| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 100000004852 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the LMTM dose of 16 mg/day with the placebo group on the following co-primary endpoints:
a. ADAS-cog11
b. ADCS-ADL23
2. To assess the safety and tolerability of LMTM 16 mg/day given for up to 52 weeks |
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| E.2.2 | Secondary objectives of the trial |
3. To compare the LMTM dose of 16 mg/day with the placebo group in annualized rate of whole brain atrophy over 52 weeks as measured by brain MRI and quantified using the BSI
4. To compare the LMTM dose of 16 mg/day with the placebo group in temporal lobe 18F-FDG-PET change in SUVR (normalized to pons) over 52 weeks, restricted to subjects with CDR 0.5 at Screening
5. To compare the LMTM dose of 8 mg/day with the placebo group in temporal lobe 18F-FDG-PET change in SUVR (normalized to pons) over 52 weeks, restricted to subjects with CDR 0.5 at Screening
6. To compare the LMTM dose of 8 mg/day with the placebo group on the co-primary endpoints (ADAS-cog11 and ADCS-ADL23)
7. To compare the LMTM doses of 8 and 16 mg/day with the placebo group in annualized rate of temporal and parietal lobe atrophy over 52 weeks as measured by MRI and quantified using the BSI
For additional secondary objectives please refer to protocol |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| A single blood sample will be obtained only from subjects who provide legally acceptable informed consent for genotyping evaluation of ApoE. The blood sample may be collected any time after eligibility for randomization and continued participation in the study has been confirmed but prior to Visit 7 (end of double-blind treatment period). A volume of approximately 2 mL is to be collected and shipped ambient to the central laboratory (Covance) on the day of collection. Genotyping results will not be provided to the study sites or to subjects. |
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| E.3 | Principal inclusion criteria |
1. AD, encompassing probable AD and mild cognitive impairment due to AD (MCI-AD) based on 2011 National Institute on Aging (NIA)/ Alzheimer's Association (AA) criteria
• All cause dementia and probably AD (probably AD) In brief, subjects with probable AD dementia must have insidious onset, worsening impairment in at least two cognitive areas (learning and recall, language, executive function, visuospatial skills), sufficient to significantly interfere with work or usual activities, that is not explained by delirium, drugs, major psychiatric disorder, medical illness, cerebrovascular disease, other forms of dementia, or neurological disorder. The accuracy of the diagnosis will be confirmed independently by the diagnosing phisician at site
OR
• MCI-AD In subjects with MCI-AD, there should be evidence of concern about a change in cognition, in comparison with the person's previous level verified by a knowledgeable informant or clinician. Other mild
cognitive deficits may also be present, but there must be preservation of independence in functional abilities. Subjects should not meet the criteria for dementia. The cognitive changes must be mild and there must be no evidence of a significant impairment in social or occupational functioning. Impairments must not be explained by delirium, drugs, major psychiatric disorder, medical illness, cerebrovascular disease, other forms of dementia, or neurological disorder.
2.Documented PET scan that is positive for amyloid; if most recent PET scan was performed >3 years prior to Screening and was negative, it
may be repeated (subjects are not eligible if their most recent PET scan was performed within the 3 years prior to Screening and was negative)
3. MMSE score of 16-27 (inclusive) at Screening
4. Global CDR score of 0.5 to 2 at Screening (if 0.5, including a score of > 0 in one of the functional domains: Community Affairs, Home and Hobbies, or Personal Care)
5. Age < 90 years at Screening
6. Females must meet one of the following:
• Surgically sterile (hysterectomy, bilateral salpingectomy / oophorectomy) for at least 6 months minimum
• Have undergone bilateral tubal occlusion / ligation at least 6 months prior
• Post-menopausal for at least 1 year
• Using adequate contraception (a barrier method [such as condom, diaphragm or cervical/vault cap] with spermicidal foam, gel, film, cream,
or suppository; intrauterine device [IUD] or system, or oral or long-acting injected or implanted hormonal contraceptives for at least 90
days prior to Baseline; or vasectomized partner [with the appropriate post-vasectomy documentation of the absence of spermatozoa in the
ejaculate]) or true abstinence (when this is in line with the preferred and usual lifestyle of the subject); subjects must be competent to use
adequate contraception and to agree to continue to maintain adequate contraception throughout participation in the study (including up to 4
weeks after the last dose of study drug).
7. Subject and/or, in the case of reduced decision-making capacity, legally acceptable representative(s) (LAR(s)), consistent with local and national law, is able to read, understand and provide written informed
consent in the designated language of the study site
8. Has one or more identified adult study partner (i.e. a caregiver or informant) who meets the following criteria:
• Either lives with the subject , or in the investigator's opinion, the extent of contact is sufficient to provide meaningful assessment of
changes in subject behavior and function over time and provide information on safety and tolerability (e.g., sees the subject on average
for ≥1 hour/day ≥3 days/week)
• Is willing to provide written informed consent for his/her own participation
• Is able to read, understand, and speak the designated language at the study site
• Agrees to accompany the subject to each study visit
• Is able to verify compliance with study drug
9. The subject must not have been taking either an AChEI, i.e., donepezil, galantamine, or rivastigmine, and/or memantine, for at least 60 days at the time of the Baseline assessments
•Screening may be extended for subjects who are using (or have recently discontinued) an AChEI and/or memantine at the initial Screening visit.
•Subjects never previously treated with an AChEI and/or memantine may be enrolled if initiation of treatment with these medications is not
planned for the time period during which the subject will be participating in this study.
10. Able to comply with the study procedures in the view of the investigator |
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| E.4 | Principal exclusion criteria |
1. Significant central nervous system (CNS) disorder other than probable Alzheimer’s disease or MCI-AD, e.g., Lewy body dementia, Parkinson’s disease, multiple sclerosis, progressive supranuclear palsy, hydrocephalus, Huntington’s disease, any condition directly or indirectly caused by Transmissible Spongiform Encephalopathy (TSE), CreutzfeldtJakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), or new variant Creutzfeldt-Jakob Disease (nvCJD)
2. Significant intracranial focal or vascular pathology seen on brain MRI scan within a maximum of 42 days before Baseline that would, based on the independent reviewer imaging evaluation, lead to a diagnosis other than probable Alzheimer’s disease or MCI-AD, including but not limited to:
•Large confluent white matter hyperintense lesions (i.e., Fazekas score of 3)
•Other focal brain lesions judged clinically relevant by the investigator
•Evidence of a prior or current macrohemorrhage
3. Clinical evidence or history of any of the following (within specified
period prior to Baseline):
• Cerebrovascular accident (2 years)
• Transient ischemic attack (6 months)
• Significant head injury, for example, with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 years)
• Other unexplained or recurrent loss of consciousness (2 years)
4. Diagnosed with epilepsy (a single prior seizure >6 months prior to Screening, is considered acceptable)
5. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria met (for any of the following within specified period:
• Major depressive disorder (current)
• Schizophrenia (lifetime)
• Other psychotic disorders, bipolar disorder (within the past 5 years)
• Substance (including alcohol) related disorders (within the past 2 years)
6. Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable items that are contraindications to MRI. MRI compatible prosthetics, clips, stents, or any other device proven to be compatible are allowed
7. Resides in hospital or moderate to high dependency continuous care facility (residence in low grade assisted living facility where there is sufficient autonomy to permit valid evaluation of activities of daily living is allowed so long as it is not mandated by an order issued either by the judicial or the administrative authorities)
8.Any physical disability that would prevent completion of study procedures or assessments (e.g., blindness or significant uncorrected visual impairment, deafness or significant hearing loss not corrected by hearing aids, non AD-related speech impairment)
9. History of swallowing difficulties (note: study drug should be swallowed whole and MUST NOT be broken, crushed, chewed, or dissolved in fluids prior to ingestion)
10. Pregnant or breastfeeding
11. Glucose-6-phosphate dehydrogenase (G6PD) deficiency based on World Health Organization classification (<60% of normal, i.e., <6.1 U/g
hemoglobin [Hgb])
12. History of significant hematological abnormality or current acute or chronic clinically significant abnormality, including:
• History of hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy
• Screening HgB value (confirmed upon repeat) below age/sex appropriate lower limit of the central laboratory normal range. Subjects in whom folate is < 4.0 ng/mL may be entered into the study provided folate supplementation (approximately 1 mg/day) is initiated and maintained for the duration of the study. Subjects in whom Vitamin B12 is < 150 pg/mL can be allowed if the investigator confirms that it does not affect the cognitive state of the subject and that the subject is supplemented as appropriate prior to the initiation of study drug
13. Abnormal serum chemistry laboratory value at Screening deemed to be clinically significant by the investigator. In addition, subjects with either of the following abnormalities must be excluded:
• Creatinine clearance <30 mL/min, estimated by the central laboratory according to the Cockcroft and Gault equation
• Thyroid stimulating hormone (TSH) above laboratory normal range (subject may be treated [if clinically indicated based on further laboratory testing] and re-screened after 90 days)
For exclusion criteria 14 to 20 please refer to the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoints for Double-Blind Treatment Period
• ADAS-cog11 (LMTM 16 mg/day versus placebo)
• ADCS-ADL23 (LMTM 16 mg/day versus placebo) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints for Double-Blind Treatment Period
• Annualized rate of whole brain atrophy on brain MRI using BSI (LMTM 16 mg/day versus placebo)
• Difference in temporal lobe 18F-FDG-PET change in SUVR normalized to pons in subjects with CDR 0.5 at Screening (LMTM 16 mg/day versus placebo, and LMTM 8 mg/day versus placebo)
• ADAS-cog11 and ADCS-ADL23 (LMTM 8 mg/day versus placebo)
• Annualized rate of temporal and parietal lobe atrophy on brain MRI using BSI (LMTM 16 mg/day versus placebo, and LMTM 8 mg/day versus placebo)
17.1.3 Secondary Endpoint for Open-Label, Delayed-Start Phase
• Difference in disease progression on the co-primary clinical endpoints and the MRI imaging endpoint for subjects who started treatment in the double-blind treatment phase and those who started treatment in the
open-label, delayed-start phase (referred to as "early" and "late" LMTM starters, respectively)
o Only ADAS-cog11 will serve as a secondary endpoint; ADCS-ADL23 and other imaging endpoints are exploratory with the aim to be directionally supportive
For exploratory endpoints, please refer to protocol. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| open label study following double blind period |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 51 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| Canada |
| France |
| Italy |
| Poland |
| Spain |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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