CREAD OLE: An Open-Label Crenezumab Study in Participants With Alzheimer's Disease

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03491150
• Collaborator: (none)
• Enrollment: 149
• Locations: 66
• Arms: 2
• Actual Duration (Months): 13.6
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

In the BN40031 OLE study, a dose of crenezumab of 60 mg/kg intravenous (IV) every 4 weeks (Q4W) will be offered to all participants who complete Study BN29552 or BN29553 and who meet eligibility criteria in order to evaluate safety in participants on long-term crenezumab treatment and to investigate the effect of crenezumab on the underlying disease process and disease course as an exploratory efficacy objective.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer's Disease	Drug: Crenezumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 149 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open Label Extension (OLE)Open Label Extension (OLE)
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open-Label, Long-Term Extension Of Phase III Studies (BN29552/BN29553) Of Crenezumab In Patients With Alzheimer's Disease
• Actual Study Start Date: Apr 11, 2018
• Actual Primary Completion Date: May 31, 2019
• Actual Study Completion Date: May 31, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Parent Placebo Participants (who were treated with Placebo in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).	Drug: Crenezumab; Crenezumab was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above.; Other Names: RO5490245
Experimental: Parent Crenezumab Participants (who were treated with Crenezumab in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).	Drug: Crenezumab; Crenezumab was administered by intravenous (IV) infusion at 60mg/kg as per the dosing schedule described above.; Other Names: RO5490245

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to 16 weeks after the last dose of study drug (up to 54 weeks).]

   An Adverse Event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

2. Percentage of Participants With Anti-Crenezumab Antibodies [Baseline up to end of study (up to 54 weeks).]

   Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for Crenezumab and Placebo groups. The prevalence of ADA at baseline was calculated as the proportion of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the proportion of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Previous participation in Study BN29552 or BN29553 and completion of the Week 105 visit.

• Able to provide written informed consent by the patient or legally authorized representative, if required.

• Every effort to have the same caregiver participate throughout the duration of the OLE (Open Label Extension) study who also participated in Study BN29552 or BN29553.

• Willingness and ability to complete all aspects of the study [including MRI (Magnetic Resonance Imaging), lumbar puncture [if applicable], and PET (Positron Emission Tomography) imaging [if applicable].

• Adequate visual and auditory acuity, in the investigator's judgment, sufficient to perform the neuropsychological testing.

• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a protocol approved contraceptive method and agreement to refrain from donating eggs for at least 8 weeks after last dose.

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a protocol approved contraceptive method for at least 8 weeks after last dose.

Exclusion Criteria:

• Patients who discontinued treatment permanently in Study BN29552 or BN29553 for safety reasons.

• Impaired coagulation.

• Evidence of more than 10 microbleeds and/or ARIA-H (amyloid-related imaging abnormalities-hemosiderin deposition) at the Study BN29552 or BN29553 Week 105 visit, as assessed by central review of MRI.

• Diagnosed with three recurrent, symptomatic ARIA-E (amyloid-related imaging abnormalities-edema/effusion) events or exacerbations of previous events.

• Presence of intracranial lesion that could potentially increase the risk of CNS (Central Nervous System) bleeding.

• At risk of suicide in the opinion of the investigator.

• Alcohol and/or substance abuse or dependence within the past 2 years and during the study.

• Inability to tolerate MRI procedures or contraindication to MRI, including, but not limited to, presence of pacemakers not compatible with MRI, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body that would contraindicate an MRI scan; or any other clinical history or examination finding that, in the judgment of the investigator, would pose a potential hazard in combination with MRI.

• Pregnant or lactating, or intending to become pregnant during the study.

• Any other severe or unstable medical condition that, in the opinion of the investigator or Sponsor, 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, or interfere with the patient's ability to complete the study assessments.

• Chronic use of anticoagulants or participation in any other investigational drug treatment trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Shankle Clinic	Newport Beach	California	United States	92663
2	Anderson Clinical Research, Inc.	Redlands	California	United States	92374
3	University of California, Davis; Alzheimers Disease Center, Department of Neurology	Sacramento	California	United States	95817
4	UCSF - Memory and Aging Center	San Francisco	California	United States	94158
5	Neurological Research Inst	Santa Monica	California	United States	90404
6	Associated Neurologists PC - Danbury	Danbury	Connecticut	United States	06810
7	Institute for Neurodegenerative Disorders	New Haven	Connecticut	United States	06510
8	Yale University School Of Medicine	New Haven	Connecticut	United States	06510
9	Research Center for Clinical Studies, Inc.	Norwalk	Connecticut	United States	06851
10	Bradenton Research Center	Bradenton	Florida	United States	34205
11	Brain Matters Research, Inc.	Delray Beach	Florida	United States	33445
12	Alzheimer's Research and Treatment Center	Lake Worth	Florida	United States	33414
13	Renstar Medical Research	Ocala	Florida	United States	34470
14	Bioclinica Research	Orlando	Florida	United States	32806
15	Progressive Medical Research	Port Orange	Florida	United States	32127
16	Stedman Clinical Trials, LLC	Tampa	Florida	United States	33613
17	NeuroStudies.net, LLC	Decatur	Georgia	United States	30033
18	Alexian Brothers Neurosci Inst	Elk Grove Village	Illinois	United States	60007
19	Southern Illinois University, School of Medicine	Springfield	Illinois	United States	62702
20	MidAmerica Neuroscience Institute	Prairie Village	Kansas	United States	66206
21	MMP Neurology	Scarborough	Maine	United States	04074
22	Precise Research Centers	Flowood	Mississippi	United States	39232
23	The Cognitive and Research Center of New Jersey	Springfield	New Jersey	United States	07081
24	Advanced Memory Research Institute of NJ	Toms River	New Jersey	United States	08755
25	Behavioral Health Research	Charlotte	North Carolina	United States	28211
26	Guilford Neurologic Associates	Greensboro	North Carolina	United States	27401
27	Oklahoma Clinical Research	Oklahoma City	Oklahoma	United States	73112
28	Summit Research Network Inc.	Portland	Oregon	United States	97210
29	Abington Neurological Associates	Willow Grove	Pennsylvania	United States	19090
30	Senior Adults Specialty Research	Austin	Texas	United States	78757
31	Sentara Medical Group	Norfolk	Virginia	United States	23507
32	National Clinical Research Inc.-Richmond	Richmond	Virginia	United States	23294
33	Heidelberg Repatriation Hospital; Medical and Cognitive Research Centre	Heidelberg West	Victoria	Australia	3081
34	Neurodegenerative Disorders Research; Neurology	West Perth	Western Australia	Australia	6005
35	Parkwood Hospital; Geriatric Medicine	London	Ontario	Canada	N6C 5J1
36	Kawartha Centre - Redefining Healthy Aging	Peterborough	Ontario	Canada	K9H 2P4
37	The Centre for Memory and Aging	Toronto	Ontario	Canada	M4G 3E8
38	Devonshire Clinical Research Inc.	Woodstock	Ontario	Canada	N4S 5P5
39	Terveystalo Tampere	Tampere		Finland	33100
40	Hopital La Grave; Place Lange	Toulouse Cedec		France	31059
41	Klinikum rechts der Isar der TU München; Klinik für Psychiatrie und Psychotherapie	München		Germany	81675
42	Prince of Wales Hospital; Dept. of Medicine & Therapeutics	Hong Kong		Hong Kong
43	Fondazione Santa Lucia IRCCS	Roma	Lazio	Italy	00179
44	Ospedale San Giovanni Calibita Fatebenefratell;Neurologia	Roma	Lazio	Italy	00186
45	Inha University Hospital	Incheon		Korea, Republic of	22332
46	Konkuk University Medical Center	Seoul		Korea, Republic of	05030
47	Asan Medical Center	Seoul		Korea, Republic of	05505
48	Ewha Womans University Mokdong Hospital	Seoul		Korea, Republic of	07985
49	Vilnius University Hospital Santariskiu Clinic	Vilnius		Lithuania	08661
50	Hospital Angeles de Culiacán, Neurociencias Estudios Clínicos SC	Culiacan		Mexico	80020
51	Hospital Uni; Dr. Jose E. Gonzalez	Monterrey		Mexico	64460
52	AVIX Investigación Clínica S.C	Monterrey		Mexico	64710
53	Hospital Universitario de Saltillo	Saltillo		Mexico	25000
54	Centrum Medyczne NeuroProtect	Warszawa		Poland	01-684
55	State Autonomous Healthcare Institution "Republican Clinical Neurological Center	Kazan		Russian Federation	420021
56	State autonomous institution of healthcare Inter-regional clinical and diagnostic center	Kazan		Russian Federation	420101
57	SHI City Psychoneurological Dispensary #7 (with Hospital)	St. Petersburg		Russian Federation	190121
58	Fundació ACE	BArcelon	Barcelona	Spain	08034
59	Hospital General De Catalunya; Servicio de Neurologia	Sant Cugat del Valles	Barcelona	Spain	8195
60	Hospital Mutua De Terrasa; Servicio de Neurologia	Terrassa	Barcelona	Spain	08222
61	Hospital Virgen del Puerto. Servicio de Neurología	Plasencia	Caceres	Spain	10600
62	Clinica Universitaria de Navarra; Servicio de Neurología	Pamplona	Navarra	Spain	31008
63	Hospital Universitario 12 de Octubre; Servicio de Neurologia	Madrid		Spain	28041
64	Ondokuz Mayis Univ. Med. Fac.; Neurology	Samsun		Turkey	55139
65	Surrey and Borders NHS Foundation Trust; Research and Development Departmant; Abraham Cowley Unit	Chertsey		United Kingdom	KT16 0AE
66	Charing Cross Hospital	London		United Kingdom	W6 8RF

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 5, 2018

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03491150
• Other Study ID Numbers: BN40031; 2017-002702-12
• First Posted: Apr 9, 2018
• Last Update Posted: Jul 13, 2020
• Last Verified: Jun 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Hoffmann-La Roche: Dementia; Neurodegenerative Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurocognitive Disorders; Mental Disorders
• Additional relevant MeSH terms: Alzheimer Disease

Study Results

Participant Flow

Recruitment Details	The study was conducted at 66 centers in 16 countries.
Pre-assignment Detail	A total of 149 participants were enrolled at 66 centers. These 149 participants represented the Safety Analysis population and data for this population is presented here.

Arm/Group Title	Parent Placebo	Parent Crenezumab
Arm/Group Description	Participants (who were treated with Placebo in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).	Participants (who were treated with Crenezumab in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).
Period Title: Overall Study
STARTED	76	73
COMPLETED	0	0
NOT COMPLETED	76	73

Baseline Characteristics

Arm/Group Title	Parent Placebo	Parent Crenezumab	Total
Arm/Group Description	Participants (who were treated with Placebo in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).	Participants (who were treated with Crenezumab in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).	Total of all reporting groups
Overall Participants	76	73	149
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	73.8 (7.6)	72.0 (7.6)	72.9 (7.6)
Sex: Female, Male (Count of Participants)
Female	37 48.7%	38 52.1%	75 50.3%
Male	39 51.3%	35 47.9%	74 49.7%
Race/Ethnicity, Customized (Number) [Number]
Hispanic or Latino	6 7.9%	3 4.1%	9 6%
Not Hispanic or Latino	69 90.8%	69 94.5%	138 92.6%
Not Stated	1 1.3%	1 1.4%	2 1.3%
Race/Ethnicity, Customized (Number) [Number]
Asian	4 5.3%	2 2.7%	6 4%
Black or African American	0 0%	1 1.4%	1 0.7%
Unknown	0 0%	3 4.1%	3 2%
White	72 94.7%	67 91.8%	139 93.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An Adverse Event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time Frame	Baseline up to 16 weeks after the last dose of study drug (up to 54 weeks).

Outcome Measure Data

Analysis Population Description

The Safety analysis population was defined as all participants who consented to the OLE study, including those who enrolled in the OLE but did not receive open-label treatment.

Arm/Group Title	Parent Placebo	Parent Crenezumab
Arm/Group Description	Participants (who were treated with Placebo in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).	Participants (who were treated with Crenezumab in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).
Measure Participants	76	73
AEs	32.9 43.3%	42.5 58.2%
SAEs	3.9 5.1%	5.5 7.5%

2. Primary Outcome

Title	Percentage of Participants With Anti-Crenezumab Antibodies
Description	Participants were considered positive or negative for ADA based on their baseline and post-baseline sample results. The number and percentage of participants with confirmed positive ADA levels were determined for Crenezumab and Placebo groups. The prevalence of ADA at baseline was calculated as the proportion of participants with confirmed positive ADA levels at baseline relative to the total number of participants with a sample available at baseline. The incidence of treatment-emergent ADAs was determined as the proportion of participants with confirmed post-baseline positive ADAs relative to the total number of participants that had at least one post-baseline sample available for ADA analysis.
Time Frame	Baseline up to end of study (up to 54 weeks).

Outcome Measure Data

Analysis Population Description

Please note that for this Outcome Measure, no Participants were evaluated at all as the existing immunogenicity data from a parent study (Study BN29552) showed a low potential of Crenezumab to induce Anti-Drug Antibodies (ADAs).

Arm/Group Title	Parent Placebo	Parent Crenezumab
Arm/Group Description	Participants (who were treated with Placebo in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).	Participants (who were treated with Crenezumab in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).
Measure Participants	0	0

Adverse Events

Time Frame	Baseline up to 16 weeks after the last dose of study drug (up to 54 weeks).
Arm/Group Title	Parent Placebo		Parent Crenezumab
Arm/Group Description	Participants (who were treated with Placebo in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).		Participants (who were treated with Crenezumab in the BN29552/BN29553 Studies) received intravenous (IV) infusion of Crenezumab every 4 weeks (Q4W).
All Cause Mortality
	Parent Placebo		Parent Crenezumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/76 (0%)		0/73 (0%)
Serious Adverse Events
	Parent Placebo		Parent Crenezumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/76 (3.9%)		4/73 (5.5%)
Eye disorders
OPTIC ISCHAEMIC NEUROPATHY	0/76 (0%)	0	1/73 (1.4%)	1
Gastrointestinal disorders
INCARCERATED INGUINAL HERNIA	1/76 (1.3%)	1	0/73 (0%)	0
RECTAL HAEMORRHAGE	1/76 (1.3%)	1	0/73 (0%)	0
Infections and infestations
PNEUMONIA	0/76 (0%)	0	1/73 (1.4%)	1
UROSEPSIS	0/76 (0%)	0	1/73 (1.4%)	1
Injury, poisoning and procedural complications
FALL	0/76 (0%)	0	1/73 (1.4%)	1
Nervous system disorders
CEREBROVASCULAR ACCIDENT	1/76 (1.3%)	1	0/73 (0%)	0
Other (Not Including Serious) Adverse Events
	Parent Placebo		Parent Crenezumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/76 (5.3%)		4/73 (5.5%)
Injury, poisoning and procedural complications
FALL	4/76 (5.3%)	5	4/73 (5.5%)	4

Limitations/Caveats

This study was discontinued due to an interim analysis in the BN29552 study, which indicated that Crenezumab was unlikely to meet its primary endpoint.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.