Alzheimer’s Disease (AD) MedDRA version: 20.0 Level: LLT Classification code 10001896 Term: Alzheimer's disease System Organ Class: 100000004852
Conditions
Sponsors
F. Hoffmann-La Roche Ltd.
Eligibility
Sex/Gender
All
Inclusion criteria
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) Aß1-42 levels as measured on the Elecsys ß-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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 150 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 600
Exclusion criteria
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: 1. Baseline (Week 1) to Week 105;Main Objective: 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);Primary end point(s): 1. Change from baseline to Week 105 in global outcomes as assessed by CDR-SB; Secondary Objective: • 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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-PE | — |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Chile, China, Colombia, Denmark, 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, Sweden, Taiwan, Turkey, United Kingdom, United States
Contacts
Public ContactTrial Information Support Line-TISL
F.Hoffmann-La Roche Ltd.
Outcome results
None listed