| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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 leuco-methylthioninium bis(hydromethanesulfonate) (also known as LMTM, TRx0237) in mild Alzheimer's disease based on change from baseline on the following coprimary
endpoints:
• Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAScog11)
and
• Alzheimer's Disease Cooperative Study – Activities of Daily Living (ADCS-ADL23)
2. To assess the safety and tolerability of LMTM 200 mg/day given for up
to 78 weeks
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
1.To further demonstrate disease modification based on the following
key secondary endpoint:
•Reduction in decline in whole brain volume (WBV) using change from
Baseline as measured by the Brain Boundary Shift Integral (BBSI) by
MRI imaging
2.To evaluate the effect of LMTM on a global measure, Alzheimer's
Disease Cooperative Study – Clinical Global Impression of Change
(ADCS-CGIC) – independently rated
3.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) |
|
| 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 20-26 (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 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 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 Baselineand accept to avoid a pregnancy 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, subject must be able to provide their own written informed consent
7. Has one or more identified adult caregivers who meet the following criteria:
•• 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 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 |
|
| E.4 | Principal exclusion criteria |
1.Significant CNS disorder other than AD 2.Significant intracranial focal or vascular pathology seen brain MRI scan
within 42 days before Baseline that would lead to a diagnosis other than
AD or that puts the subject at risk of ARIA, inc: 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 prior to Baseline:
•Cerebrovascular accident (2 yrs) •Transient ischemic attack (6 mnths)
•Significant head injury with associated loss of consciousness, skull
fracture or persisting cognitive impairment (2 yrs)
•Other unexplained or recurrent loss of consciousness ≥15 minutes
(2yrs)
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 (within the past 5 yrs), or
substance (inc alcohol) related disorders (within past 2 yrs)
6.Metal implants in the head (ex dental), pacemaker, cochlear implants,
or other non-removable items that are contraindications to MRI; MR
compatible prosthetics, clips, stents, or other device proven compatible
will be allowed.
7.Resides in hospital or moderate - high dependency continuous care
facility
8.swallowing difficulties
9.Pregnant /breastfeeding
10.G6PD deficiency 11.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
•Screening hemoglobin value below age/sex appropriate lower limit of
the central lab normal range for any of the following:
oHemoglobin(subject may be treated and re-screened)
oVitamin B12 or folate (subject may be treated and re-screened after 3
mths)12.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 lab normal
range (subject may be treated and 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 mths preceding Baseline
•Signs or symptoms of clinical heart failure within the 12 mths
preceding 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 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
•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 or symptoms of respiratory failure.
Subjects with previously diagnosed moderate to severe sleep apnea not
adequately controlled should be excluded.
15.Concurrent acute or chronic clinically significant immunologic,
hepatic, or endocrine disease (not adequately treated) and/or other
unstable or major disease other than AD.
•Subjects with hepatitis or primary biliary cirrhosis should be excluded.
•HTLV-III, LAV (incl.any mutants/derivatives), any condition associated
with Acquired Immunodeficiency Syndrome
16.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 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:
•Tacrine •Antipsychotics: clozapine, olanzapine. Other antipsychotics are
allowable provided they have not been initiated within 3 mths 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 (dapsone, local anesthetics ie
benzocaine used chronically, primaquine and related antimalarials)
19.Current or prior participation in a clinical trial as follows:
•trial of a product for cognition within the 3 mths prior to Screening
(unless confirmed to have been randomized to placebo)
•A trial of a drug, biologic, device or medical food in which the last dose
was received within 28 days prior to Baseline |
|
| 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 |
|
| 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 |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints: ADCS-ADL23, NPI, MADRS, MMSE, FDG-PET
Other endpoints: RUD Lite questionnaire, blood samples for PK and
genotyping, cerebrospinal fluid samples, brain MRI
|
|
| 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
•FDG-PET:at Screening/Baseline, at Weeks 39 and 78
•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 |
|
| 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 | 31 |
| 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 |
| Belgium |
| Canada |
| Croatia |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United Kingdom |
|
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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