An Efficacy and Safety Study of Crenezumab in Patients with Prodromal to Mild Alzheimer’s Disease

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2016-003288-20-ES
• Date of registration: 19/01/2017
• Prospective Registration: Yes
• Primary sponsor: Roche Farma, S.A., que representa en España a F. Hoffmann-La Roche LTD
• Public title: An Efficacy and Safety Study of Crenezumab in Patients with Prodromal to Mild Alzheimer’s Disease
• Scientific title: 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
• Date of first enrolment: 21/03/2017
• Target sample size: 750
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2016-003288-20
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: yes; Other specify the comparator: PET Ligand florbetapir F18 & florbetaben F18; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

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

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd.

• Name: Trial Information Support Line-TISL
• Affiliation: F.Hoffmann-La Roche Ltd.

Key inclusion & exclusion 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 early screening (up to 4 weeks before screening begins) or 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
- 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 the People’s Republic of China
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:
- Any evidence of a condition other than AD that may affect cognition
- 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 (including hypoglycemic episodes)
- 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
- 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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Alzheimer’s Disease
MedDRA version: 19.1 Level: LLT Classification code 10001896 Term: Alzheimer's disease System Organ Class: 100000004852

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Intervention(s)

Product Name: crenezumab
Product Code: Ro 549-0245/F05
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: crenezumab
CAS Number: 1095207-05-8
Current Sponsor code: RO5490245
Other descriptive name: Crenezumab, Anti Abeta, MABT5102A
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 180-
Pharmaceutical form of the placebo: Concentrate for solution for infusion
Route of administration of the placebo: Intravenous use

Primary Outcome(s)

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)

Timepoint(s) of evaluation of this end point: 1. Baseline (Week 1) to Week 105

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:
o Change from baseline to W 105 on cognition using Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog)-12 , ADAS-Cog-13 and Mini Mental State Examination (MMSE)
o Time to clinically evident decline
o Change from baseline to W 105 on severity of dementia
o Effect on function using Alzheimer’s Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), ADCS-ADL Instrumental Subscale (ADCS-iAD) and Functional Activities Questionnaire (FAQ)
o Effect on behavioral and neuropsychological symptoms of AD
o Effect on health-related quality of life (HRQOL), caregiver burden and health outcomes
• 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

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1-6. Baseline to Week 105
7-16. Up to Week 153
17. Up to Week 105
18. Up to Week 117
19. Weeks 1, 5, 13, 25, 37, 53, 77, 105, and 117
20-21. Screening (Weeks -8 to -1), Weeks 1, 5, 25, 53, 77, 105, and 117
22-23. Up to Week 105

Secondary end point(s): 1. Change from baseline to Week 105 on cognition as measured by ADAS-Cog-13
2. Time to clinically evident decline
3. Change from baseline to Week 105 on severity of dementia, assessed using the CDR-GS
4. Change from baseline to Week 105 in effect on cognition, assessed using the MMSE
5. Change from baseline to Week 105 in effect on cognition, assessed using the ADAS-Cog-12
6. Change from baseline to Week 105 in effect on cognition, assessed by time to an increase of
>= 4 points from baseline at any time before or on Week 105 (i.e., worsening) in the ADAS-Cog-13
7. Effect on function, assessed using the ADCS-iADL
8. Effect on function, assessed using the ADCS-ADL total score
9. Effect on dependence level derived from the ADCS-ADL score
10. Effect of function, assessed using the FAQ total score
11. Effect on behavioral and neuropsychological symptoms of AD, assessed using the Neuropsychiatric Inventory Questionnaire
12. Effect of crenezumab on HRQOL, assessed using the quality of life -AD scale
13. Effect of crenezumab on caregiver burden, assessed using the Zarit Caregiver Interview for Alzheimer’s Disease scale
14. Effect of crenezumab on health outcomes in patient and caregiver as measured by EQ-5D
15. 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
16. Incidence of abnormal vital sign measurements, laboratory test results, ECG assessments, Physical and neurologic examination abnormalities
17. Changes in Columbia Suicide Severity Rating Scale (CSSR-S) scores from baseline over time
18. Incidence of immunogenicity as evidenced by antibodies to crenezumab or other components of drug product
19. Serum concentration of crenezumab (administered at a dose of 60 mg/kg IV)
20. Plasma PD biomarkers
21. Plasma Abeta concentrations
22. Imaging biomarkers
23. MRI-derived measurements over time such as volumetric changes in whole brain, ventricles, hippocampus, or other structures

Secondary ID(s)

2016-003288-20-GB

BN29553

Source(s) of Monetary Support

F. Hoffmann-La Roche Ltd.

Ethics review

Status: Approved
Approval date:
Contact: