A 3 Year Study to Evaluate the Safety and Efficacy of Low Dose Ladostigil in Patients With Mild Cognitive Impairment

NCT01429623 | Completed Phase 2 Results DMC

• 2 other identifiers: CO177302011-004187-30
• Study Type: interventional
• Target: 210
• Locations: 3 countries
• Sites: 12

Brief Summary

The purpose of this study is to determine whether treatment with the investigational drug ladostigil will delay the onset of Alzheimer's disease(AD) in patients with Mild Cognitive Impairment (MCI). MCI is now recognized as a precursor to AD and clinical tools are available to assess cognitive performance at this earlier stage. Ladostigil is currently under investigation for the treatment of AD. In this study, the investigators will be examining ladostigil at a lower dose level. At this dose level, ladostigil has been shown to reduce signs of early memory loss in animals. Thus, in this study the investigators are attempting to determine if earlier invention with a lower dose of ladostigil will significantly reduce initial memory loss and delay the subsequent progression to more serious cognitive dysfunction.

Conditions

Mild Cognitive Impairment; Dementia

Keywords

Mild Cognitive Impairment; Early Stage Dementia; Conversion to Alzheimer's disease; Memory Impairment

Outcome Measures

Primary Outcomes (1)

• Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo

  Total number of conversions from Mild Cognitive Impairment to Alzheimer's disease across entire 3 year study period. Conversion is determined, or defined, by a Clinical Dementia Rating (CDR) score of greater than or equal to one. Composite rating ranges from 0 no symptoms of dementia to 3 Severe symptoms of dementia.

  3,6,12,18,24,30 and 36 months

Secondary Outcomes (3)

• Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population

  3,6,12,18,24,30 and 36 months

• Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population

  3,6,12,18,24,30 and 36 months

• Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population

  3,6,12,18,24,30 and 36 months

Study Arms (2)

ladostigil hemitartrate

EXPERIMENTAL

10mg ladostigil base

Drug: ladostigil hemitartrate

Placebo Control

PLACEBO COMPARATOR

drug product excipients

Drug: Placebo

Interventions

ladostigil hemitartrate DRUG

10mg ladostigil base administered once daily as hard gelatin capsule

Also known as: ladostigil, Ladostigil capsules

ladostigil hemitartrate

Placebo DRUG

Placebo comparator

Placebo Control

Eligibility Criteria

• Age: 55 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women (non-childbearing potential) with a diagnosis of Mild Cognitive Impairment (MCI) according to consensus criteria as defined by Petersen
• Abnormal memory function will be evaluated by Verbal Paired Associates from the Wechsler Memory Scale - Revised. Norm values for healthy adults in two age cohorts are: a) 50-70 years 19.7 (SD=2.9) and b) 75-95 years 18.3 (SD=2.8). Patients that score \< or = 23 will be included.
• Clinical Dementia Rating (CDR) score of 0.5 (Memory box score 0.5 or 1, no box score \> 1)
• Mini Mental State Examination (MMSE) \> 24 and \< or = 30
• General cognition and functional performance is sufficiently preserved such that a diagnosis of AD can be excluded by the site physician at the time of the screening visit.
• No significant cerebrovascular disease indicated by Modified Hackinski Ischaemic Score equal to or below 4
• Age 55-85 years based upon correlation of cognition and Scheltens score observed in this age range
• Geriatric Depression Scale (GDS) of \< or = 5
• An informer who has frequent contact with the subject (e.g. an average of 10 hours per week or more) is available and agrees to monitor administration of study drug, to observe the subject for adverse events and to accompany the subject to clinical visits during the trial, if the presence of the informer is required.
• All patients have to undergo an MRI scan after the screening visit, i.e. during the screening visit, irrespective of MRIs having been performed prior to entry into the study. MRI findings have to be consistent with a diagnosis of MCI.
• Central rating of medial temporal lobe according to Scheltens scale. The right and left medial temporal structures will be rated separately and an overall estimate will be deduced using the average of the two ratings. An average score \> 1 is required to make patients eligible for the study.
• Adequate visual and auditory acuity must be demonstrated to allow for neuropsychological testing.
• Good general health status acceptable for participation in a 36-month clinical trial, with no additional diseases expected to interfere with the study

You may not qualify if:

• Subject is not pregnant, lactating or of childbearing potential (i.e. women must be two years post menopausal or surgically sterile)
• Signed informed consent by patient and informer prior to any study specific procedure
• Failure to perform screening or baseline examinations
• Any significant neurological disease other than suspected MCI
• Thromboembolic infarction
• Other focal lesions which may be responsible for the cognitive status of the patient such as infectious disease, space-occupying lesions, normal pressure hydrocephalus or any other abnormalities associated with significant central nervous disease
• More than one lacunar infarct defined as a focal lesion of CSF signal intensity with a diameter of \< 1.5cm in any dimension
• Any lacunar infarct in a strategically important location such as the thalamus, hippocampus of either hemisphere, head of the left caudate
• White matter lesions involving more than 25% of the hemispheric white matter
• Implants such as pacemakers, insulin pumps, cochlear implants, nerve stimulators, implantable cardioverter defibrillators, and other medical implants that have not been certified for MRI
• Ferromagnetic foreign bodies such as shell fragments need to be considered on an individual basis
• Metallic implants that can cause artifacts and RF induced heating such as surgical prostheses or aneurysm clips need to be considered on an individual basis
• Clinical or laboratory findings consistent with:
• Central nervous system diseases such as those resulting from severe head trauma, tumours, subdural haematomas or other space occupying processes, etc
• Seizure disorder

Sponsors & Collaborators

• Avraham Pharmaceuticals Ltd: lead

Study Sites (12)

Medizinische Universitat Graz, Abteilung fur Neurologie

Graz, 8036, Austria

Location

Landeskrankenhaus Hall, Memory Klinik

Hall in Tirol, 6060, Austria

Location

Privatordination Rainer

Vienna, 1130, Austria

Location

Studienambulanz St. Joseph Krankenhaus Berlin, Emovis GmbH

Berlin, 13088, Germany

Location

Otto-von-Guericke-Universitat, Universitatsklinik fur Neurologie und fur Stereotaktische

Magdeburg, 30120, Germany

Location

Studienzentrum Nordwest

Westerstede, 26655, Germany

Location

Department of Geriatrics and Memory Clinic, Mental Health Center, Israel

Beersheva, 84170, Israel

Location

Cognitive Neurology Unit, Rambam Health Care Campus

Haifa, 31096, Israel

Location

Cognitive Clinic, Department of Geriatrics, Carmel Medical Center

Haifa, 34362, Israel

Location

Department of Physical Medicine and Rehabilitation, Hadassah University Hospital, PO Box 24035

Jerusalem, 91240, Israel

Location

Memory Clinic, Sheba Medical Center at Tel Hashomer

Ramat Gan, 52621, Israel

Location

Center for Memory and Attention Disorders, Department of Neurology, Sourasky Medical Center

Tel Aviv, 64239, Israel

Location

Related Publications (3)

• Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund LO, Nordberg A, Backman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC. Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004 Sep;256(3):240-6. doi: 10.1111/j.1365-2796.2004.01380.x.

  PMID: 15324367 BACKGROUND

• DeCarli C, Frisoni GB, Clark CM, Harvey D, Grundman M, Petersen RC, Thal LJ, Jin S, Jack CR Jr, Scheltens P; Alzheimer's Disease Cooperative Study Group. Qualitative estimates of medial temporal atrophy as a predictor of progression from mild cognitive impairment to dementia. Arch Neurol. 2007 Jan;64(1):108-15. doi: 10.1001/archneur.64.1.108.

  PMID: 17210817 BACKGROUND

• Schneider LS, Geffen Y, Rabinowitz J, Thomas RG, Schmidt R, Ropele S, Weinstock M; Ladostigil Study Group. Low-dose ladostigil for mild cognitive impairment: A phase 2 placebo-controlled clinical trial. Neurology. 2019 Oct 8;93(15):e1474-e1484. doi: 10.1212/WNL.0000000000008239. Epub 2019 Sep 6.

  PMID: 31492718 DERIVED

MeSH Terms

Conditions

Cognitive Dysfunction; Dementia; Memory Disorders

Interventions

(N-propargyl-(3R) aminoindan-5-yl)-ethyl methyl carbamate

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Jonathan Rabinowitz, PhD
• Organization: Bar Ilan University

Jonathan.Rabinowitz@biu.ac.il

+972544643889

Study Officials

• Tzvi Dwolatzky, MD

  Director, Department of Geriatrics and Memory Clinic, Mental Health Center, Israel P.O. Box 4600, Beersheva 84170

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2011
• First Posted: September 7, 2011
• Study Start: February 1, 2012
• Primary Completion: July 1, 2016
• Study Completion: September 1, 2016
• Last Updated: June 15, 2017
• Results First Posted: June 15, 2017

Record last verified: 2017-06

Locations

AU (3); IL (6); DE (3)