EVOLVE: A Study of Aducanumab in Participants With Mild Cognitive Impairment Due to Alzheimer's Disease or With Mild Alzheimer's Disease Dementia to Evaluate the Safety of Continued Dosing in Participants With Asymptomatic Amyloid-Related Imaging Abnormalities

• Sponsor: Biogen (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03639987
• Collaborator: (none)
• Enrollment: 52
• Locations: 22
• Arms: 2
• Actual Duration (Months): 7.3
• Patients Per Site: 2.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary objective of the study is to assess the safety impact of continuing aducanumab dosing in asymptomatic Amyloid-related Imaging Abnormalities (ARIA) in participants with mild cognitive impairment (MCI) due to Alzheimer's disease (AD) or with mild AD dementia. The secondary objective of the study is to characterize ARIA, from both the imaging and the clinical perspective and to characterize the safety, tolerability, pharmacokinetics (PK), and immunogenicity of aducanumab.

Condition or Disease	Intervention/Treatment	Phase
Cognitive Dysfunction; Alzheimer's Disease	Drug: Aducanumab; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Multicenter, Randomized, Parallel-Group, Double-Blind, Controlled Study of Aducanumab (BIIB037) in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease or With Mild Alzheimer's Disease Dementia to Evaluate the Safety of Continued Dosing in Subjects With Asymptomatic Amyloid-Related Imaging Abnormalities
• Actual Study Start Date: Dec 20, 2018
• Actual Primary Completion Date: Jul 30, 2019
• Actual Study Completion Date: Jul 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 Aducanumab, intravenous infusion, every 4 weeks for up to Week 52 during the randomized treatment period. The dose will be titrated to a desirable dose. Participants will be managed for drug continuation and suspension. Following a 4-week follow-up period, eligible participants will continue to receive aducanumab, intravenous infusion, every 4 weeks for an additional 104 weeks in the long-term extension period.	Drug: Aducanumab; Administered as specified in the treatment arm.; Other Names: BIIB037 ; Drug: Placebo; Administered as specified in the treatment arm.
Experimental: Group 2 Aducanumab, intravenous infusion, every 4 weeks for up to Week 52 during the randomized treatment period. The dose will be titrated to a desirable dose. Participants will be managed for drug continuation and suspension. Following a 4-week follow-up period, eligible participants will continue to receive aducanumab, intravenous infusion, every 4 weeks for an additional 104 weeks in the long-term extension period.	Drug: Aducanumab; Administered as specified in the treatment arm.; Other Names: BIIB037

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Clinically Impactful Amyloid-related Imaging Abnormalities (ARIA) [up to Week 54]

Secondary Outcome Measures

1. Number of Participants With ARIA by Severity as Obtained on Magnetic Resonance Imaging (MRI) [up to Week 54]

   ARIA by severity was obtained on Magnetic Resonance Imaging (MRI).

2. Time to Onset of ARIA as Obtained on MRI [up to Week 54]

3. Time to Resolution of ARIA as Obtained on MRI [up to Week 54]

4. Number of Participants With Symptomatic ARIA by Severity [up to Week 54]

   ARIA by severity was obtained on Magnetic Resonance Imaging (MRI).

5. Time to Onset of Symptomatic ARIA [up to Week 54]

6. Time to Resolution of Symptomatic ARIA [up to Week 54]

7. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [up to Week 54]

   An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose: results in death, in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event), however, this does not include an event that, had it occurred in a more severe form, might have caused death; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect or is a medically important event.

8. Change From Baseline in the Montreal Cognitive Assessment (MoCA) at Week 54 [Baseline, Week 54]

9. Number of Participants With Aducanumab Concentration in Serum [up to Week 54]

10. Number of Participants With Antiaducanumab Antibodies in Serum [up to Week 54]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion/ Exclusion Criteria

Key Inclusion Criteria:

• Ability of the participant or his/her legally authorized representative to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use confidential health information in accordance with national and local participant privacy regulations.

• Must have at least 6 years of education or work experience to exclude mental deficits other than MCI due to AD or mild AD dementia.

• Must have evidence of cerebral Aβ accumulation, based on a positive PET scan of the brain. Previously obtained positron emission tomography (PET) scan (within 12 months of screening) is permissible. Previous PET scan images must be submitted to the central imaging vendor to confirm that study inclusion criteria are met.

• Must consent to apolipoprotein E (ApoE) genotyping.

• Must meet all of the following clinical criteria for MCI due to AD or mild AD dementia according to NIA-AA criteria [Albert 2011; McKhann 2011], and must have the following: MCI due to AD (a CDR global score of 0.5, and an MMSE score between 24 and 30 (inclusive)), or Mild AD dementia (a CDR global score of 0.5 or 1, and as MMSE score between 20 and 26 (inclusive)).

Key Exclusion Criteria:

• Any uncontrolled medical or neurological/neurodegenerative condition (other than AD) that, in the opinion of the Investigator, might be a contributing cause of the participant's cognitive impairment (e.g., substance abuse, vitamin B12 deficiency, abnormal thyroid function, stroke or other cerebrovascular condition, Lewy body dementia, frontotemporal dementia, head trauma).

• Clinically significant unstable psychiatric illness (e.g., uncontrolled major depression, uncontrolled schizophrenia, uncontrolled bipolar affective disorder) within 6 months prior to Screening.

• Transient ischemic attack or stroke or any unexplained loss of consciousness within 1 year prior to Screening.

• Vaccinations within 10 days prior to randomization (Day 1).

• Female participants who are pregnant or currently breastfeeding.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Banner Alzheimer's Institute	Phoenix	Arizona	United States	85006
2	Center for Neurosciences	Tucson	Arizona	United States	85718
3	Neurology Center of North Orange County	Fullerton	California	United States	92835
4	Pacific Neuroscience Medical Group	Oxnard	California	United States	93030
5	Pacific Research Network, Inc	San Diego	California	United States	92103
6	California Neuroscience Research Medical Group Inc.	Sherman Oaks	California	United States	91403
7	JEM Research Institute	Atlantis	Florida	United States	33462
8	Brain Matters Research	Delray Beach	Florida	United States	33445
9	Neuropsychiatric Research Center of Southwest Florida	Fort Myers	Florida	United States	33912
10	Bioclinica Orlando	Orlando	Florida	United States	32806
11	Bioclinica Orlando	The Villages	Florida	United States	32162
12	Medical Research Health and Education Foundation, Inc	Columbus	Georgia	United States	31909
13	Josephson, Wallack, Munshower Neurology, P.C.	Indianapolis	Indiana	United States	46256
14	Las Vegas Medical Research	Las Vegas	Nevada	United States	89113
15	Advanced Memory Research Institute of NJ, PC	Toms River	New Jersey	United States	08755
16	Lynn Health Science Institute	Oklahoma City	Oklahoma	United States	73112
17	Neurology Clinic, PC	Cordova	Tennessee	United States	38108
18	Senior Adult Specialty Research	Austin	Texas	United States	78757
19	Baylor College Of Medicine	Houston	Texas	United States	77030
20	Clinical Trial Network	Houston	Texas	United States	77074
21	National Clinical Research Inc.-Richmond	Richmond	Virginia	United States	23294
22	Kingfisher Cooperative, LLC	Spokane	Washington	United States	99202

Sponsors and Collaborators

• Biogen

Investigators

• Study Director: Medical Director, Biogen

Study Documents (Full-Text)

• Study Protocol - Jul 6, 2018
• Statistical Analysis Plan - May 29, 2019

More Information

Publications

None provided.

• Responsible Party: Biogen
• ClinicalTrials.gov Identifier: NCT03639987
• Other Study ID Numbers: 221AD205; 2018-002102-31
• First Posted: Aug 21, 2018
• Last Update Posted: Sep 16, 2021
• Last Verified: Aug 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Biogen: Aducanumab; BIIB037
• Additional relevant MeSH terms: Alzheimer Disease; Dementia; Cognitive Dysfunction

Study Results

Participant Flow

Recruitment Details	Participants were enrolled at 10 investigative sites in the United States from 20 December 2018 to 30 July 2019.
Pre-assignment Detail	A total of 52 participants with Alzheimer's disease were enrolled in this study in one of the 2 groups: Group 1 and Group 2 to receive aducanumab titrated up to 10 mg/kg. The groups differed in the protocol specified management rules for amyloid-related imaging abnormalities (ARIA), in the event that moderate or severe asymptomatic ARIA was detected on MRI.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Period Title: Overall Study
STARTED	26	26
COMPLETED	0	0
NOT COMPLETED	26	26

Baseline Characteristics

Arm/Group Title	Group 1	Group 2	Total
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.	Total of all reporting groups
Overall Participants	26	26	52
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.5 (7.17)	73.3 (7.14)	72.9 (7.09)
Sex: Female, Male (Count of Participants)
Female	14 53.8%	15 57.7%	29 55.8%
Male	12 46.2%	11 42.3%	23 44.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 3.8%	2 7.7%	3 5.8%
Not Hispanic or Latino	25 96.2%	24 92.3%	49 94.2%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	26 100%	26 100%	52 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Clinically Impactful Amyloid-related Imaging Abnormalities (ARIA)
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

Clinically Impactful ARIA was to be assessed by an independent Adjudication Committee. At the time the study was terminated, the Adjudication Committee had not been formed; therefore, this outcome measure was not evaluated due to lack of data.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	0	0

2. Secondary Outcome

Title	Number of Participants With ARIA by Severity as Obtained on Magnetic Resonance Imaging (MRI)
Description	ARIA by severity was obtained on Magnetic Resonance Imaging (MRI).
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

The safety population is defined as all randomized participants who had received at least one dose of aducanumab.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	26	26
Count of Participants [Participants]	2 7.7%	0 0%

3. Secondary Outcome

Title	Time to Onset of ARIA as Obtained on MRI
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

Due to small number of ARIA events, data is not reported due to participant confidentiality/human subjects protection assurances.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	0	0

4. Secondary Outcome

Title	Time to Resolution of ARIA as Obtained on MRI
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

Due to small number of ARIA events, data is not reported due to participant confidentiality/human subjects protection assurances.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	0	0

5. Secondary Outcome

Title	Number of Participants With Symptomatic ARIA by Severity
Description	ARIA by severity was obtained on Magnetic Resonance Imaging (MRI).
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

The safety population is defined as all randomized participants who had received at least one dose of aducanumab.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	26	26
Count of Participants [Participants]	1 3.8%	0 0%

6. Secondary Outcome

Title	Time to Onset of Symptomatic ARIA
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

Due to small number of ARIA events, data is not reported due to participant confidentiality/human subjects protection assurances.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	0	0

7. Secondary Outcome

Title	Time to Resolution of Symptomatic ARIA
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

Due to small number of ARIA events, data is not reported due to participant confidentiality/human subjects protection assurances.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	0	0

8. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose: results in death, in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event), however, this does not include an event that, had it occurred in a more severe form, might have caused death; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital anomaly/birth defect or is a medically important event.
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

The safety population is defined as all randomized participants who had received at least one dose of aducanumab.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	26	26
AEs	15 57.7%	9 34.6%
SAEs	2 7.7%	0 0%

9. Secondary Outcome

Title	Change From Baseline in the Montreal Cognitive Assessment (MoCA) at Week 54
Time Frame	Baseline, Week 54

Outcome Measure Data

Analysis Population Description

Due to early termination of the study, none of the participants reached the week 54 timepoint; therefore, data is not available for analysis.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	0	0

10. Secondary Outcome

Title	Number of Participants With Aducanumab Concentration in Serum
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

The safety population is defined as all randomized participants who had received at least one dose of aducanumab.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	26	26
Count of Participants [Participants]	1 3.8%	1 3.8%

11. Secondary Outcome

Title	Number of Participants With Antiaducanumab Antibodies in Serum
Time Frame	up to Week 54

Outcome Measure Data

Analysis Population Description

The safety population is defined as all randomized participants who received at least one dose of aducanumab.

Arm/Group Title	Group 1	Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
Measure Participants	26	26
Count of Participants [Participants]	0 0%	0 0%

Adverse Events

Time Frame	Up to Week 54
Adverse Event Reporting Description	The safety population is defined as all randomized participants who had received at least one dose of aducanumab.
Arm/Group Title	Group 1		Group 2
Arm/Group Description	Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 1 ARIA management rules.		Aducanumab dose titrated up to 10 mg/kg, IV infusion, following Group 2 ARIA management rules.
All Cause Mortality
	Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/26 (0%)
Serious Adverse Events
	Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/26 (7.7%)		0/26 (0%)
Cardiac disorders
Bradycardia	1/26 (3.8%)		0/26 (0%)
Injury, poisoning and procedural complications
Fall	2/26 (7.7%)		0/26 (0%)
Femur Fracture	1/26 (3.8%)		0/26 (0%)
Humerus fracture	1/26 (3.8%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Group 1		Group 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/26 (42.3%)		7/26 (26.9%)
Infections and infestations
Nasopharyngitis	1/26 (3.8%)		2/26 (7.7%)
Urinary tract infection	1/26 (3.8%)		2/26 (7.7%)
Injury, poisoning and procedural complications
Fall	3/26 (11.5%)		0/26 (0%)
Nervous system disorders
Headache	5/26 (19.2%)		4/26 (15.4%)
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits	2/26 (7.7%)		0/26 (0%)
Psychiatric disorders
Depression	2/26 (7.7%)		0/26 (0%)

Limitations/Caveats

Study was discontinued based on futility analysis conducted on Phase 3 trials (NCT02477800 and NCT02484547). Enrolment and dosing was halted immediately upon the study termination announcement.

More Information

Certain Agreements

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

Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.