
timeFrame: Baseline, Month 12
measure: Percentage of Participants with Adverse Events
timeFrame: Baseline up to 13 months
measure: Percentage of Participants with Change in Lens Opacity Grading
timeFrame: Baseline; Months 6, and 12
measure: Percentage of Participants with Abnormal Visual Acuity Test Results
timeFrame: Baseline, Months 6, and 12
measure: Change From Baseline in Michigan Neuropathy Screening Instrument Score
timeFrame: Baseline, Weeks 8, 18, 30, 44, 52, and at the last follow-up visit (12 weeks after last dose, up to 64 weeks)
measure: Percentage of Participants Receiving Concomitant Medications
timeFrame: Baseline to 13 Months
measure: Apparent Total Clearance of the Drug From Plasma After Administration of RO4602522
timeFrame: Day -1, pre-dose (0 hour) on Days 14, 28, 84, 168, 252, and 364; 1 to 2 hour post dose on Days 14, 84, 252; 2-4 and 5-6 hours post dose on Days 28, 168, and 364
measure: Apparent Volume of Distribution at Steady State after Administration of RO4602522
timeFrame: Day -1, pre-dose (0 hour) on Days 14, 28, 84, 168, 252, and 364; 1 to 2 hour post dose on Days 14, 84, 252; 2-4 and 5-6 hours post dose on Days 28, 168, and 364
measure: Area Under the Plasma Concentration-Time Curve of RO4602522
timeFrame: Day -1, pre-dose (0 hour) on Days 14, 28, 84, 168, 252, and 364; 1 to 2 hour post dose on Days 14, 84, 252; 2-4 and 5-6 hours post dose on Days 28, 168, and 364
measure: Maximum Plasma Concentration of RO4602522
timeFrame: Day -1, pre-dose (0 hour) on Days 14, 28, 84, 168, 252, and 364; 1 to 2 hour post dose on Days 14, 84, 252; 2-4 and 5-6 hours post dose on Days 28, 168, and 364
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: Advanced Research Center, Inc.;In-Patient Unit
state: California
city: Fullerton
country: United States
facility: Neurology Center of North Orange County
state: California
city: Lomita
country: United States
facility: Torrance Clinical Research
state: California
city: San Diego
country: United States
facility: Artemis Institute for Clinical Research, LLC
state: California
city: San Diego
country: United States
facility: Sharp Mesa Vista Hospital
state: California
city: San Francisco
country: United States
facility: San Francisco Clinical Research Center
state: California
city: Santa Monica
country: United States
facility: Neurological Research Inst
state: California
city: New Haven
country: United States
facility: Yale University School Of Medicine
state: Connecticut
city: Norwalk
country: United States
facility: Research Center for Clinical Studies, Inc.
state: Connecticut
city: Boca Raton
country: United States
facility: Parkinson's Disease and Movement Disorders Center of Boca Raton
state: Florida
city: Brooksville
country: United States
facility: Meridien Research
state: Florida
city: Delray Beach
country: United States
facility: Brain Matters Research, Inc.
state: Florida
city: Fort Lauderdale
country: United States
facility: Neurologic Consultants, P.A.
state: Florida
city: Hialeah
country: United States
facility: Galiz Research, LLC
state: Florida
city: Miami
country: United States
facility: Miami Jewish Health Systems
state: Florida
city: Orange City
country: United States
facility: Medical Research Group of Central Florida
state: Florida
city: Orlando
country: United States
facility: Compass Research East, LLC
state: Florida
city: Saint Petersburg
country: United States
facility: Comprehensive Clinical Development, Inc.- St. Petersburg, FL
state: Florida
city: Tampa
country: United States
facility: Axiom Clinical Research of Florida
state: Florida
city: West Palm Beach
country: United States
facility: Premiere Research Institute
state: Florida
city: Decatur
country: United States
facility: iResearch Atlanta
state: Georgia
city: Decatur
country: United States
facility: NeuroStudies.net, LLC
state: Georgia
city: Elk Grove Village
country: United States
facility: Alexian Brothers Neurosci Inst
state: Illinois
city: New Orleans
country: United States
facility: Louisiana Research Associates
state: Louisiana
city: Shreveport
country: United States
facility: Booker, J. Gary, MD, APMC
state: Louisiana
city: Traverse City
country: United States
facility: Northern Michigan Neurology
state: Michigan
city: Hattiesburg
country: United States
facility: Hattiesburg Clinic
state: Mississippi
city: Creve Coeur
country: United States
facility: Millennium Psychiatric Associates, LLC
state: Missouri
city: Eatontown
country: United States
facility: Memory Enhancement Center of America, Inc.
state: New Jersey
city: Albuquerque
country: United States
facility: Albuquerque Neuroscience Inc.
state: New Mexico
city: New York
country: United States
facility: New York University Medical Center;Child Study Center
state: New York
city: Staten Island
country: United States
facility: Richmond Behavioral Associates
state: New York
city: Raleigh
country: United States
facility: Raleigh Neurology Associates
state: North Carolina
city: Winston-Salem
country: United States
facility: PMG Research of Winston-Salem, LLC
state: North Carolina
city: Oklahoma City
country: United States
facility: Lynn Health Science Institute
state: Oklahoma
city: Oklahoma City
country: United States
facility: Cutting Edge Research Group
state: Oklahoma
city: Jenkintown
country: United States
facility: The Clinical Trial Center, LLC
state: Pennsylvania
city: Wyomissing
country: United States
facility: Radiant Research, Inc.
state: Pennsylvania
city: East Providence
country: United States
facility: Rhode Island Mood & Memory Research Institute
state: Rhode Island
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Alzheimer's Research & Clinical Programs
state: South Carolina
city: Fort Worth
country: United States
facility: University of North Texas Health Science Center
state: Texas
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Erina
country: Australia
facility: Central Coast Neurosciences Research
state: New South Wales
city: Kogarah
country: Australia
facility: Southern Neurology
state: New South Wales
city: Woodville
country: Australia
facility: Queen Elizabeth Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Box Hill Hospital; Eastern Clinical Research Unit
state: Victoria
city: Geelong
country: Australia
facility: A.G.Mander Pty Ltd
state: Victoria
city: Heidelberg
country: Australia
facility: Heidelberg Repatriation Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Hollywood Specialist Centre
state: Western Australia
city: Subiaco
country: Australia
facility: Neurodegenerative Disorders Research
state: Western Australia
city: Powell River
country: Canada
facility: The Medical Arts Health Research Group
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver Hospital - UBC Hospital Site
state: British Columbia
city: Victoria
country: Canada
facility: Vancouver Island Health Authority
state: British Columbia
city: Halilfax
country: Canada
facility: Capitol District Health Authority
state: Nova Scotia
city: Kentville
country: Canada
facility: True North Clinical Research Kentville
state: Nova Scotia
city: Burlington
country: Canada
facility: Jbn Medical Diagnostic Services Inc.
state: Ontario
city: Ottawa
country: Canada
facility: Bruyere Continuing Care
state: Ontario
city: Peterborough
country: Canada
facility: Ingram, Jennifer MD
state: Ontario
city: Toronto
country: Canada
facility: Toronto Memory Program (Neurology Research Inc.)
state: Ontario
city: Toronto
country: Canada
facility: The Centre for Memory and Aging
state: Ontario
city: Toronto
country: Canada
facility: Toronto Sunnybrook Hospital
state: Ontario
city: Gatineau
country: Canada
facility: Recherches Neuro-Hippocame
state: Quebec
city: Greenfield Park
country: Canada
facility: Clinique Neuro Rive-Sud
state: Quebec
city: Sherbrooke
country: Canada
facility: Institut Universitaire de gériatrie de Sherbrooke; Service de gériatrie/pavillon Argyll
state: Quebec
city: Verdun
country: Canada
facility: McGill Univeristy; Douglas Mental Health University Institute; Neurological and Psychiatric
state: Quebec
city: Quebec
country: Canada
facility: CHU de Quebec - Hôpital de l' Enfant Jésus
city: Chocen
country: Czechia
facility: NEUROHK s.r.o.
city: Kladno
country: Czechia
facility: P-P Klinika
city: Kutna Hora - Vnitrni Mesto
country: Czechia
facility: Supervize s.r.o.
city: Prague
country: Czechia
facility: Nemocnice Na Bulovce
city: Praha 10
country: Czechia
facility: Clintrial,s.r.o.
city: Praha 10
country: Czechia
facility: AD71 s.r.o.
city: Praha 4 - Krc
country: Czechia
facility: Thomayerova nemocnice
city: Praha 5
country: Czechia
facility: Psychiatry Trial s.r.o.
city: Praha 6
country: Czechia
facility: Neurologicka ambulance
city: Praha 6
country: Czechia
facility: FORBELI s.r.o.
city: Bayonne
country: France
facility: Centre Hospitalier de la côte Basque
city: Bron
country: France
facility: Hopital Neurologique Pierre Wertheimer
city: Nantes
country: France
facility: Hopital Nord Laënnec - CHU Nantes
city: Nice
country: France
facility: Hopital Cimiez; CMRR
city: Paris
country: France
facility: Hôpital Lariboisière
city: Pessac
country: France
facility: Groupe Hospitalier Sud - Hôpital Xavier Arnozan
city: Reims
country: France
facility: Hôpital Maison Blanche
city: Rennes
country: France
facility: CHU Rennes - Hopital Hôtel Dieu
city: Toulouse
country: France
facility: CHU Toulouse - La Grave
city: Tours
country: France
facility: CHU Tours - Hôpital Bretonneau
city: Vandoeuvre-les-nancy
country: France
facility: Hôpital de Brabois Adultes
city: Villeurbanne
country: France
facility: Hopital des Charpennes
city: Ellwangen
country: Germany
facility: Gemeinschaftspraxis
city: Hannover
country: Germany
facility: Henriettenstiftung Hannover
city: Mannheim
country: Germany
facility: ISPG - Institut fuer Studien zur Psychischen Gesundheit
city: Munchen
country: Germany
facility: Klinikum rechts der Isar der Technischen Universität München
city: Siegen
country: Germany
facility: Zentrum f. Neurologisch- Psychiatrische Studien und Begutachtung
city: Modena
country: Italy
facility: Nuovo Ospedale Civile S.Agostino - Estense
state: Emilia-Romagna
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli; Farmacia
state: Lazio
city: Roma
country: Italy
facility: Fondazione Santa Lucia IRCCS
state: Lazio
city: Roma
country: Italy
facility: Umberto I Policlinico di Roma-Università di Roma La Sapienza
state: Lazio
city: Genova
country: Italy
facility: Ente Ospedaliero Ospedali Galliera
state: Liguria
city: Genova
country: Italy
facility: Università degli Studi di Genova
state: Liguria
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria Pisana; Uff. Sperim. Clin. U.O. Farmaceutica
state: Toscana
city: Perugia
country: Italy
facility: Università degli studi di Perugia
state: Umbria
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Gyeonggi-do
country: Korea, Republic of
facility: Ajou University Hospital
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital; Pulmonary Medicine
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Hospital
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Bialystok
country: Poland
facility: Podlaskie Centrum Psychogeriatrii
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Katowice
country: Poland
facility: Specjal. Praktyka Lekarska; Prof. Grzegorz Opala
city: Katowice
country: Poland
facility: Centrum Medyczne Dendryt
city: Poznan
country: Poland
facility: NZOZ NEURO-KARD Ilkowski i Partnerzy Sp. Partn. Lek
city: Pruszcz Gdanski
country: Poland
facility: NZOZ Syntonia
city: Sopot
country: Poland
facility: NZOZ Pro-Cordis Sopockie Centrum Bad. Kardiolog
city: Warszawa
country: Poland
facility: mMED Maciej Czarnecki
city: Warszawa
country: Poland
facility: Instytut Psychiatrii i Neurologii
city: Elche
country: Spain
facility: Hospital General Universitario de Elche; Servicio de Farmacia
state: Alicante
city: BArcelon
country: Spain
facility: Fundació ACE
state: Barcelona
city: Sant Cugat del Valles
country: Spain
facility: Hospital General De Catalunya; Servicio de Neurologia
state: Barcelona
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro Majadahonda
state: Madrid
city: Plasencia
country: Spain
facility: Hospital Virgen del Puerto
state: Palencia
city: Seville
country: Spain
facility: Hospital Universitario Virgen Macarena
state: Sevilla
city: BaraKaldo
country: Spain
facility: CAE Oroitu
state: Vizcaya
city: Albacete
country: Spain
facility: Hospital Perpetuo Socorro, Servicio de Geriatria
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Universitario Clínico San Carlos
city: Valencia
country: Spain
facility: Hospital Universitari i Politecnic La Fe
city: Malmö
country: Sweden
facility: Skanes Universitetssjukhus, Malmo Skanes Universitetssjukhus, Malmo
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Huddinge
city: Crowborough
country: United Kingdom
facility: Cognitive Treatment & Research Unit
city: Dundee
country: United Kingdom
facility: Ninewells Hospital
city: Glasgow
country: United Kingdom
facility: Glasgow Memory Clinic
city: Isleworth
country: United Kingdom
facility: West London Cognitive Disorders Treatment and Research Unit; Lakeside Metal Health Unit
city: London
country: United Kingdom
facility: Institute of Psychiatry
city: Norwich
country: United Kingdom
facility: Norwich Medical School
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Sheffield
country: United Kingdom
facility: Memory Service North
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Nave S, Doody RS, Boada M, Grimmer T, Savola JM, Delmar P, Pauly-Evers M, Nikolcheva T, Czech C, Borroni E, Ricci B, Dukart J, Mannino M, Carey T, Moran E, Gilaberte I, Muelhardt NM, Gerlach I, Santarelli L, Ostrowitzki S, Fontoura P. Sembragiline in Moderate Alzheimer's Disease: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Trial (MAyflOwer RoAD). J Alzheimers Dis. 2017;58(4):1217-1228. doi: 10.3233/JAD-161309.