| 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 | 18.1 |
| 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 |
|
| 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 TRx0237 in mild to moderate Alzheimer's disease as based on change from baseline on the following co-primary endpoints:
• Alzheimer's Disease Assessment Scale – Cognitive Subscale (ADAScog11)
• Alzheimer's Disease Cooperative Study – Clinical Global Impression of
Change (ADCS-CGIC) - independently rated 2. To determine the safety and tolerability of TRx0237 150 and 250
mg/day given for up to 65 weeks |
|
| E.2.2 | Secondary objectives of the trial |
3. To evaluate the effect of TRx0237 on functional activities of daily living using the Alzheimer's Disease Cooperative Study– Activities of Daily Living(ADCS-ADL23)
4. To evaluate the effects of TRx0237on other aspects of Alzheimer's disease including cognition (Mini-Mental Status Examination,MMSE) Exploratory (in centers with appropriate capability)
5. To evaluate the effect of TRx0237 on Alzheimer's disease modification as evidenced by reduction in decline in glucose uptake in the temporal lobe on 18F-flurodeoxyglucose positron emission tomography (FDGPET) imaging
6. To determine effects of TRx0237 on Alzheimer's disease modification by showing retardation of the expected decline in whole brain volume as evaluated by brain magnetic resonance imaging(MRI)
7.To determine effects of TRx0237 on resource utilization using the Resource Utilization in Dementia Lite
8.To explore changes in certain cerebrospinal fluid biomarkers of Alzheimer's disease (total tau,phospho-tau & Aβ1−42) |
|
| 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
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 OR In Italy, accept to avoid a pregnancy for at least 3 months prior to Baseline and 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 |
|
| 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 42days before Baseline that would lead to a diagnosis other than probable Alzheimer's disease or that puts the subject at risk of ARIA, including: 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 mths), 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 (2 yrs),
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 years), or 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 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.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 laboratory normal range
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 and TSH above laboratory normal range (subject may be treated and rescreened after 3 months)
13.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 uncontrolled atrial fibrillation on Screening ECG or history of atrial fibrillation 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 unstable or major disease other than Alzheimer's disease.
•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 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 years
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 following medications:
•Tacrine
•Antipsychotics: clozapine, olanzapine. Other 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 associated with methemoglobinemia
19. Current or prior participation in a clinical trial as follows:
•Clinical trial of a product for cognition within the 3 months prior to Screening (unless randomized to placebo)
•A clinical trial of a drug, biologic, therapeutic device, or medical food in which the last dose/administration 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. |
|
| 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 52 weeks of treatment, and at the 4 week off-treatment follow-up visit. |
|
| 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 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•ADCS-ADL23: at Baseline, after 13, 26, 39, 52 weeks of treatment, at follow-up visit.
•MMSE: at Screening, after 26 and 52 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 through 8 while on treatment.
•Brain MRI: at Screening and at Weeks 13, 26, 39, 52.
•CSSR-S: at Baseline (+prior clinic discharge) and at each visit.
•At screening and at each visit: oral T°, respiratory rate, ECG, blood pressure and pulse (+within 1 hour before and approx. 2 hours after administration of the first dose), MetHB (+approx. 1 hour before and approx. 2.5 hours after administration of the first dose of study drug). |
|
| 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 | 3 |
| 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 |
| Canada |
| Croatia |
| Korea, Republic of |
| Malaysia |
| Russian Federation |
| Singapore |
| Taiwan |
| United States |
|
| 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 |
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