Alzheimer Disease Proof of Concept Study With BI 409306 Versus Placebo

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

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

Study Overview

• Status: Completed
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Placebo; Drug: BI 409306

• Study Type: Interventional
• Enrollment (Actual): 128
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Hall in Tirol, Austria, 6060
    • Landeskrankenhaus Hall, Abt.f. Psychatrie & Psychotherapie A
  • Wien, Austria, 1130
    • Private Practice for Psychiatry and Neurology
• Belgium
  • Brussel, Belgium, 1020
    • Brussels-UNIV Brugmann -Horta
• Canada
  • Quebec, Canada, J1J 3H5
    • Institut universitaire de geriatrie Sherbrooke
  • Alberta
    • Calgary, Alberta, Canada, T2N 4Z6
      • University of Calgary
  • British Columbia
    • Victoria, British Columbia, Canada, V8R 1J8
      • Royal Jubilee Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3S 1M7
      • True North Clinical Research Halifax, Inc.
    • Kentville, Nova Scotia, Canada, B4B 4K9
      • True North Clinical Research Kentville, Inc.
  • Ontario
    • Toronto, Ontario, Canada, M3B 2S7
      • Toronto Memory Program
• France
  • Bron, France, 69677
    • HOP Pierre Wertheimer
  • Montpellier, France, 34295
    • HOP Gui de Chauliac
  • Nantes, France, 44093
    • HOP Nord Laennec
  • Paris, France, 75651
    • HOP La Pitié Salpêtrière
  • Poitiers, France, 86021
    • HOP Jean Bernard, Géria, Poitiers
• Germany
  • Berlin, Germany, 10629
    • emovis GmbH
  • Berlin, Germany, 10245
    • Praxis Dr. med. Volker Schumann
  • Leipzig, Germany, 04107
    • AFL Arzneimittelforschung Leipzig GmbH
  • Mannheim, Germany, 68159
    • Zentralinstitut für seelische Gesundheit
  • Ulm, Germany, 89081
    • Universitatsklinikum Ulm
  • Westerstede, Germany, 26655
    • Neurologie und Psychiatrie / Psychotherapie
• Italy
  • Brescia, Italy, 25123
    • A.O. Spedali Civili di Brescia
  • Firenze, Italy, 50143
    • Osp. S. Giovanni di Dio
  • Roma, Italy, 00168
    • Policlinico Gemelli
• Netherlands
  • Amsterdam, Netherlands, 1081 GN
    • Brain Research Center
• Poland
  • Bialystok, Poland, 15-732
    • Podlassian Center of Psychogeriatry, Bialystok
  • Bydgoszcz, Poland, 85-796
    • Non-Public Outpat. Clinic "Dom Sue Ryder", PALLMED Sp. z o.o
  • Kielce, Poland, 25-103
    • Non-Public Outpatient Clinic "Synapsa" Pawel Polrola, Kielce
  • Kielce, Poland, 25-411
    • Mental Health Center Biomed
  • Poznan, Poland, 61-853
    • Non-Public Outpatient Clinic Neuro-Kard Ilkowski & Partners
  • Sopot, Poland, 81-855
    • Medical Center Senior
  • Szczecin, Poland, 70-111
    • EUROMEDIS Sp. z o.o., Szczecin
  • Wroclaw, Poland, 51-124
    • Reg. Specialist Hospital Wroclaw, Research & Develop. Center
• Portugal
  • Amadora, Portugal, 2700-276
    • Hospital Fernando Fonseca, EPE
  • Coimbra, Portugal, 3000-075
    • CHUC - Centro Hospitalar e Universitário de Coimbra, EPE
  • Lisboa, Portugal, 1349-019
    • CHLO, EPE - Hospital Egas Moniz
  • Lisboa, Portugal, 1649-035
    • CHLN, EPE - Hospital de Santa Maria
• Spain
  • Alcorcon (Madrid), Spain, 28922
    • Hospital Universitario Fundacion Alcorcon
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08041
    • Hospital Santa Creu i Sant Pau
  • El Palmar (murcia), Spain, 30120
    • Hospital Universitario Virgen de la Arrixaca
  • Sant Cugat del Vallès, Spain, 08190
    • Hospital Universitari General de Catalunya
  • Terrasa (Barcelona), Spain, 08221
    • Hospital Mutua Terrassa
• United Kingdom
  • Bath, United Kingdom, BA1 3NG
    • Royal United Hospital
  • Plymouth, United Kingdom, PL21 9AB
    • Derriford Hospital
  • Plymouth, United Kingdom, PL6 8BT
    • Re-Cognition Health
• United States
  • California
    • Orange, California, United States, 92868
      • Orange County Neuropsychiatric Research Center LLC
    • Sherman Oaks, California, United States, 91403
      • California Neuroscience Research
  • Florida
    • West Palm Beach, Florida, United States, 33407
      • Premiere Research Institute
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Memory Enhancement Center of America, Inc.
  • New York
    • Staten Island, New York, United States, 10312
      • Richmond Behavioral Associates
  • North Carolina
    • Charlotte, North Carolina, United States, 28270
      • ANI Neurology, PLLC, dba Alzheimer's Memory Center
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • Tulsa Clinical Research, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo
Experimental: BI 409306 dose 1	Drug: Placebo; Drug: BI 409306
Experimental: BI 409306 dose 2	Drug: Placebo; Drug: BI 409306
Experimental: BI 409306 dose 3	Drug: Placebo; Drug: BI 409306
Experimental: BI 409306 dose 4	Drug: Placebo; Drug: BI 409306

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Neuropsychological Test Battery in Total Z-score After 12-week Treatment.	Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. Change from baseline will be calculated as the post-baseline composite z-score minus the pre-treatment z-score, such that a positive change indicates an improvement from baseline	Baseline and 12 weeks
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)	Neuropsychological Test Battery (NTB) response, defined as change from baseline in total z-score after 12 weeks of treatment. The NTB Z-score indicates the number of standard deviations away from the mean. A Z-score of 0 is equal to the mean at baseline. Negative numbers indicate values lower than baseline and positive numbers indicate values higher than baseline. Change from baseline will be calculated as the post-baseline composite z-score minus the pre-treatment z-score, such that a positive change indicates an improvement from baseline	Baseline and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) is a rating scale used to assess basic and instrumental activities of daily living. In the full version of the scale, 23 items are rated by the investigator using information supplied by the caregiver. Each item has a score range varying from 0-3 to 0-5. The sum score can range from 0 to 78. Higher scores indicate better function. Least Squares Mean is actually an adjusted mean change from baseline.	Baseline and 12 weeks
Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) Total Score After 12-week Treatment	The CDR-SB is obtained through semi-structured interviews of patients and informants, and cognitive functioning was rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Each domain was rated on a 5-point scale of functioning as follows: 0-no impairment; 0.5-questionable impairment; 1-mild impairment; 2-moderate impairment and 3-severe impairment. Only personal care was scored on a 4-point scale without a 0.5 rating available. The higher the score, the greater the severity of dementia. Least Squares Mean is actually an adjusted mean change from baseline.	Baseline and 12 weeks
Change From Baseline in Alzheimer's Disease Assessment Scale-cognitive Subscale (ADAS-cog11) Total Score After 12-week Treatment	Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog11) is an 11-item cognitive subscale that objectively measures memory, language, orientation, and praxis with a total score range of 0 to 70. The greater the dysfunction, the greater the score. Least Squares Mean is actually an adjusted mean change from baseline.	Baseline and 12 weeks

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2015
• Primary Completion (Actual): September 18, 2017
• Study Completion (Actual): October 9, 2017

Study Registration Dates

• First Submitted: September 15, 2014
• First Submitted That Met QC Criteria: September 15, 2014
• First Posted (Estimate): September 16, 2014

Study Record Updates

• Last Update Posted (Actual): November 28, 2018
• Last Update Submitted That Met QC Criteria: October 31, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Phosphodiesterase Inhibitors; BI 409306
• Other Study ID Numbers: 1289.5; 2013-005031-24 (EudraCT Number)