NCT02670083: CREAD

A Study Evaluating the Efficacy and Safety of Crenezumab Versus Placebo in Participants With Prodromal to Mild Alzheimer's Disease (AD).

Terminated Phase 3 Results posted Last updated 16 July 2020

What this trial tests

Phase 3 trial testing Crenezumab in Alzheimer's Disease in 813 participants. Terminated before completion.

Timeline

22 March 2016

Primary endpoint
31 May 2019

31 May 2019

Quick facts

Lead sponsor	Hoffmann-La Roche
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	double
Primary purpose	treatment
Enrollment	813
Start date	22 March 2016
Primary completion	31 May 2019
Estimated completion	31 May 2019
Sites	196 locations across Hong Kong, Italy, Finland, Japan, Poland, South Korea, Croatia, Denmark

Drugs / interventions tested

• Crenezumab — full drug profile →
• Placebo

Conditions studied

• Alzheimer's Disease — all drugs for Alzheimer's Disease →

Sponsor

Hoffmann-La Roche — full company profile →

Who can join

Adults 50 to 85, any sex, with Alzheimer's Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Change From Baseline to Week 105 in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score Primary · Baseline, Week 105

The CDR-SB rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment = 0, questionable impairment = 0.5 and mild, moderate and severe impairment = 1, 2 and 3 respectively. The score range is from 0 to 18 with a high score indicating a high disease severity. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographi

Group	Value	95% CI
Placebo	3.42	± 0.263
Crenezumab	3.59	± 0.264

Change From Baseline to Week 105 on Cognition, as Assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (Subscale) 13 (ADAS-Cog-13) Secondary · Baseline, Week 105

The ADAS-Cog-13 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 further items: delayed word recall and total digit cancellation. The score range for ADAS-Cog-13 is from 0 to 85 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusti

Group	Value	95% CI
Placebo	9.55	± 0.824
Crenezumab	9.82	± 0.841

Change From Baseline to Week 105 on Cognition, as Assessed by Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) (Subscale) 11 (ADAS-Cog-11) Secondary · Baseline, Week 105

The ADAS-Cog-11 assesses multiple cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Most of these are assessed by tests although some are rated by the clinician on a 5-point scale. The score range for ADAS-Cog-11 is from 0 to 70 with high scores representing severe dysfunction. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medicati

Group	Value	95% CI
Placebo	8.43	± 0.758
Crenezumab	8.53	± 0.773

Change From Baseline to Week 105 on Severity of Dementia, Assessed Using the CDR-Global Score (CDR-GS) Secondary · Baseline, Week 105

The CDR-GS represents a semi-structured interview which rates impairment in 6 categories (memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care) on a 5-point scale in which CDR 0 = no dementia and CDR 0.5, 1, 2 or 3 = questionable, mild, moderate or severe dementia respectively. The range in scores for the CDR-GS is from 0 to 3 and a high score on the CDR-GS would indicate a high disease severity. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated me

Group	Value	95% CI
Placebo	0.55	± 0.056
Crenezumab	0.50	± 0.056

Change From Baseline to Week 105 on Severity of Dementia, Assessed Using the Mini Mental State Evaluation (MMSE) Secondary · Baseline, Week 105

The MMSE is a set of standardized questions used to evaluate possible cognitive impairment and help stage the severity level of this impairment. The questions target 6 areas: orientation, registration, attention, short-term recall, language and constructional praxis/visuospatial abilities. The scores on the MMSE range from 0 to 30, with higher scores indicating better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic

Group	Value	95% CI
Placebo	-4.63	± 0.377
Crenezumab	-4.96	± 0.383

Change From Baseline to Week 105 on Function as Assessed by the ADCS-ADL Total Score Secondary · Baseline, Week 105

The ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) is the scale most widely used to assess functional outcomes in participants with AD. The ADCS-ADL covers both basic ADL (e.g., eating and toileting) and more complex 'instrumental' ADL or iADL (e.g., using the telephone, managing finances and preparing a meal). The ADCS-ADL consists of 23 questions with a score range of 0 to 78 where a higher score represents better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeat

Group	Value	95% CI
Placebo	-11.51	± 1.226
Crenezumab	-13.39	± 1.242

Change From Baseline to Week 105 on Function as Assessed by the ADCS-instrumental (ADCS-iADL) Subscore Secondary · Baseline, Week 105

The ADCS-iADL (Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living) measures activities such as using the telephone, managing finances and preparing a meal. The ADCS-iADL consists of 16 questions with a score range of 0 to 56 where a higher score represents better function. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeated measures (MMRMs) adjusting for disease severity, APOEe4 status, geographic region, and the use or non-use of anti-dementia medications at baseline were use

Group	Value	95% CI
Placebo	-9.22	± 0.967
Crenezumab	-10.44	± 0.979

Change From Baseline to Week 105 Assessed Using the Neuropsychiatric Inventory Questionnaire (NPI-Q) Secondary · Baseline, Week 105

The NPI-Q is an informant-based instrument that evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavioral disturbances and appetite and eating abnormalities. The severity of each neuropsychiatric symptom is rated on a 3-point scale (mild, moderate and marked). The total severity score range is from 0 to 36 with higher scores representing higher severity. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo

Group	Value	95% CI
Placebo	1.02	± 0.562
Crenezumab	1.55	± 0.556

Quality of Life-Alzheimer's Disease (QoL-AD) Scale Score Secondary · Baseline up to Week 105

The QoL-AD (Quality of Life - Alzheimer's Disease) scale assesses QoL in participants who have dementia. The QoL-AD consists of 13 items covering aspects of participants' relationships with friends and family, physical condition, mood, concerns about finances and overall assessment of QoL. Items are rated on 4-point Likert-type scales ranging from 1 \[poor\] to 4 \[excellent\]. The score range is from 13 to 52, with higher scores indicating a better QoL. The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants was estimated. Mixed model repeat

Group	Value	95% CI
Placebo	-1.69	± 0.501
Crenezumab	-2.08	± 0.513

Zarit Caregiver Interview for Alzheimer's Disease (ZCI-AD) Scale Score Secondary · Baseline up to Week 105

The ZCI-AD is a modified version of the Zarit Burden Interview, which was originally designed to reflect the stresses experienced by caregivers of people with dementia. This modified version includes slight modifications in item and title wording (e.g., removal of "your relative" to refer directly to the patient, removal of "burden" from title) and the use of 11-point numerical rating scales. The ZCI-AD scale consists of a total of 30 items. Total scores will be calculated with a total score range from 0 to 300 (higher scores indicate a higher burden on the caregiver). The difference in mean c

Group	Value	95% CI
Placebo	22.72	± 5.135
Crenezumab	24.11	± 5.106

EQ-5D Questionnaire Domain Score for Participants Secondary · Baseline up to Week 105

The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants wa

Group	Value	95% CI
Placebo	-4.54	± 1.732
Crenezumab	-6.35	± 1.761

EQ-5D Questionnaire Domain Score for Caregivers Secondary · Baseline up to Week 105

The EQ-5D is a standardized measure of health status designed to provide a simple generic measure of health for clinical and economic appraisal. It is broadly applicable across a wide range of health conditions and treatment. The EQ-5D assesses five domains to provide a health state index. These are anxiety/depression, pain/discomfort, usual activities, mobility, and self-care. The scores on the EQ-5D ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The difference in mean change from Baseline to Week 105 between Crenezumab and Placebo treated participants wa

Group	Value	95% CI
Placebo	-3.16	± 1.713
Crenezumab	-4.09	± 1.721

Adverse events — posted to ClinicalTrials.gov

Time frame: Baseline up until 16 weeks after the last dose of study drug (up to 117 weeks).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo

Serious: 63/405 (16%)

Deaths: 5/405

Crenezumab

Serious: 67/404 (17%)

Deaths: 8/404

Serious adverse events (119 terms)

Reaction	System	Placebo	Crenezumab
PNEUMONIA	Infections and infestations	—	—
FALL	Injury, poisoning and procedural complications	—	—
SUBDURAL HAEMATOMA	Injury, poisoning and procedural complications	—	—
SYNCOPE	Nervous system disorders	—	—
DIVERTICULITIS	Infections and infestations	—	—
DEHYDRATION	Metabolism and nutrition disorders	—	—
BRADYCARDIA	Cardiac disorders	—	—
MYOCARDIAL INFARCTION	Cardiac disorders	—	—
GASTROINTESTINAL HAEMORRHAGE	Gastrointestinal disorders	—	—
RECTAL HAEMORRHAGE	Gastrointestinal disorders	—	—
CHEST PAIN	General disorders	—	—
NON-CARDIAC CHEST PAIN	General disorders	—	—
PYELONEPHRITIS	Infections and infestations	—	—
URINARY TRACT INFECTION	Infections and infestations	—	—
SKIN LACERATION	Injury, poisoning and procedural complications	—	—
WRIST FRACTURE	Injury, poisoning and procedural complications	—	—
DIABETIC KETOACIDOSIS	Metabolism and nutrition disorders	—	—
OSTEOARTHRITIS	Musculoskeletal and connective tissue disorders	—	—
CEREBROVASCULAR ACCIDENT	Nervous system disorders	—	—
LOSS OF CONSCIOUSNESS	Nervous system disorders	—	—
SEIZURE	Nervous system disorders	—	—
AGITATION	Psychiatric disorders	—	—
ACUTE CORONARY SYNDROME	Cardiac disorders	—	—
ANGINA UNSTABLE	Cardiac disorders	—	—
ATRIAL FLUTTER	Cardiac disorders	—	—

Other adverse events (14 terms — click to expand)

Reaction	System	Placebo	Crenezumab
HEADACHE	Nervous system disorders	—	—
FALL	Injury, poisoning and procedural complications	—	—
NASOPHARYNGITIS	Infections and infestations	—	—
UPPER RESPIRATORY TRACT INFECTION	Infections and infestations	—	—
BACK PAIN	Musculoskeletal and connective tissue disorders	—	—
ANXIETY	Psychiatric disorders	—	—
DEPRESSION	Psychiatric disorders	—	—
DIZZINESS	Nervous system disorders	—	—
HYPERTENSION	Vascular disorders	—	—
DIARRHOEA	Gastrointestinal disorders	—	—
URINARY TRACT INFECTION	Infections and infestations	—	—
WEIGHT DECREASED	Investigations	—	—
RASH	Skin and subcutaneous tissue disorders	—	—
BRONCHITIS	Infections and infestations	—	—

Most-reported serious reactions: PNEUMONIA, FALL, SUBDURAL HAEMATOMA, SYNCOPE, DIVERTICULITIS, DEHYDRATION, BRADYCARDIA, MYOCARDIAL INFARCTION.

Data from ClinicalTrials.gov NCT02670083 adverse events section.

Sponsor's own description

This randomized, double-blind, placebo-controlled, parallel group study will evaluate the efficacy and safety of crenezumab versus placebo in participants with prodromal to mild AD. Participants will be randomized 1:1 to receive either intravenous (IV) infusion of crenezumab or placebo every 4 weeks (Q4W) for 100 weeks. The final efficacy and safety assessment will be performed 52 weeks after the last crenezumab dose. Participants will then have the option to enter the Open Label Extension (OLE) study if eligible. Participants who do not enter the OLE study will have additional follow-up visits at 16 and 52 weeks after the last dose, primarily for safety and also for limited efficacy assessments.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Alzheimer's disease drug development pipeline: 2019.
   Cummings J, Lee G, Ritter A, Sabbagh M, et al · · 2019 · cited 485× · PMID 31334330 · DOI 10.1016/j.trci.2019.05.008
2. Clinical trials of new drugs for Alzheimer disease.
   Huang LK, Chao SP, Hu CJ. · · 2020 · cited 426× · PMID 31906949 · DOI 10.1186/s12929-019-0609-7
3. Anti-Amyloid-β Monoclonal Antibodies for Alzheimer's Disease: Pitfalls and Promise.
   van Dyck CH. · · 2018 · cited 415× · PMID 28967385 · DOI 10.1016/j.biopsych.2017.08.010
4. History and progress of hypotheses and clinical trials for Alzheimer's disease.
   Liu PP, Xie Y, Meng XY, Kang JS. · · 2019 · cited 412× · PMID 31637009 · DOI 10.1038/s41392-019-0063-8
5. Alzheimer's disease drug development pipeline: 2018.
   Cummings J, Lee G, Ritter A, Zhong K. · · 2018 · cited 402× · PMID 29955663 · DOI 10.1016/j.trci.2018.03.009
6. Treatment Combinations for Alzheimer's Disease: Current and Future Pharmacotherapy Options.
   Cummings JL, Tong G, Ballard C. · · 2019 · cited 371× · PMID 30689575 · DOI 10.3233/jad-180766
7. Drug candidates in clinical trials for Alzheimer's disease.
   Hung SY, Fu WM. · · 2017 · cited 281× · PMID 28720101 · DOI 10.1186/s12929-017-0355-7
8. Alzheimer's disease drug development pipeline: 2017.
   Cummings J, Lee G, Mortsdorf T, Ritter A, et al · · 2017 · cited 258× · PMID 29067343 · DOI 10.1016/j.trci.2017.05.002