E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mild to moderate Alzheimer’s disease |
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E.1.1.1 | Medical condition in easily understood language |
Mild to moderate Alzheimer’s disease |
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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 | 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 |
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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 |
To assess the long-term safety and tolerability of crenezumab administered subcutaneously (SC) every 2 weeks (q2w) or intravenously (IV) every 4 weeks (q4w), in eligible patients with Alzheimer’s disease who participated in Study ABE4869g or ABE4955g and completed the Week 73 study visit, including brain MRI. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the long term effect of crenezumab on disease progression and evaluation of:
• the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of crenezumab
• the PK/PD relationship of crenezumab using exploratory PD biomarkers
• changes in MRI biomarkers, such as global and regional brain volumes and functional connectivity |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Ability to provide written informed consent by the patient or the patient’s authorized representative under applicable local law
• Ability and willingness of the patient to comply with the protocol’s requirements
• Previous participation in Study ABE4869g or ABE4955g and completion of the Week 73 visit
– Patients who discontinued from study treatment or from the study prior to completion of the Week 73 visit are not eligible.
• Adequate visual and auditory acuity, in the investigator's judgment, to allow for neuropsychological testing
• Availability of a person ("caregiver") who can provide information on activities of daily living and behavior in order to complete the study-specific assessments
– This caregiver must have sufficient cognitive capacity, in the judgment of the investigator, to accurately report upon the patient's function and behavior. In addition, the caregiver must spend sufficient time with the patient to be familiar with the overall function and behavior of the patient. As guidance, a caregiver would ordinarily need to spend an average of at least 8 hours per week with the patient in order for the caregiver to meet the requirements for this study.
• Diagnosis of probable Alzheimer’s disease according to the National Institute on Neurological and Communication Disease and Stroke/Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria (McKhann et al. 1984)
• MMSE score of 10 or more at screening (Folstein et al. 1975)
• For male patients with partners with reproductive potential, agreement to use a reliable means of contraception (e.g., condoms) during the study
• For female patients, a negative urine dipstick pregnancy test at screening (not required if patient has undergone documented surgical sterilization or have not experienced menstruation for at least 12 consecutive months). |
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E.4 | Principal exclusion criteria |
• Early treatment and/or study discontinuation prior to completion of the Week 73 visit of Genentech Study ABE4869g or ABE4955g
• Inability to tolerate MRI procedures or contraindication to MRI, including but not limited to pacemakers; implantable cardioverter defibrillators; cochlear implants; cerebral aneurysm clips; implanted infusion pumps; implanted nerve stimulators; metallic splinters in the eye; other magnetic, electronic, or mechanical implants; or any other clinical history or examination finding that, in the judgment of the investigator, would pose a potential hazard in combination with MRI
• Female patient with reproductive potential: Female patients must either have undergone documented surgical sterilization or have not experienced menstruation for at least 12 consecutive months.
• Severe or unstable medical condition that, in the opinion of the investigator or Sponsor, would interfere with the patient's ability to complete the study assessments or would require the equivalent of institutional or hospital care
• History or presence of clinically evident vascular disease potentially affecting the brain
• History of severe, clinically significant (persistent neurologic deficit or structural brain damage) central nervous system trauma (e.g., cerebral contusion)
• History or presence of clinically relevant intracranial tumor (e.g., meningioma, glioma)
• Presence of infections that affect the brain function or history of infections that resulted in neurologic sequelae (e.g., syphilis, neuroborreliosis, viral or bacterial meningitis/encephalitis, HIV encephalopathy)
• History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease (e.g., multiple sclerosis, lupus erythematosus, anti-phospholipid antibody syndrome, Behçet disease)
• History or presence of a neurologic disease other than Alzheimer’s disease that may affect cognition, including but not limited to Parkinson’s disease, corticobasal degeneration, dementia with Lewy bodies, Creutzfeldt–Jakob disease, progressive supranuclear palsy, frontotemporal degeneration, Huntington’s disease, normal pressure hydrocephalus, and hypoxia
• Patients with medical conditions (including Alzheimer's Disease) that, in the opinion of the investigator or Sponsor, would interfere with the patient's ability to complete the study assessments, pose an unacceptable risk, or would require the equivalent of institutional or hospital care
• History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins
• Evidence of malignancies (except squamous cell cancer or basal cell cancer of the skin), acute infections, renal failure that requires dialysis, or other unstable medical disease not related to Alzheimer’s disease that, in the investigator’s opinion, would preclude patient participation
– Cancer that is not being actively treated with anti-cancer therapy or radiotherapy as well as cancers that are considered to have low probability of recurrence (with supporting documentation from the treating oncologist if possible) are allowed
• History or presence of atrial fibrillation that, in the investigator’s judgment, poses a risk for future stroke
• Chronic kidney disease of Stage ≥ 4, according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines for chronic kidney disease (CKD)
• Impaired hepatic function, as indicated by transaminases > 2 times the upper limit of normal (ULN) or abnormalities in synthetic function tests judged by the investigator to be clinically significant
• Impaired coagulation (aPTT > 1.2 × ULN)
• Platelet count < 100,000/μL
• Presence of superficial siderosis of central nervous system, more than eight cerebral microhemorrhages, or evidence of a prior cerebral macrohemorrhage as assessed by T2*-weighted gradient echo (GRE) MRI
• Presence of any other significant cerebral abnormalities, including ARIA-E, as assessed by MRI
• Treatment with anticoagulation medications (e.g., heparin, warfarin, thrombin inhibitors, Factor Xa inhibitors) within 2 weeks prior to enrollment
– Clopidogrel, dipyridamole, and aspirin are permitted.
•Treatment with anticholinergic antidepressants, typical antipsychotics, or barbiturates, within 2 weeks prior to enrollment.
• Chronic use of opiates, opioids, or benzodiazepines
• Any biologic therapy within 75 weeks prior to enrollment
• Any investigational agent (other than crenezumab) within 75 weeks
prior to enrollment
• Treatment with anticholinergic antidepressants, typical antipsychotics, barbiturates, or narcotics within 5 half-lives or 3 months prior to screening, whichever is longer
– All other antidepressants and atypical antipsychotics are allowed. Chronic use of benzodiazepines is not allowed; however, the intermittent use of benzodiazepines is allowed, except within 2 days prior to any neurocognitive assessment. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability will be assessed through regular neurologic and physical examinations
and MRI assessments. In addition, the following information will be collected and analyzed:
• Frequency of adverse events during the treatment period
• Nature and severity of adverse events during the treatment period
• Changes in vital signs and physical and neurological findings
• Changes in clinical laboratory test results including routine hematology, chemistry, coagulation, and urinalysis
• Incidence of human anti-therapeutic antibody (ATA) formation
• Incidence of ARIA-E and amyloid-related imaging abnormalities-hemorrhage (ARIA-H)
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the
date on which the last data point required for statistical analysis or safety follow-up is received
from the last patient, whichever occurs later. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
153 weeks after the last patient is enrolled. |
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E.5.2 | Secondary end point(s) |
The exploratory outcome measures for this study are as follows:
• Change in ADAS-Cog (12-item) score from baseline to Week 153
• Change in CDR-SOB score from baseline to Week 153
• Change in ADCS-ADL score from baseline to Week 153
• Change in the following ENTP scores from baseline to Week 153:
– Free and Cued Selective Reminding Test (FCSRT)
– Trail-Making Test (TMT)
– Digit Span Test (DST)
– Digit Symbol Substitution Test (DSST)
– Letter Fluency Test (LFT)
– Category Fluency Test (CFT)
• Change in NPI score from baseline to Week 153
• Change in NPI Caregiver Distress Scale score from baseline to Week 153
• Change in Dependence Scale total score from baseline to Week 153
• Changes in MRI biomarkers, such as global and regional brain volumes, from baseline to Week 153
• Serum crenezumab concentration at protocol-specified time points; PK parameters including trough serum concentrations at steady state (Ctrough, ss) will be explored, as applicable
• Plasma Abeta1-40 and Abeta1-42 concentrations |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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 | 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 | No |
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 | No |
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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Canada |
France |
Germany |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
|
LVLS or the date on which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. |
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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 | 1 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 1 |