E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
behavioral variant Frontotemporal Dementia (bvFTD) |
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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 | 17.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10068968 |
E.1.2 | Term | Frontotemporal dementia |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To demonstrate the efficacy of LMTM as assessed by the change from Baseline on: • Addenbrooke’s Cognitive Examination Scale Revised (ACE-R) • Modified Alzheimer’s Disease Cooperative Study – Clinical Global Impression of Change (Modified ADCS-CGIC) - independently rated
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E.2.2 | Secondary objectives of the trial |
To evaluate the safety and tolerability of LMTM To evaluate the effect of LMTM as measured by the following additional disease severity, self-care, and motor impairment scales: • Frontotemporal Dementia Rating Scale (FRS) • Functional Activities Questionnaire (FAQ) • Unified Parkinson’s Disease Rating Scale (UPDRS Parts II and III) |
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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 |
MT plasma concentrations: Provided the site has a refrigerated centrifuge and adequate capability to reliably freeze samples, blood will be collected at Baseline (Visit 2; pre-dose and approximately 3.5 hours post-dose) and, to the extent possible, at each subsequent on-treatment visit through Week 52 for purposes of population pharmacokinetic (PK) analysis of MT concentrations; samples may also be analyzed for other analytes, such as metabolites, depending on method availability. The time of the prior dose and the time of the blood sample will be recorded. All samples will be tested in accordance with the terms of the subjects’ consent. |
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E.3 | Principal inclusion criteria |
1. Diagnosis of probable bvFTD according to the International Consensus Criteria for bvFTD 2. Centrally rated frontotemporal atrophy score of 2 or greater, taken as the maximum of right or left frontal or anterior temporal lobes on brain MRI of sufficient quality obtained at Screening or within a maximum of 42 days before Baseline, irrespective of pre-existing structural or functional imaging evidence supporting a diagnosis of bvFTD 3. MMSE ≥20 at the Screening visit 4. Age <80 years at the Screening visit 5. Modified Hachinski ischemic score of ≤4 at the Screening visit 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 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, have avoided a pregnancy for at least 3 months prior to Baseline and accept to avoid a pregnancy throughout participation in the study 7. 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 8. Has one or more identified adult caregivers who meets 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 9. If currently taking an 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 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 CNS disorder other than bvFTD 2.Other significant intracranial pathology seen on brain MRI scan that would lead to a diagnosis other than probable bvFTD or that puts the subject at risk of Amyloid Related Imaging Abnormalities 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.Biomarker evidence of underlying AD pathology as etiology of dementia 4.Expressive language deficits such that the subject is too severely impaired to allow testing at Baseline 5.Meets research criteria for Amyotrophic Lateral Sclerosis or motor; evidence of mild motor neuron disease on examination is allowed if not expected to interfere with subject’s completion of study but prominent bulbar symptoms would be exclusionary 6.Meets diagnostic criteria for probable bvFTD but has a proven mutation producing non-tau, non-TDP-43 pathology 7.Clinical evidence or history of: ∙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) 8.Epilepsy(a single prior seizure is considered acceptable) 9.Rapid eye movement sleep behavior disorder 10.DSM IV-TR criteria met for the following (within specified period): ∙Major depressive disorder(current) ∙Schizophrenia (lifetime) ∙Other psychotic disorders, bipolar disorder (within the past 5 years), or substance related disorders (within the past 2 years) 11.Metal implants in the head (except dental),pacemaker, any other non-removable items that are contraindications to MR imaging;any device proven to be MR compatible will be allowed 12.Resides in hospital or moderate to high dependency continuous care facility 13.History of swallowing difficulties 14.Pregnant or breastfeeding 15.G6PD deficiency 16.History of significant hematological abnormality or current acute or chronic clinically significant abnormality, including: ∙Hereditary or acquired methemoglobinemia or Baseline measurement of MetHb >2.0% ∙Hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy ∙Screening hemoglobin value below lower limit of the normal range 17.Abnormal serum chemistry laboratory value at Screening clinically relevant. In addition, subjects with the following abnormalities must be excluded: ∙Creatinine clearance <50 mL/min at Screening ∙Thyroid stimulating hormone above laboratory normal range 18.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 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 ∙Hypotension ∙Heart rate <48 bpm or >96 bpm by measurement of vital signs or by ECG at Screening 19.Preexisting or current signs or symptoms of respiratory failure. Subjects with previously diagnosed moderate to severe sleep apnea not adequately controlled should be excluded 20.Concurrent acute or chronic clinically significant immunologic, hepatic,or endocrine disease and/or other unstable or major disease other than bvFTD. ∙Subjects with hepatitis or primary biliary cirrhosis should be excluded ∙HTLV-III, LAV (incl.any mutants/derivatives),any condition associated with Acquired Immunodeficiency Syndrome 21.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 22.Prior intolerance or hypersensitivity to MT-containing drug, similar organic dyes, or any of the excipients 23.Treatment currently or within 3 months before Baseline with the following medications: ∙Tacrine ∙Amphetamine or dexamphetamine ∙Antipsychotics:clozapine, olanzapine (other antipsychotics are allowable if they have not been initiated within 3 months before Baseline and are used in a stable dose and regimen) ∙Carbamazepine, primidone ∙Other mood stabilizers ∙Drugs associated with methemoglobinemia 24.Current or prior participation in a clinical trial: ∙Clinical trial of a product for cognition with last dose received within 90 days prior to Screening (unless randomized to placebo) ∙Clinical trial of a drug, biologic,device, or medical food with last dose received within 28 days prior to Baseline |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy endpoint: • Change from Baseline to Week 52 in the ACE-R • Modified ADCS-CGIC at Week 52. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Efficacy will be evaluated at baseline and after 4 months (16 weeks), 8 months (32 weeks), and 12 months (52 weeks) |
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E.5.2 | Secondary end point(s) |
Secondary endpoints are change from Baseline to Week 52 for the following parameters: • FRS • FAQ • UPDRS Parts II and III
Several exploratory analyses are pre-specified (additional post hoc analyses may be performed): •Change from Baseline to Week 52 in the ACE-III • Early effect on Modified ADCS-CGIC (after 8 weeks of treatment) • Effect on MMSE at Week 52 • Change in whole brain volume assessed by brain MRI •Effect of LMTM in subjects with known genetic mutations associated with bvFTD (mutations in the coding regions of Tau and TDP-43 genes) (in subjects by or for whom legally acceptable informed consent is provided) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety assessment will performed during screening, then at Baseline (pre-dose and post-dose during the 4-hour observation), and 4,8,16,24,32,42 and 52 weeks after Baseline, and approximately 4 weeks after the last dose of study drug (if applicable) Blood will be collected at Baseline and as possible at each subsequent on-treatment visit through Week 52 for purposes of population pharmacokinetic (PK) analysis of MT concentrations. A single blood sample for genotyping may be collected any time after eligibility for randomization and participation in the study has been confirmed at Baseline (Visit 2). |
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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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Singapore |
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 | |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 24 |