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 | 16.1 |
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 demonstrate the clinical efficacy of leuco-methylthioninium bis(hydromethanesulfonate) (also known as LMTM, TRx0237) in mild Alzheimer’s disease as assessed by change from baseline on:
• Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog11)
• Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change (ADCS-CGIC) - independently rated
2. To evaluate the effect of LMTM on Alzheimer’s disease modification as evidenced by reduction in decline in glucose uptake in the temporal lobe on 18F-flurodeoxyglucose positron emission tomography (FDG-PET) / computerized tomography (CT) imaging
3. To assess the safety and tolerability of LMTM 200 mg/day given for up to 78 weeks |
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E.2.2 | Secondary objectives of the trial |
Secondary:
1. To evaluate the effect of LMTM on functional activities of daily living using the ADCS-ADL23
2. To evaluate the effects of LMTM on other aspects of Alzheimer’s disease including cognition (Mini-Mental Status Examination, MMSE), behavior (Neuropsychiatric Inventory, NPI), and mood (Montgomery-Asberg Depression Rating Scale, MADRS)
Exploratory:
1. To determine the effects of LMTM on Alzheimer’s disease modification by showing retardation of the expected decline in whole brain volume as evaluated by brain magnetic resonance imaging (MRI)
2. To determine the effects of LMTM on resource utilization using the Resource Utilization in Dementia (RUD) Lite
3. To explore changes in certain cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (total tau, p-tau-181, and Aβ42) in subjects who consent to lumbar puncture
4. To explore the influence of the Apolipoprotein E genotype on the primary and selected secondary outcomes (in subjects who provide separate consent) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Diagnosis according to the National Institute on Aging (NIA) and Alzheimer’s Association (AA) criteria of:
• All cause dementia
and
• Probable Alzheimer’s disease
2. Clinical Dementia Rating (CDR) total score of 0.5 or 1 (mild) and MMSE score of 22-26 (inclusive) at Screening
3. Age ≤90 years at Screening
4. Modified Hachinski ischemic score of ≤4 at Screening
5. Females must meet one of the following:
• Surgically sterile (hysterectomy, bilateral oophorectomy) for at least 6 months minimum
• Have undergone bilateral tubal ligation at least 6 months prior
• Post-menopausal for at least 1 year
• Using adequate contraception (such as condoms, foams, jellies, diaphragm, intrauterine device [IUD], oral or long-acting injected contraceptives for at least 3 months prior to Baseline or vasectomized partner) or true abstinence (when this is in line with the preferred and usual lifestyle of the subject; periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception); subjects must agree to continue to maintain adequate contraception throughout participation in the study
6. Subject and/or, in the case of reduced decision-making capacity, legally acceptable representative(s) consistent with national law, is/are able to read, understand, and provide written informed consent in the designated language of the study site
7. Has an identified caregiver who meets the following criteria:
• Either lives with the subject or sees the subject on average for ≥ 2 hours/day ≥ 3 days/week, and 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
• 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 daily compliance with study drug
8. If currently taking an acetylcholinesterase inhibitor (AChEI), i.e., donepezil, galantamine, or rivastigmine, and/or memantine:
• The subject must have been taking such medication(s) for ≥ 3 months
• The current dosage regimen and dosage form must be within the locally approved dose range and must have remained stable for ≥ 6 weeks before Baseline (Visit 2)
• It must be planned that the dosage regimen will remain stable throughout participation in the study
Subjects not being treated with an AChEI or memantine (for ≥ 6 weeks before Baseline) may also be enrolled if initiation of an AChEI or memantine is not planned for the time period during which the subject will be participating in this study
9. Able to comply with the study procedures in the view of the investigator |
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E.4 | Principal exclusion criteria |
1.Significant CNS disorder other than Alzheimer’s disease
2.Significant intracranial focal or vascular pathology seen on brain MRI scan within a maximum of 28 days before Baseline that would lead to a diagnosis other than probable Alzheimer’s disease or that puts the subject at risk of ARIA, including: other focal brain lesions, a single area of superficial siderosis, > 4 cerebral microhemorrhages, evidence of a prior 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 with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 years)
•Other unexplained or recurrent loss of consciousness ≥15 minutes (2 years)
4.Epilepsy (a single prior seizure is considered acceptable)
5.DSM IV-TR criteria met for any of the following within specified period:
•Major depressive disorder (current)
•Schizophrenia (lifetime)
•Other psychotic disorders, bipolar disorder, substance (including alcohol) related disorders (within the past 5 years)
6.Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable items that are contraindications to MR imaging; MR compatible prosthetics, clips, stents, or any other device proven to be compatible will be allowed.
7.Resides in hospital or moderate to high dependency continuous care facility
8.History of swallowing difficulties
9.Pregnant or breastfeeding
10.History of significant hematological abnormality or current acute or chronic clinically significant abnormality, including:
•History of hereditary or acquired methemoglobinemia or baseline measurement of MetHb >2.0%
•History of hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy
•G6PD deficiency
•Baseline value below age/sex appropriate lower limit of the central laboratory normal range for any of the following:
oHemoglobin (subject may be treated and re-screened after 3 months)
oVitamin B12 or folate (subject may be treated and re-screened after 3 months)
11.Abnormal serum chemistry laboratory value at Screening. In addition, subjects with either of the following abnormalities must be excluded: creatinine clearance <30 mL/min at Screening, TSH above laboratory normal range (subject may be treated and re-screened after 3 months)
12.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
•Evidence of atrial fibrillation on ECG or history of atrial fibrillation that is not currently controlled
•QTcB at Screening or Baseline >450 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 >160 mmHg, or diastolic blood pressure >100 mmHg, at Screening or at Baseline
•Hypotension: systolic blood pressure <100 mmHg at Screening or at Baseline
•Heart rate <48 bpm or >96 bpm by measurement of vital signs or by ECG at Screening or at Baseline
13.Preexisting or current signs or symptoms of respiratory failure; in addition, subjects should be excluded if they have: previously diagnosed moderate to severe sleep apnea not adequately controlled
14.Concurrent acute or chronic clinically significant immunologic, hepatic, or endocrine disease (not adequately treated) and/or other unstable or major disease other than Alzheimer’s disease. Subjects with primary biliary cirrhosis should be excluded.
15.Diagnosis of cancer within the past 2 years prior to Baseline (other than basal cell or squamous cell skin cancer or Stage 1 prostate cancer) unless treatment has resulted in complete freedom from disease for at least 2 years
16.Prior intolerance or hypersensitivity to MT-containing drug, similar organic dyes, or any of the excipients
17.Treatment currently or within 3 months before Baseline with any of the following medications:
•Moderate to strong inhibitors of CYP1A2 (e.g., ciprofloxacin, fluvoxamine)
•Tacrine
•Anxiolytics and/or sedatives/hypnotics before cognitive testing (exceptions: sedation for MRI or short-acting benzodiazepines, chloral hydrate, or zolpidem as needed at bedtime)
•Antipsychotics: clozapine, olanzapine. Other antipsychotics are allowable, preferably at a stable dose and regimen.
•Carbamazepine, primidone
•Drugs associated with methemoglobinemia
18.Prior participation in a clinical trial as follows:
•Phase 3 clinical trial of a product for cognition within the 3 months prior to Screening (unless confirmed to have been randomized to placebo)
•A clinical trial of a drug, biologic, or device 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: ADAS-cog11, ADCS-CGIC, FDG-PET/CT.
Primary safety and tolerability endpoints: adverse events (AEs), vital
signs, methemoglobin and oxygen content, 12-lead ECGs, clinical
laboratory findings, physical and neurological examinations, potential for
serotonin toxicity, brain MRI, and potential for suicide or self-harm |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
•ADAS-cog11, ADCS-CGIC: Assessments will be made at Baseline (Visit
2, pre-dose) and after 13, 26, 39, 52, 65, and 78 weeks, and at the 4-
week off-treatment follow-up visit.
•FDG-PET/CT: at Screening/Baseline, at Weeks 39 and 78
•At screening and at each visit: oral T°, respiratory rate, ECG, blood
pressure and pulse (+within 1 hour before and approx. 2 hours after first
dose), MetHB and oxygen content (+approx. 1 hour before and approx.
2.5 hours after first dose), potential for serotonin toxicity, clinical
laboratory testing, and physical and neurological examinations
•AEs: from the ICF signature and throughout the study
•Brain MRI: at Screening, at Weeks 13, 26, 39, 52, 65, and 78
•CSSR-S: at Baseline (+prior clinic discharge), at each visit |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints: ADCS-ADL23, NPI, MADRS, MMSE
Other endpoints: RUD Lite questionnaire, blood samples for PK and
genotyping, cerebrospinal fluid samples, brain MRI
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•ADCS-ADL23, NPI and MADRS: at Baseline, at Weeks 13, 26, 39, 52, 65
and 78, at follow-up visit
•MMSE: at Screening, at Weeks 26, 52 and 78, at follow-up visit
•Brain MRI: at Screening, at Weeks 13, 26, 39, 52, 65, and 78
•Genotyping: single collection at Baseline
•PK: at Baseline, each visit during treatment period
•RUD Lite questionnaire: at Baseline, at Weeks 26, 52 and 78
•Cerebrospinal fluid samples: at Baseline (prior to dosing), at Week 78 |
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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 | No |
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 | No |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
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 | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 33 |
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 |
Croatia |
Netherlands |
Australia |
Finland |
Germany |
Spain |
Poland |
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 | 8 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |