Clinical trial NCT02240693: Alzheimer Disease Proof of Concept Study With BI 409306 Versus Placebo
Official title: A Multi-centre, Double-blind, Parallel-group, Randomized Controlled Study to Investigate the Efficacy, Safety and Tolerability of Orally Administered BI 409306 During a 12-week Treatment Period Compared to Placebo in Patients With Alzheimer Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer Disease
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2014-09-16
Enrollment: 128
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The study is designed to compare the effects of 4 different doses of orally administered BI 409306 to placebo in patients with Alzheimers Disease


Eligibility criteria: Inclusion criteria:

* Male and female patients with an age of at least 55 years
* Body weight not lower than 50 kgs
* Patients with a confirmed diagnosis of prodromal Alzheimer's Dementia (AD) on neuropsychological testing defined as:

Mini-Mental State Examination (MMSE) score: greater or equal 24 and a global Clinical Dementia Rating (CDR)-score of 0 or 0.5 and

Free and Cued Selective Recall Reminding Test (FCSRT) score:

free recall test: lower or equal 20 (out of 48) and total recall test: lower or equal 42 (out of 48)

Patients who do not reach the required score in FCSRT will additionally perform the Wechsler Memory Visual Paired Associates test. If the Wechsler Memory Visual Paired Associates test shows a cognitive deficit worse than 1 standard deviation to the mean (compared to the reference values of age and educational norms for inclusion), then the patients can be considered to be eligible for the study.

* Confirmation of abnormal markers of AD pathology either via a), or alternatively b) mentioned below:

  1. Presence in cerebrospinal fluid of (samples taken within past 4 months may be eligible,:

     low Aß1-42 concentrations (\< 640 pg/mL) and increased total tau concentrations (\> 375 pg/ml), or / and low Aß1-42 concentrations (\< 640 pg/mL) and increased phospho-tau concentrations (\> 52 pg/mL in cerebrospinal fluid), or
  2. Abnormal amyloid deposition in a cerebral Positron Emission Tomography (PET) scan. Scans performed in the past according to the recommendation in the protocol are acceptable
* Patients who have not received prescribed drugs for treatment of AD (including acetyl cholinesterase inhibitors (donepezil, galantamine, rivastigmine, tacrine, phenserine) and Memantine within three months prior to screening
* Patients must have at least 6 years of formal education and fluency in the test language as verbally confirmed by the patient and documented by the study investigator.
* Patients must have given written informed consent in accordance with Good Clinical Practice (GCP) and local legislation prior to any study procedures. All patients must be able to give informed consent personally and have capacity for such consent. An informed consent given by a legal representative will not be accepted.
* Patients must have a reliable study partner (per investigator judgement, for instance a family member, partner, guardian etc.)

Exclusion criteria:

* Mild cognitive impairment with any etiology other than prodromal AD (for example: neurosyphilis, craniocerebral trauma, small vessel disease) based on clinical data and/or current laboratory findings and/or a pre-existing MRI or CT of the brain (CCT). If previous cranial imaging is not available or older than 12 months prior to screening then a CCT or MRI needs to be performed at screening
* Substantial concomitant cerebrovascular disease (defined by a history of a stroke / intracranial haemorrhagia) temporally related to the onset of worsening of cognitive impairment per investigator judgement
* Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer within the last 5 years
* Medical history or diagnosis of any of symptomatic and unstable/uncontrolled conditions per investigator judgement
* Severe renal impairment defined with a glomerular filtration rate (GFR) \< 30ml/min/1.73m2 in the screening central lab report
* Any other psychiatric disorders such as schizophrenia, or mental retardation
* Any suicidal actions in the past 2 years (per investigator judgement i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behaviour)
* Any suicidal ideation of type 4 or 5 in the Columbia Suicide Severity Rating Scale (C-SSRS) in the past 3 months (i.e. active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent)
* Previous participation in investigational drug studies of mild cognitive impairment within three months prior to screening. Having received active treatment in any other study targeting disease modification like Aß immunization and tau therapies. Previous participation in studies with non-prescription medications, vitamins or other nutritional formulations is allowed.
* Significant history of drug dependence or abuse (including alcohol, as defined in Diagnostic and Statistical Manual of Mental Disorders \[DSM-V\] or in the opinion of the investigator) within the last two years, or a positive urine drug screen for cocaine, heroin, or marijuana.
* Known history of HIV infection
* Any planned surgeries requiring general anaesthesia, or hospitalisation for more than 1 day during the study period
* Pre-menopausal women (last menstruation \<= 1 year prior to informed consent) who are nursing or pregnant or are of child-bearing potential and are not practicing an acceptable method of birth control
* For male patients: Men who are able to father a child, unwilling to be abstinent or to use an adequate form of effective contraception for the duration of study participation and for at least 28 days after treatment has ended.
* Use of any investigational drug or procedure for other indications within 3 months or 6 half-lives (whichever is longer) prior to randomization.
* Intake of the following medications within 3 months prior to randomization and intended to be initiated during the duration of the trial:

  1. tricyclic antidepressants,
  2. antidepressants that are monoamine oxidase inhibitors,
  3. neuroleptics with moderate or greater anticholinergic potency (e.g. chlorpromazine, fluphenazine, loxapine, perphenazine, thioridazine),
  4. anticholinergic medications

The following drugs may be given as needed if the total daily dose was stable 8 weeks prior to randomisation and is expected to be for the duration of the trial:

1. neuroleptics listed in the protocol
2. benzodiazepines and sedatives listed in the protocol

   * Clinically significant uncompensated hearing loss in the judgment of the investigator. Use of hearing aids is allowed.
   * Known hypersensitivity to the drug product excipients

Primary outcomes:
measure: Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment.
timeFrame: Baseline and 12 weeks
measure: Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment From Two Twin Trials, Present 1289.5 (NCT02240693) and 1289.7 (NCT02337907)
timeFrame: Baseline and 12 weeks
Secondary outcomes:
measure: Change From Baseline in ADCS-MCI-ADL (Alzheimer's Disease Cooperative Study/Activities of Daily Living for Patients With Mild Cognitive Impairment) Total Score After 12-week Treatment
timeFrame: Baseline and 12 weeks
measure: Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Total Score After 12-week Treatment
timeFrame: Baseline and 12 weeks
measure: Change From Baseline in Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog11) Total Score After 12-week Treatment
timeFrame: Baseline and 12 weeks
Other outcomes:
Locations:
city: Orange
country: United States
facility: Orange County Neuropsychiatric Research Center LLC
state: California
city: Sherman Oaks
country: United States
facility: California Neuroscience Research
state: California
city: West Palm Beach
country: United States
facility: Premiere Research Institute
state: Florida
city: Eatontown
country: United States
facility: Memory Enhancement Center of America, Inc.
state: New Jersey
city: Staten Island
country: United States
facility: Richmond Behavioral Associates
state: New York
city: Charlotte
country: United States
facility: ANI Neurology, PLLC, dba Alzheimer's Memory Center
state: North Carolina
city: Tulsa
country: United States
facility: Tulsa Clinical Research, LLC
state: Oklahoma
city: Hall in Tirol
country: Austria
facility: Landeskrankenhaus Hall, Abt.f. Psychatrie & Psychotherapie A
city: Wien
country: Austria
facility: Private Practice for Psychiatry and Neurology
city: Brussel
country: Belgium
facility: Brussels-UNIV Brugmann -Horta
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Victoria
country: Canada
facility: Royal Jubilee Hospital
state: British Columbia
city: Halifax
country: Canada
facility: True North Clinical Research Halifax, Inc.
state: Nova Scotia
city: Kentville
country: Canada
facility: True North Clinical Research Kentville, Inc.
state: Nova Scotia
city: Toronto
country: Canada
facility: Toronto Memory Program
state: Ontario
city: Quebec
country: Canada
facility: Institut universitaire de geriatrie Sherbrooke
city: Bron
country: France
facility: HOP Pierre Wertheimer
city: Montpellier
country: France
facility: HOP Gui de Chauliac
city: Nantes
country: France
facility: HOP Nord Laënnec
city: Paris
country: France
facility: HOP La Pitié Salpêtrière
city: Poitiers
country: France
facility: HOP Jean Bernard, Géria, Poitiers
city: Berlin
country: Germany
facility: Praxis Dr. med. Volker Schumann
city: Berlin
country: Germany
facility: emovis GmbH
city: Leipzig
country: Germany
facility: AFL Arzneimittelforschung Leipzig GmbH
city: Mannheim
country: Germany
facility: Zentralinstitut für seelische Gesundheit
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Westerstede
country: Germany
facility: Neurologie und Psychiatrie / Psychotherapie
city: Brescia
country: Italy
facility: A.O. Spedali Civili di Brescia
city: Firenze
country: Italy
facility: Osp. S. Giovanni di Dio
city: Roma
country: Italy
facility: Policlinico Gemelli
city: Amsterdam
country: Netherlands
facility: Brain Research Center
city: Bialystok
country: Poland
facility: Podlassian Center of Psychogeriatry, Bialystok
city: Bydgoszcz
country: Poland
facility: Non-Public Outpat. Clinic "Dom Sue Ryder", PALLMED Sp. z o.o
city: Kielce
country: Poland
facility: Non-Public Outpatient Clinic "Synapsa" Pawel Polrola, Kielce
city: Kielce
country: Poland
facility: Mental Health Center Biomed
city: Poznan
country: Poland
facility: Non-Public Outpatient Clinic Neuro-Kard Ilkowski & Partners
city: Sopot
country: Poland
facility: Medical Center Senior
city: Szczecin
country: Poland
facility: EUROMEDIS Sp. z o.o., Szczecin
city: Wroclaw
country: Poland
facility: Reg. Specialist Hospital Wroclaw, Research & Develop. Center
city: Amadora
country: Portugal
facility: Hospital Fernando Fonseca, EPE
city: Coimbra
country: Portugal
facility: CHUC - Centro Hospitalar e Universitário de Coimbra, EPE
city: Lisboa
country: Portugal
facility: CHLO, EPE - Hospital Egas Moniz
city: Lisboa
country: Portugal
facility: CHLN, EPE - Hospital de Santa Maria
city: Alcorcon (Madrid)
country: Spain
facility: Hospital Universitario Fundación Alcorcón
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Barcelona
country: Spain
facility: Hospital Santa Creu i Sant Pau
city: El Palmar (murcia)
country: Spain
facility: Hospital Universitario Virgen de la Arrixaca
city: Sant Cugat del Vallès
country: Spain
facility: Hospital Universitari General de Catalunya
city: Terrasa (Barcelona)
country: Spain
facility: Hospital Mútua Terrassa
city: Bath
country: United Kingdom
facility: Royal United Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Plymouth
country: United Kingdom
facility: Re-Cognition Health
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Frolich L, Wunderlich G, Thamer C, Roehrle M, Garcia M Jr, Dubois B. Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease. Alzheimers Res Ther. 2019 Feb 12;11(1):18. doi: 10.1186/s13195-019-0467-2.