E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild cognitive impairment due to Alzheimer's Disease or mild Alzheimer's Disease. |
Mirná kognitivní porucha v důsledku Alzheimerovy choroby nebo mírná forma Alzheimerovy poruchy |
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E.1.1.1 | Medical condition in easily understood language |
Mental disabilities due to Alzheimer's Disease or mild Alzheimer's Disease. |
Mentální postižení v důsledku Alzheimerovy choroby nebo mírná forma Alzheimerovy choroby. |
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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 | 20.0 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009846 |
E.1.2 | Term | Cognitive impairment |
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 |
The primary objective is to evaluate the neuroprotective effect of T 817MA on Tau protein phosphorylated at threonine 181 (p-tau181) in CSF compared with placebo, in patients with a diagnosis of MCI due to AD or mild AD, according to the National Institute on Aging - Alzheimer Association (NIA-AA) criteria, with a Mini Mental Status Examination (MMSE) score of 24 to 30 (inclusive), and Aß1-42 and p-tau181 abnormality in CSF (≤1000 pg/ml for Aß1-42, ≥19 pg/ml for p-tau181) or (p-tau181/Aß1-42 ratio >0.020 for patients with p-tau181 ≥ 19pg/ml and 1000 < Aß1-42 < 1700pg/ml). |
Primární cíl je posoudit neuroprotektivní účinek přípravku T 817MA na tau protein fosforylovaný na 181. aminokyselině (threoninu) (p-tau181) v mozkomíšním moku (CSF) ve srovnání s placebem u pacientů s diagnózou MCI v důsledku AD nebo mírné formy AD, dle kritérií Národního institutu pro stárnutí - Alzheimerova asociace (NIA-AA), se skóre Testu kognitivních funkcí (MMSE) 24-30 (včetně), a Aß1-42 a p-tau181 abnormalit v mozkomíšním moku (≤1000 pg/ml pro Aß1-42, ≥19 pg/ml pro p-tau181) nebo ( poměr mezi p-tau181/Aß1-42 >0.020 u pacientů s p-tau181 ≥ 19pg/ml a 1000 < Aß1-42 < 1700pg/ml). |
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E.2.2 | Secondary objectives of the trial |
To evaluate in patients on T-817MA and placebo: • cognitive function measured by the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) and Cognitive Functional Composite (CFC) • AD-related biomarkers in CSF (Tau protein phosphorylated at threonine 217 (p-tau217), total tau, Aβ1-40, Aβ1-42, neurofilament light (NFL), neurogranin, YKL-40 and Aβ1-42/Aβ1-40 ratio) and in plasma (Aβ1-40, Aβ1-42 and NFL) • imaging analysis using volumetric magnetic resonance imaging (vMRI) • alpha/theta ratio of the electroencephalogram (EEG) To evaluate the safety of T 817MA by clinical laboratory tests and AEs To evaluate the pharmacokinetics of T 817MA in plasma and CSF
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Vyhodnotit u pacientů, kterým je podáván T-817MA a placebo: • kognitivní funkce měřené pomocí klinického hodnocení demence (CDR Sum of Boxes / CDR-sb), pracovní paměť a doménu pozornosti měřené kompozitním skóre kognitivních funkcí (CFC) • biomarkery související s AD v CSF (Tau protein foforylovaný na threoninu 217 (p-tau217), celkový tau, Aβ1-40, Aβ1-42, neurofilament light (NFL), neurogranin, YKL-40 a poměr Aβ1-42/Aβ1-40) a v plazmě (Aβ1-40, Aβ1-42 a NFL) • analýzu snímkování pomocí volumetrické magnetické rezonance (vMRI) • alfa/théta poměr měřený elektroencefalogramem (EEG) Vyhodnotit bezpečnost přípravku T 817MA na základě klinických laboratorních testů a nežádoucích příhod (AE) Vyhodnotit farmakokinetické vlastnosti přípravku T 817MA v plazmě a mozkomíšním moku
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrolment: 1. Male or female, age 50 to 80 inclusive at date of ICF signature. 2. Diagnosis by the investigator of a clinical syndrome of cognitive impairment consistent with either MCI due to AD or mild AD per NIA-AA diagnostic criteria (Jack et al., 2018), with MMSE 24 to 30 (inclusive). 3. CSF results at screening consistent with the presence of Aß1-42 and p-tau181 abnormality (≤1000 pg/ml for Aß, ≥19 pg/ml for p-tau181) or (p-tau181/Aß1-42 ratio >0.020 for patients with p-tau181 ≥ 19pg/ml and 1000 < Aß1-42 < 1700pg/ml). 4. A brain MRI not-inconsistent with the clinical diagnosis of MCI due to AD or mild AD 5. Receiving an AChE inhibitor (donepezil, galantamine or rivastigmine) at a stable dose for more than 3 months prior to randomization, or not receiving any AChE inhibitors. 6. Weight of ≤ 100 kg (220 pounds) at Screening 7. Ability (patients and their study partners) to read, speak and understand local language to ensure compliance with cognitive testing and study visit procedures 8. Living in the community (includes assisted living facilities, but excludes long-term care nursing facilities) 9. Ambulatory, or able to walk with an assistive device, such as a cane or walker 10. If male, patients must: a. agree he will not donate sperm during the study and until 104 days after the last dose, AND b. be required to use the following highly effective methods of contraception during the study and until 104 days after the last dose: i. Abstain from sexual intercourse OR ii. Use a condom during sexual intercourse with pregnant or non-pregnant women of childbearing potential (WOCBP) partner even if he is vasectomized. I n addition, WOCBP partner of the male patient (except a vasectomized male) must use one of the following highly effective methods of contraception. • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: - oral - intravaginal - transdermal • Progestogen-only hormonal contraception associated with inhibition of ovulation: - oral - injectable - implantable • Intrauterine device (IUD) • Intrauterine hormone-releasing system (IUS) • Bilateral tubal occlusion 11. If female, patients must: a. be post-menopausal (i.e. no menses for 12 months without an alternative medical cause) OR b. be permanently sterilized with methods including hysterectomy, bilateral salpingectomy and bilateral oophorectomy 12. A study partner who has regular contact with the patient for at least 10 hours per week and is able to participate in the patient’s clinical assessment and complete the questionnaire about the patient’s daily life at Screening, Baseline and Weeks 28, 52 and 78 13. Patient is clearly able to understand the nature, meaning and consequences of the clinical trial and its interventions and conveys his/her will to participate by personally signing the informed consent form 14. Written informed consent obtained from study partner |
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E.4 | Principal exclusion criteria |
Patients meeting any of the following criteria must not be included in the study: 1. Has had an MRI of the brain within the previous 2 years that showed pathology that would be inconsistent with a diagnosis of AD 2. Use of prohibited medications, including memantine. 3. Has any contraindications for MRI including claustrophobia, the presence of metal (ferromagnetic) implants, or a cardiac pacemaker that is not compatible with MRI 4. Has any contraindications to lumbar puncture 5. Pregnant or breastfeeding woman 6. Psychiatric disorder such as schizophrenia or dementia not of the Alzheimer’s type according to the criteria of DSM-5 7. Other neurodegenerative diseases, including Parkinson’s disease and Huntington’s disease, or cerebral tumor 8. Dementia other than AD 9. History of untreated thyroid disorder, Type I diabetes, and insulin-dependent or uncontrolled Type II diabetes, as determined by the investigator (except non-insulin-controlled Type II diabetes, whose HbA1c value must be below 8.0 %) The HbA1c value should not be older than 6 months prior screening. If no recent HbA1c value is avaliable, then HbA1c should be assessed locally. 10. History of a seizure disorder or stroke, unless >5 years ago 11. History of alcohol abuse or dependence or drug abuse in the past 5 years 12. Uncorrected impairment of vision or hearing that would preclude the patient from taking tests or patients lacking the ability to communicate 13. Clinically significant abnormal laboratory values in the opinion of the investigator 14. Severe hepatic or severe renal impairment (e.g. bilirubin > 3 x ULN, AST/ALT > 5 x ULN, eGFR < 30 ml/min/1.73m2 or CrCl <30 ml/min) 15. Clinically significant B12 deficiency (i.e., no macrocytosis) in the opinion of the investigator 16. Severe heart disease (history of myocardial infarction, congestive heart disease, history of unstable angina pectoris, clinically significant ECG abnormality) within 6 months prior to screening. Patients with arterial thrombosis will not be excluded if they are stable for at least 6 months prior to Screening 17. Cancer or a malignant tumor within the past 3 years, except patients who underwent potentially curative therapy with no evidence of recurrence. 18. Participation in another clinical trial for an investigational agent and having taken at least one dose of study medication, unless confirmed as having been on placebo, within 12 weeks prior to screening. (The end of a previous investigational trial is defined as the date of the last dose of an investigational agent.) 19. Participation in a previous clinical trial with T 817MA 20. Patients whom the investigator deems to be otherwise ineligible 21. Has an MRI of the brain at screening indicative of significant abnormali ty, including, but not limited to, prior hemorrhage or infarct, large (>1 cm) infarct, >2 lacunar infarcts outside the brain stem, severe white matter changes (Fazekas grade 3), >4 microbleeds, superficial hemosiderosis >1 cm, aneurysm, vascular malformati on, subdural hematoma, hydrocephalus, space occupying lesion (e g, abscess or brain tumor such as meningioma).
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the change in the CSF biomarker p-tau181 from Baseline to Week 78. |
Primární cílový parametr je změna p-tau181 v CSF při srovnání výchozího stavu a stavu v 78. týdnu |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline, week 52 and week 78. |
Výchozí návštěva, týden 52 a týden 78. |
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E.5.2 | Secondary end point(s) |
The secondary efficacy endpoints are: 1. The change in cognitive function assessed by CDR-sb and CFC from Baseline to Weeks 28, 52 and 78. 2. The change in the CSF biomarker p-tau181 from Baseline to Week 52. 3. The change in the CSF biomarkers p-tau217, total tau, Aβ1-42, Aβ1-40, NFL, neurogranin, YKL-40 and Aβ1-42/Aβ1-40 ratio from Baseline to Weeks 52 and 78. 4. The change in plasma biomarkers Aβ1-42, Aβ1-40 and NFL from Baseline to Weeks 52 and 78. 5. The change in brain volume (total brain volume (TBV), ventricular volume and hippocampal volume) and cortical thickness measured by vMRI from Baseline to Weeks 52 and 78 6. The change in alpha/theta ratio measured by the EEG from Baseline to Weeks 52 and 78 7. Safety as assessed by the occurrence of AEs, clinical laboratory tests, vital signs, physical examinations, ECGs 8. Population PK analysis of T-817MA with assessment of maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), and total daily exposure (AUC0-24h)
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Sekundární cílévé parametry jsou: 1. Změna kognitivních funkcí hodnocená pomocí CDR-sb a pracovní paměti a domény pozornosti hodnocená pomocí CFC při srovnání výchozího stavu a stavu ve 28., 52. a 78. týdnu. 2. Změna p-tau181 v CSF při srovnání výchozího stavu a stavu v 52. týdnu 3. Změna biomarkerů souvisejících s AD v CSF (p-tau217, celkové tau, Aβ1-42, Aβ1-40, lehké řetězce neurofilament [NFL], neurogranin, YKL-40 a poměr Aβ1-42/Aβ1-40) při srovnání výchozího stavu a stavu v 52. a 78. týdnu 4. Změna biomarkerů souvisejících s AD v plazmě (Aβ1-42, Aβ1-40, NFL) při srovnání výchozího stavu a stavu v 52. a 78. týdnu 5. Změna v objemu mozku (celkový objem mozku (TBV), ventrikulární objem a hipokampální objem) a v tloušťce kortexu měřená pomocí vMRI při srovnání výchozího stavu a stavu v 52. a 78. týdnu 6. Změna poměru alfa/théta vln měřená pomocí EEG při srovnání výchozího stavu a stavu v 52. a 78. týdnu 7. Bezpečnost posuzovaná podle výskytu AE, na základě klinických laboratorních testů, základních životních funkcí, lékařských prohlídek, EKG 8. Farmakokinetická analýza T 817MA s hodnocením maximální koncentrace v plazmě (Cmax), minimální koncentrace v plazmě (Cmin) a celkové denní expozice (AUC0-24h) v populaci
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, week 52 and week 78. |
Výchozí návštěva, týden 52 a týden 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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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LVLS |
Poslední návštěva posledního pacienta (LVLS) - byla z důvodu pandemie COVID-19 posunuta o cca 3 měsíce. Nyní je plánovaná LVLS na březen 2023. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |