| 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 |
1. 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 |
1. 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
2. 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
3. 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
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
For more information 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 |
To be eligible for enrollment in this study, a subject must meet all of the following inclusion criteria:
1. AD, encompassing probable AD and MCI-AD based on 2011 NIA/AA criteria:
• All cause dementia and probable AD (probable 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 physician 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.
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 (a negative amyloid PET scan within the 3 years prior to Screening is exclusionary)
3. MMSE score of 16-27 (inclusive) at Screening, subject to stratification requirements
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(s) at the study site
• Agrees to accompany the subject to each study visit
• Is able to verify compliance with study drug
9. If the subject has previously taken either an AChEI, i.e., donepezil, galantamine, or rivastigmine, and/or memantine, it must have been discontinued prior to informed consent due to intolerance, lack of efficacy, or recommendation by the primary care provider
• 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 disorder other than probable AD or MCI-AD
2. Significant intracranial focal or vascular pathology seen on brain MRI scan that would, based on the independent reviewer imaging evaluation, lead to a diagnosis other than probable AD or MCI-AD, including but not limited to:
• Large confluent white matter hyperintense lesions
• 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 :
• Cerebrovascular accident
• Transient ischemic attack
• Significant head injury, for example, associated loss of consciousness, skull fracture or persisting cognitive impairment
• Other unexplained or recurrent loss of consciousness ≥15 minutes
4. Diagnosed with epilepsy
5. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria met:
• Major depressive disorder
• Schizophrenia
• Other psychotic disorders, bipolar disorder
• Substance (including alcohol) related disorders
6. Metal implants in the head, pacemaker, cochlear implants, or any other non-removable items that are contraindications to MRI.
7. Resides in hospital or moderate to high dependency continuous care
8. Any physical disability that would prevent completion of study procedures or assessments
9. History of swallowing difficulties
10. Pregnant or breastfeeding
11. G6PD deficiency based on World Health Organization classification
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 below age/sex appropriate lower limit of the central laboratory normal range
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
• TSH above laboratory normal range
14. Clinically significant cardiovascular disease or abnormal assessments such as:
• Hospitalization for acute coronary syndrome or symptoms consistent with angina pectoris, within the 12 months preceding Baseline
• Signs or symptoms of clinical heart failure within the 12 months preceding Baseline
• Atrial fibrillation on Screening ECG or history of atrial fibrillation that is not currently controlled
• QTcF at Screening >460 msec in males or >470 msec in females, or low or flat T waves making measurement of QT interval unreliable
• Recent history of poorly controlled hypertension, systolic blood pressure >180 mmHg, or diastolic blood pressure >100 mmHg
• Hypotension: systolic blood pressure <100 mmHg
• Heart rate <48 bpm or >96 bpm by measurement of vital signs or by local ECG at Screening
15. Pre-existing or current signs or symptoms of respiratory failure,
• Subjects with currently diagnosed moderate to severe sleep apnea should be excluded; the definition of moderate to severe includes oxygen supplementation
16.Concurrent acute or chronic clinically significant immunologic, hepatobiliary, or endocrine disease, and/or other unstable or major disease other than probable AD or MCI-AD; the following are specifically excluded:
• Active hepatitis or primary biliary cirrhosis
• Active Human T-Cell Lymphocytic Virus Type III, Lymphadenopathy Associated Virus, any mutants or derivatives of HLTV-III or LAV, any condition associated with active Acquired Immunodeficiency Syndrome or similar condition however named
17.Diagnosis of cancer meeting either of the following criteria:
• Newly diagnosed within past 2 years
• Previous diagnosis of cancer that has required any form of intervention or treatment within the past 2 years
18.Prior intolerance or hypersensitivity to MT-containing drug or methemoglobinemia induced by MT-containing drug, similar organic dyes, or any of the excipients
19.Treatment currently or within 90 days before Baseline with any of the following:
• Souvenaid®
• Antipsychotics
o Clozapine
o Other antipsychotics are allowable provided they have not been initiated within 90 days before Baseline and preferably at a stable dose and regimen
• Carbamazepine, primidone, valproate
• Drugs for which there is a warning or precaution in the labeling about methemoglobinemia at approved doses (e.g., dapsone, local anesthetics such as benzocaine used chronically, primaquine, and related antimalarials)
20. Current or prior participation in a clinical trial as follows:
• Any clinical trial of LMTM
• Clinical trial of a product for cognition prior to Baseline in which the last dose was received within 90 days prior to Baseline unless confirmed to have been randomized to placebo
• A clinical trial of any other investigational drug, biologic, device, or medical food in which the last dose was received within 28 days prior to Baseline
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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)
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)
• 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 | 7 |
| 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 |
| Canada |
| United States |
| Belgium |
| France |
| Italy |
| Poland |
| Spain |
| United Kingdom |
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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 | |
| 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 |
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