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 |
Alzheimer's disease is a chronic neurodegenerative disease that results in memory loss and impairments in other important mental functions |
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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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
T-o assess the long-term safety and tolerability of crenezumab (60 mg/kg IV Q4W) in eligible patients with AD who participated in Study BN29552 or BN29553 and completed the Week 105 study visit. |
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E.2.2 | Secondary objectives of the trial |
For exploratory efficacy objectives, the study aims to evaluate the long-term effect of crenezumab on global outcomes of disease progression, cognition, disease severity, patient dependence, patient function, patient behaviour and neuropsychological symptoms, health-related quality of life, and effect on caregiver burden.
For exploratory pharmacokinetic objectives, the study aims to evaluate PK characteristics of crenezumab and to explore exposure-response relationships in patients with prodromal to mild Alzheimer’s disease.
For exploratory biomarker objectives, the study aims to evaluate the effect of crenezumab on biomarkers.
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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 |
Amyloid-PET Longitudinal Substudy & Tau-PET Longitudinal Substudy included in the main protocol V1 dated 18.Sept 2017 |
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E.3 | Principal inclusion criteria |
•Previous participation in Study BN29552 or BN29553 and completion of the Week 105 visit
•Able to provide written consent signed by the patient or the patient’s authorized representative under applicable local law
•A caregiver, defined as:
–Has frequent and sufficient contact with the patient to be able to provide accurate information regarding the patient’s cognitive and functional abilities
–Be in sufficiently good general health
•Willingness and ability to complete all aspects of the study
•Adequate visual and auditory acuity, in the investigator’s judgment, sufficient to perform the neuropsychological testing
•For women of childbearing potential, must follow protocol specified acceptable methods of contraception
•For men with female partners of childbearing potential, must follow protocol specified acceptable methods of contraception
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E.4 | Principal exclusion criteria |
•Patients who discontinued treatment permanently in Study BN29552 or BN29553 for safety reasons
•Evidence of more than 10 microbleeds and/or ARIA-H at the Study BN29552 or BN29553 Week 105 visit, as assessed by central review of MRI
•Diagnosed with three recurrent, symptomatic ARIA-E events or exacerbations of previous events
•Presence of intracranial lesion that could potentially increase the risk of CNS bleeding (e.g., intracranial aneurysm; arterio-venous malformation)
•At risk of suicide in the opinion of the investigator
•Alcohol and/or substance abuse or dependence (according to Diagnostic and Statistical Manual of Mental Disorders Version 5 criteria) within the past 2 years and during the study (nicotine use is allowed; marijuana use is not allowed within the past 2 years)
•Inability to tolerate MRI procedures or contraindication to MRI
•Pregnant or lactating, or intending to become pregnant during the study
•Any other severe or unstable medical condition that, in the opinion of the investigator or Sponsor, could be expected to progress, recur, or change
•Chronic use of anticoagulants or participation in any other investigational drug treatment trial
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E.5 End points |
E.5.1 | Primary end point(s) |
•Nature, frequency, severity, and timing of adverse events, serious adverse events, and adverse events of special interest
•Physical and neurologic examinations, vital signs, blood tests, ECGs, and C-SSRS
•Incidence of ARIA E and ARIA H
•The immunogenic potential of crenezumab
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Change from baseline at Week 105 |
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E.5.2 | Secondary end point(s) |
For exploratory efficacy endpoints, change from baseline in the double-blind treatment period of BN29552 or BN29553 in BN40031 for CDR-SB, ADAS-Cog13, ADAS-Cog12, MMSE, CDR-GS, ADCS-ADL, FAQ, NPI-Qz, QoL-AD and ZCI-AD.
For exploratory pharmacokinetic endpoints, serum concentrations of crenezumab, CSF concentrations of crenezumab, correlation between crenezumab concentration and biomarkers as well as safety and efficacy outcomes.
For exploratory biomarker endpoints, brain amyloid load over time measured by PET, brain tau load and spread over time measured by PET, CSF markers of disease change over time, plasma pharmacodynamic markers of disease over time and MRI derived measurements over time
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 25, 53, 77, 105 and every year thereafter, as well as at follow up 4 weeks after the last dose. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
PET Ligand (florbetapir F18) and GTP1 |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 184 |
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 |
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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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The OLE study will continue until crenezumab is commercially available in the patient’s country, as per local regulation, or should the Sponsor decide to terminate the program for prodromal to mild AD. The study will not exceed approx. 2 years after the last patient enters the OLE study.
For UK only:The OLE study will not exceed approx. 2 years after the last patient enters the OLE study or until a decision to terminate the program for pAD to mAD is made by the Sponsor ( Protocol section 3.3) |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |