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Mild Cognitive ImpairmentPhase 2NCT01429623

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

A Phase 2 study testing ladostigil hemitartrate in people with Mild Cognitive Impairment and Dementia, run by Avraham Pharmaceuticals Ltd at 12 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 55 to 85 years
Conditions the study is for
Mild Cognitive Impairment, Dementia
What is being tested?
ladostigil hemitartrate
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
210 participants
Where
12 sitesin 3 countries
Study dates
Feb 2012to Sep 2016
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 55 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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
  • ECG without clinically significant abnormalities according to exclusion criteria listed below
  • 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

Who cannot join

  • Failure to perform screening or baseline examinations
  • Any significant neurological disease other than suspected MCI
  • MRI exclusion criteria which allow for mild concomitant vascular lesions are:
  • 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
Show all 36Show fewer
  • 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
  • Other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc)
  • History or evidence of schizophrenia or bipolar disorder (DSM IV criteria); active major depression
  • Clinically significant advanced or unstable disease that may interfere with primary or secondary variable evaluations, and which may bias the assessment of the clinical or mental status of the patient or put the patient at special risk, such as:
  • Malignant tumours within the last five years except skin malignancies (other than melanoma) or indolent prostate cancer
  • Metastases
  • History of myocardial infarction within one year prior to screening or unstable or severe cardiovascular disease including angina or congestive heart failure with symptoms at rest
  • Uncontrolled hypertension (systolic pressure > 170mmHg or diastolic pressure > 100mmHg)
  • Bradycardia (persistent heart beat < 50/min) or tachycardia ( persistent heart beat > 100/min)
  • AV block (type II / Mobitz II and type III), congenital long QT syndrome, sinus node dysfunction or prolonged QTcB-interval (males > 450msec, females > 470msec)
  • Clinically significant obstructive pulmonary disease or asthma
  • Clinically significant laboratory findings that indicate abnormalities in blood biochemistry, blood haematology or urinalysis
  • Uncontrolled diabetes mellitus defined by HbA1c > 8.5
  • Clinically significant liver disease, coagulopathy or vitamin K deficiency within the past two years prior to screening
  • Renal insufficiency (serum creatinine > mg/dl or creatinine clearance < or = to 45ml/min according to Cockgroft-Gault formula); in case of creatinine clearance < or = 45ml/min, an alternative verification of the renal function must be completed using cystatin C analysis. In case of normal level of cystatin C, the patient can be included in the study.
  • Any prior use of medications approved by local authorities for the treatment of Alzheimer's disease (e.g. tacrine, donepezil, rivastigmine, galantamine, memantine or other newly approved medications)
  • Disability that may prevent the subject from completing all study requirements (e.g. blindness, deafness, severe language difficulty, etc)
  • Women who are fertile and of child bearing potential
  • Chronic daily intake of antidepressants as noted in section 9.5 of the clinical study protocol
  • Suspected or known drug or alcohol abuse, i.e. more than approximately 60g alcohol (approximately 1 lter of beer or 0.5 liter of wine) per day as indicated by elevated MCV significantly above normal value at screening
  • Suspected or known allergy to any components of the study treatments
  • Enrollment in another investigational study or intake of investigational drug within the previous three months
  • Any condition (e.g. epilepsy) which in the opinion of the investigator makes the patient unsuitable for inclusion

Trial locations and contacts

12 sites in 3 countries.

12 sites in 3 countries

Israel6 sites

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

    Beersheva, 84170

  • Cognitive Neurology Unit, Rambam Health Care Campus

    Haifa, 31096

  • Cognitive Clinic, Department of Geriatrics, Carmel Medical Center

    Haifa, 34362

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

    Jerusalem, 91240

  • Memory Clinic, Sheba Medical Center at Tel Hashomer

    Ramat Gan, 52621

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

    Tel Aviv, 64239

Other trials in Israel

Austria3 sites

  • Medizinische Universitat Graz, Abteilung fur Neurologie

    Graz, 8036

  • Landeskrankenhaus Hall, Memory Klinik

    Hall in Tirol, 6060

  • Privatordination Rainer

    Vienna, 1130

Other trials in Austria

Germany3 sites

  • Studienambulanz St. Joseph Krankenhaus Berlin, Emovis GmbH

    Berlin, 13088

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

    Magdeburg, 30120

  • Studienzentrum Nordwest

    Westerstede, 26655

Other trials in Germany

About this study

Official title: A 36-month, Multi-centre, Randomized, Double Blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of Low Dose Ladostigil in Patients With Mild Cognitive Impairment (MCI)

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.

Read the detailed description

Ladostigil shows neuroprotective activity, reducing oxidative stress, activating microglia, and inhibiting pro-inflammatory cytokines in pre-clinical models. Study assessed its safety and potential efficacy in a 3-year, randomised, double-blind, placebo-controlled, phase 2 clinical trial in patients with mild cognitive impairment (MCI). Patients from 16 centers in Austria, Germany and Israel with MCI (Albert et al 2011), Clinical Dementia Rating (CDR) = 0.5, Mini-Mental State Examination (MMSE) > 24, Wechsler Memory Scale - Revised Verbal Paired Associates ≤ 18, and medial temporal lobe atrophy were stratified by APOE4 genotype and randomly assigned (1:1 allocation) using blocks of 4, to receive either ladostigil, 10 mg per day, or placebo as identically-appearing capsules. The primary endpoint was onset of Alzheimer's disease (AD). Secondary endpoints were the NTB, DAD, and GDS. Exploratory outcomes were MRI-derived whole brain, hippocampus, and entorhinal cortex volumes; the NeuroTrax Mindstreams computerized cognitive battery; and the CDR. Between February 17, 2012 and August 1, 2013, we randomly allocated 210 patients to placebo (107 patients) or ladostigil (103 patients); 4 patients in each group lacked post baseline assessments. After 36 months 20.4% (21 of 103 patients) of the placebo group and 14.1% (14 of 99 patients) of the ladostigil group progressed to AD (log-rank test p=.16). There were no significant effects on NTB, DAD, or GDS outcomes. There was less decline in whole brain volume in the ladostigil group as compared to placebo (p<.02), but not hippocampus and entorhinal cortex volumes, and CDR and a trend for less decline on the RAVLT total delayed score component of the NTB (p=.09). Fourteen patients taking placebo and 21 taking ladostigil discontinued treatment because of adverse events. Serious adverse events were reported by 26 (25.2%) patients in the ladostigil group and 28 (26.2%) patients in the placebo group. Ladostigil appeared safe, well-tolerated, and may have potential for improving memory and delaying progression to dementia.

Being tested
ladostigil hemitartrate, Placebo
Keywords
Mild Cognitive Impairment, Early Stage Dementia, Conversion to Alzheimer's disease, Memory Impairment
Medical subject headings
Cognitive Dysfunction, Dementia, Memory Disorders

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ladostigil hemitartrateDrug

    Also called ladostigil, Ladostigil capsules

    10mg ladostigil base administered once daily as hard gelatin capsule

  • PlaceboDrug

    Placebo comparator

Study groups in NCT01429623
Study groupRoleWhat they receive
ladostigil hemitartrateExperimental10mg ladostigil base
Receives: Drug: ladostigil hemitartrate
Placebo ControlPlacebo comparatordrug product excipients
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (3)

  1. Change in Geriatric Depression Scale for Ladostigil Versus Placebo Population

    Mean value change (from baseline) in Geriatric Depression Scale (GDS) across entire study period. The GDS ranges from 0 to 30. Scores of 0-9 are considered "normal", 10-19 "mildly depressed", and 20-30 "severely depressed".

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

  2. Change in Neuropsychiatric Test Battery for Ladostigil Versus Placebo Population

    Mean value change (from baseline) in Neuropsychiatric Test Battery (NTB) across entire study period. The NTB included the following well known cognitive tests: Rey Auditory Verbal Learning Test (RAVLT), Controlled Word Association Test (COWAT), Category Fluency Test (CFT), WMS-R Digit Span, and Trail Making Part A and B. The mean value was comprised of the z score of each of these tests with all z scores in the direction of higher scores better functioning. Range -3 to +3.

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

  3. Change in Disability Assessment in Dementia for Ladostigil Versus Placebo Population

    Mean value change (from baseline) in Disability Assessment in Dementia (DAD) across entire study period. DAD evaluates the basic and instrumental activities in daily activities of elderly people with dementia. Higher scores reflect better functioning. DAD ranges from 0 to 100.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted7 Sep 2011 (estimated)
  2. Study startFeb 2012
  3. Primary completionJul 2016
  4. Study completionSep 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
210 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01429623
Sponsor's protocol ID
CO17730
Other IDs
2011-004187-30
Status last verified
Jun 2017
First submitted
3 Sep 2011
Last updated
15 Jun 2017
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 15324367

  • 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.

    PubMed 17210817

  • 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.

    PubMed 31492718

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing ladostigil hemitartrate in people with Mild Cognitive Impairment and Dementia, run by Avraham Pharmaceuticals Ltd at 12 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 16 inclusion and 36 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 12 sites in Israel, Austria, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Jun 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Conversion From Mild Cognitive Impairment to Alzheimer's Disease Compared to Placebo (time frame: 3,6,12,18,24,30 and 36 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01429623, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jun 2017.

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Clinical Trial NCT01429623 | AzTrials