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 |
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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 |
To evaluate the efficacy of crenezumab compared with placebo based on change from baseline to Week (W) 105 in global outcomes as assessed by Clinical Dementia Rating-Sum of Boxes (CDR-SB) |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of crenezumab compared with placebo based on additional cognitive, functional, and behavioral outcomes
•To evaluate the efficacy of crenezumab compared with placebo on caregiver and quality of life endpoints
• To evaluate the safety of crenezumab compared with placebo
• To characterize the crenezumab pharmacokinetic (PK) profile
• To explore exposure-response relationships in patients with prodromal to mild AD
• To evaluate the effect of crenezumab compared with placebo on biomarker changes
•To explore exposure response relationships in patients with prodromal to mild AD based on CSF biomarkers, Plasma PD biomarkers, Imaging biomarkers, and Efficacy and safety outcomes |
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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 |
PET LONGITUDINAL SUBSTUDY ASSOCIATED WITH:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE
CSF LONGITUDINAL SUBSTUDY ASSOCIATED WITH:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE
RESEARCH SUBSTUDY ASSOCIATED WITH:
A PHASE III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL-GROUP, EFFICACY AND SAFETY STUDY OF CRENEZUMAB IN PATIENTS WITH PRODROMAL TO MILD ALZHEIMER’S DISEASE |
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E.3 | Principal inclusion criteria |
- Aged between 50 and 85 years at screening, inclusive
- Weight between 40 and 120 kg, inclusive
- Availability of caregiver
- Fluency in the language used at the study site
- Willingness and ability to complete all aspects of the study (including magnetic resonance imaging [MRI], lumbar puncture [if applicable], clinical genotyping, and positron emission tomography (PET)imaging [if applicable]); the patient should be capable of completing assessments either alone or with the help of the caregiver
- Adequate visual and auditory acuity, in the investigator’s judgment, sufficient to perform the neuropsychological testing (eye glasses and hearing aids are permitted)
- For men and women Use appropriate contraceptive measures or agreement to refrain from heterosexual intercourse for at least 8 weeks after last dose of drug study
- For men only: agreement to refrain from donating sperm during treatment for at least 8 weeks after last dose of drug study
- Evidence of the AD pathological process, by a positive amyloid assessment either on cerebrospinal fluid (CSF) Aβ1−42 levels as measured on the Elecsys β-Amyloid(1-42) Test System OR amyloid PET scan by qualitative read by the core/central PET laboratory
- Demonstrated abnormal memory function at early screening (up to 4 weeks before screening begins) or at screening
- Evidence of retrospective decline confirmed by a diagnosis verification form
- Mild symptomatology, as defined by a screening MMSE score of ≥ 22 points and Clinical Dementia Rating-Global Score (CDR-GS) of 0.5 or 1.0. MMSE may be performed at FCSRT/MMSE consent or main screening
- Meets National Institute on Aging/Alzheimer’s Association core clinical criteria for probable AD dementia or prodromal Alzheimer’s disease
- If the patient is receiving symptomatic AD medications, the dosing regimen must have been stable for 3 months prior to screening. If the patient is taking medical food supplements (e.g., Axona® or
Souvenaid®), these must also have been stable for 3 months prior to screening.
- Inclusion is subject to review of clinical criteria at screening
- Patient must have completed at least 6 years of formal education after the age of 5 years
- For enrollment into the China Extension Phase, patients must have residence in mainland China, Hong Kong, or Taiwan and be of Chinese ancestry
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E.4 | Principal exclusion criteria |
- Any evidence of a condition other than AD that may affect cognition
- Seizure history that, in the opinion of the investigator, is likely to result in cognitive impairment
- History of any condition that is clinically significant and may result in cognitive impairment including
• Infections with neurological sequelae such as syphilis
• Autoimmune disorders that cause progressive neurological disease associated with cognitive deficits
• History of central nervous system trauma (e.g. cerebral contusion)
• History of presence of intracranial tumour (e.g. glioma)
- History or presence of clinically evident vascular disease that could potentially affect the brain and that in the opinion of the investigator has the potential to affect cognitive function
- History or presence of any stroke with clinical symptoms within the past 2 years, or documented history within the last 6 months of an acute event consistent, in the opinion of the investigator, with a transient ischemic attack
- Presence on MRI of any cortical stroke regardless of age
- History of schizophrenia, schizoaffective disorder, major depression, or bipolar disorder
- At risk of suicide in the opinion of the investigator
- Alcohol and/or substance abuse or dependence
- Inability to tolerate MRI procedures or contraindication to MRI
- MRI evidence of a) > 2 lacunar infarcts, b) any territorial infarct > 1 cm3, or c) any white matter lesion that corresponds to an overall Fazekas score of 3 that requires at least 1 confluent hyperintense lesion on the fluid−attenuated inversion recovery sequence, which is >= 20 mm in any dimension
- Evidence of more than 4 microbleeds and/or areas of leptomeningeal hemosiderosis (ARIA-H) as assessed by central review
- Presence of significant cerebral vascular pathology as assessed by MRI review
- Patients with cardiovascular disorders, hepatic/renal disorders, infections and immune disorders, metabolic/endocrine disorders as defined in protocol
- History of cancer unless considered cured or unlikely to require treatment within 5 years
- Screening folic acid or vitamin B12 levels that are sufficiently low that deficiency may be contributing to cognitive impairment
- Screening hemoglobin A1c (HbA1C) > 8% (retesting is permitted if slightly elevated) or poorly controlled insulin-dependent diabetes (past including hypoglycemic episodes) are considered one example of poor control)
- Pregnant or lactating, or intending to become pregnant during the study
- Poor peripheral venous access
- Other causes of intellectual disability that may account for cognitive deficits observed at screening
- Clinically significant sleep apnea that may be contributing to cognitive impairment. Sleep apnea which in the clinical judgment of the investigator is adequately treated (e.g., continuous positive airway
pressure adequate patient treatment compliance should be documented) is allowed
- Significant respiratory diseases (e.g., severe COPD – Global Initiative for Obstructive Lung Disease criteria Stage IV)
- Sleep apnea that requires treatment or other significant respiratory diseases likely to result in cognitive impairment
- Clinically significantly abnormal blood or urine test results at screening and that remain abnormal at retest
- Impaired coagulation
- Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins
- Any other severe or unstable medical condition that, could be expected to progress, recur, or change to such an extent that it could put the patient at special risk, bias the assessment of the clinical or mental status of the patient to a significant degree, interfere with the patient’s ability to complete the study assessments, or would require the equivalent of institutional or hospital care
- Residence in a skilled nursing facility such as a convalescent home or long-term care facility: Patients who subsequently require residence in these facilities during the study may continue in the study and be followed for efficacy and safety provided that they have a caregiver who meets the minimum requirement
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Change from baseline to Week 105 in global outcomes as assessed by CDR-SB |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Baseline (Week 1) to Week 105 |
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E.5.2 | Secondary end point(s) |
1. Change from baseline to Week 105 on cognition as measured by ADAS-Cog-13 and ADAS-Cog-11
2. Change from baseline to Week 105 on severity of dementia, assessed by the CDR-GS and MMSE
3. Change from baseline to Week 105 on function as assessed by the ADCS-ADL total score and its ADCS-iADL subscore and by the FAQ total score
4. Change from baseline to Week 105 on a measure of dependence derived from the ADCS-ADL score
5. Change from baseline to Week 105 on behavior assessed by the Neuropsychiatric Inventory Questionnaire total score
6. Effect of crenezumab on HRQOL, assessed using the quality of life -AD scale
7. Effect of crenezumab on caregiver burden, assessed using the Zarit Caregiver Interview for Alzheimer’s Disease scale
8. Effect of crenezumab on health outcomes in patient and caregiver as measured by EQ-5D
9. Incidence of adverse events, serious adverse events, adverse events of special interest, treatment discontinuations due to adverse events, and Amyloid−related imaging abnormalities and Amyloid−related imaging abnormalities-edema/effusion assessed by MRI
10. Incidence of abnormal vital sign measurements, laboratory test results, ECG assessments, Physical and neurologic examination abnormalities
11. Changes in Columbia Suicide Severity Rating Scale (CSSR-S) scores from baseline over time
12. Incidence of immunogenicity as evidenced by antibodies to crenezumab or other components of drug product
13. Serum concentration of crenezumab (administered at a dose of 60 mg/kg IV)
14.CSF concentration of crenezumab (administered at a dose of 60 mg/kg IV) at specified timepoints in a subset of consenting patients in a substudy (BN29553-CSF longitudinal)
15. Brain amyloid load over time measured by amyloid-PET in a substudy (BN29552/BN29553-Amyloid PET longitudinal)
16. Brain tau load over time measured by tau-PET in a substudy (BN29552/BN29553-tau PET longitudinal) CSF markers of disease over time in a substudy (BN29553-CSF longitudinal)
17. CSF biomarkers
18. Plasma PD biomarkers
19. Plasma Abeta concentrations
20. Imaging biomarkers
21. MRI-derived measurements over time such as volumetric changes in whole brain, ventricles, hippocampus, or other structures |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5. Baseline to Week 105
7-10. Up to Week 153
11. Up to Week 105
12. Up to Week 117
13. Weeks 1, 5, 13, 25, 37, 53, 77, 105, and 117
14-17. Screening (Weeks -8 to -1), Weeks 53 and 105
18-19. Screening (Weeks -8 to -1), Weeks 1, 5, 25, 53, 77, 105, and 117
20-21. Up to Week 105 |
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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 | 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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
florbetapir F18) & Florbetaben F 18 (Neuraceq ®) |
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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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 78 |
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 |
Argentina |
Australia |
Belgium |
Brazil |
Canada |
Chile |
China |
Colombia |
Estonia |
France |
Germany |
Greece |
Guatemala |
Israel |
Italy |
Japan |
Korea, Democratic People's Republic of |
Mexico |
Netherlands |
Norway |
Peru |
Poland |
Portugal |
Russian Federation |
Serbia |
Slovakia |
South Africa |
Spain |
Taiwan |
Turkey |
United Kingdom |
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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last patient, last visit (LPLV) occurs or the date at which the last data point required for safety analyses or safety follow up is received for the last patient, whichever occurs later. LPLV for the double blind treatment period is expected to occur 153 weeks after the last patient is enrolled (i.e., 52 weeks after the last dosing visit at week 101) |
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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 |