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 | 18.0 |
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 demonstrate clinical efficacy of at least one dose level of leuco-methylthioninium bis(hydromethanesulfonate) (also known as LMTM, TRx0237) in mild to moderate Alzheimer’s disease based on change from baseline on the following co-primary endpoints:
•Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog11)
and
•Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL23)
2.To assess the safety and tolerability of LMTM 150 and 250 mg/day given for up to 65 weeks
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E.2.2 | Secondary objectives of the trial |
Secondary:
3.To demonstrate disease modification based:
•Reduction in decline in whole brain volume using change from Baseline as measured by the BBS Integral by MRI imaging
4.evaluate the effect of LMTM on a global measure, ADCS-CGIC – independently rated
5.To evaluate the effects of LMTM on other aspects of AD including cognition (MMSE)
Exploratory:
6.To determine the effects of LMTM on AD by showing retardation of the rate of brain atrophy by reducing the expected increase in ventricular volume and decline in hippocampal volume as evaluated by MRI
7.evaluate the effect of LMTM on AD modification by reduction in decline in glucose uptake in the temporal lobe on FDG-PET imaging in sites with appropriate capability
8.To determine the effects of LMTM on resource utilization using the RUD Lite
9.explore changes in CSF
biomarkers of AD in subjects who are mentally capable of providing their own separate IC & agree to have lumbar puncture performed
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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 1 (mild) to 2 (moderate) and Mini-Mental State Examination (MMSE) score of 14-26 (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 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 methor [such as condom,
diaphragm or cervical/vault cap] with spermicidal foam, gel, film, cream
or suppository; intrauterine device [IUD] or system; or oral or longacting
injected or implanted hormonal contraceptives for at least 3 months
prior to Baseline; or vasectomized partner [with the appropriate postvasectomy
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 OR In Italy, have avoided a pregnancy for at least 3 months prior to Baseline and accept to avoid a pregnancy 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
• In Germany, subjects must be able to provide their own written
informed consent
7. Has one or more identified adult caregivers who meet the
followingcriteria:
• Either lives with the subject or sees the subject on average for ≥ 2
hours/day ≥ 3 days/week, 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
• 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 at the time
of the Screening:
• 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
• 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 Screening) 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.CNS disorder other than AD
2.intracranial focal or vascular pathology seen on brain MRI scan within a max of 42 days before Baseline that would lead to a diagnosis other than probable AD or that puts the subject at risk of ARIA, incl: large confluent white matter hyperintense lesions, other focal brain lesion(s), 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 before Baseline:
•Cerebrovascular accident (2 yrs)
•Transient ischemic attack (6 mnts)
•Significant head injury with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 yrs)
•Other unexplained or recurrent loss of consciousness ≥15 mins (2 yrs)
4.Epilepsy (single prior seizure is acceptable)
5.DSM IV-TR criteria met for any of the following:
•Major depressive disorder (current)
•Schizophrenia (lifetime)
•Other psychotic disorders, bipolar disorder (in past 5yrs), or substance (including alcohol) related disorders (in 2yrs)
6.Metal implants in the head (except dental), pacemaker, cochlear implants, or any non-removable items that are contraindications to MR imaging; MR compatible prosthetics, clips, stents, or any device proven to be compatible will be allowed.
7.Resides in hospital or moderate to high dependency on care facility.
8.History of swallowing difficulties
9.Pregnant/breastfeeding
10.G6PD deficiency
11.History of significant hematological abnormality or current acute or chronic clinically significant abnormality, inc:
•History of hereditary or acquired methemoglobinemia or baseline measurement of MetHb >2.0%
•History of hemoglobinopathy, myelodysplastic hemolytic anemia, or splenectomy
•Screening hemoglobin value below age/sex appropriate lower limit of the central lab normal range for any of the following: hemoglobin &vitamin B12 or folate (subject may be treated and re-screened after 3 mths)
12.Abnormal serum chemistry value at Screening. Subjects with either : creatinine clearance <30 mL/min at Screening &TSH above lab normal range (subject may be treated &re-screened after 3 mths)
13.Clinically significant cardiovascular disease or abnormal assessments such as:
•Hospitalization for acute coronary syndrome or symptoms consistent with angina pectoris, within the 12 mnts preceding Baseline
•Signs/symptoms of clinical heart failure within the 12 mnts receding Baseline
•Evidence of uncontrolled atrial fibrillation on Screening ECG or history of atrial fibrillation that is not currently controlled or where the QT interval cannot be assessed by triplicate ECGs
•QTcF at Screening >460 msec 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
•Hypotension: systolic blood pressure <100 mmHg at Screening
•Heart rate <48 bpm or >96 bpm by measurement of vital signs or by ECG at Screening
14.Preexisting or current signs / symptoms of respiratory failure. Subjects with previously diagnosed moderate - severe sleep apnea not adequately controlled should be excluded.
15.Concurrent acute /chronic clinically significant immunologic, hepatic, or endocrine disease (not adequately treated) and/or unstable or major disease other than AD.
•Subjects with hepatitis or primary biliary cirrhosis should be excluded.
•HTLV-III, LAV, any mutants/derivatives of HLTV-III or LAV, any condition associated with AIS
16.Diagnosis of cancer within the past 2 yrs 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 yrs
17.Prior intolerance or hypersensitivity to MT-containing drug, similar organic dyes, or any of the excipients
18.Treatment currently or within 3 months before Baseline with any of the following medications (unless otherwise noted; see Section 4.7.4):
•Tacrine
•Antipsychotics
oClozapine, olanzapine (and there is no intent to initiate therapy during the course of the study)
oOther antipsychotics are allowable provided they have not been initiated within 3 months before Baseline and preferably at a stable dose and regimen
•Carbamazepine, primidone
•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)
19.Current or prior participation in a clinical trial as follows:
•trial of a product for cognition prior to Screening in which the last dose was received within 90 days prior to Screening unless confirmed to have been randomized to placebo
•A trial of a drug, biologic, therapeutic device, or medical food in which the last dose/administration 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessments will be made at Baseline (Visit 2, pre-dose), after 13, 26, 39, and 65 weeks of treatment, and at the 4 week off-treatment follow-up visit. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints: ADCS-ADL23, MMSE, FDG-PET/CT, CDR
Secondary safety and tolerability endpoints: adverse events (AEs), vital sign and methemoglobin measurements, 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.5.2.1 | Timepoint(s) of evaluation of this end point |
•ADCS-ADL23: at Baseline, after 13, 26, 39, 52 and 65 weeks of treatment, at follow-up visit.
•MMSE: at Screening, after 26 52 and 65 weeks of treatment, at follow-up visit.
•FDG-PET/CT: at Screening/Baseline and after 26 and 52 weeks of treatment.
•CDR: at Screening.
•AEs: from the ICF signature and throughout the study.
•Lab testing:at Screening,Baseline,Visits 3 - 10
•Serotonin toxicity:at Baseline &at each subsequent visit
•Brain MRI:at Screening & at Weeks 13,26,39,52,65
•At screening & each visit: oral T°, respiratory rate, ECG, BP &pulse (+within 1 hour before & approx. 2 hours after administration of the first dose), MetHB (+approx. 1 hour before &approx. 2.5 hrs after administration of the first dose of study drug). |
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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 | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 50 |
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 |
Australia |
Bulgaria |
Canada |
Croatia |
Germany |
Italy |
Korea, Republic of |
Malaysia |
Poland |
Romania |
Russian Federation |
Singapore |
Spain |
Taiwan |
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 | 3 |
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 | 6 |