NCT02477800: ENGAGE

221AD301 Phase 3 Study of Aducanumab (BIIB037) in Early Alzheimer's Disease

Terminated Phase 3 Results posted Last updated 2 September 2021

What this trial tests

Phase 3 trial testing Aducanumab (BIIB037) in Alzheimer's Disease in 1,653 participants. Terminated before completion.

Timeline

13 August 2015

Primary endpoint
8 August 2019

8 August 2019

Quick facts

Lead sponsor	Biogen
Phase	Phase 3
Status	Terminated
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	1,653
Start date	13 August 2015
Primary completion	8 August 2019
Estimated completion	8 August 2019
Sites	181 locations across Denmark, France, Italy, Japan, Austria, Taiwan, United Kingdom, Germany

Drugs / interventions tested

• Aducanumab (BIIB037) — full drug profile →
• Aducanumab (BIIB037) — full drug profile →
• Placebo

Conditions studied

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

Sponsor

Biogen — 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 in Clinical Dementia Rating Sum of Boxes (CDR-SB) Score at Week 78 Primary · Baseline, Week 78

CDR-SB integrates assessments from 3 domains of cognition (memory, orientation, judgment/problem-solving) and 3 domains of function (community affairs, home/hobbies, personal care). Following caregiver interview and systematic patient examination, the rater assigns a score describing the participant's current performance level in each of these domains of life functioning. Prespecified severity anchors range from none = 0, questionable = 0.5, mild = 1, moderate = 2 to severe = 3 (the personal care domain omits the 0.5 score). "Sum of boxes" scoring methodology sums the score for each of the 6 d

Group	Value	95% CI
Placebo (PC Period)	1.56	± 0.108
BIIB037 Low Dose (PC Period)	1.38	± 0.108
BIIB037 High Dose (PC Period)	1.59	± 0.111

Change From Baseline in Mini-Mental State Examination (MMSE) Score at Week 78 Secondary · Baseline, Week 78

The MMSE is a widely used performance-based test of global cognitive status. It consists of 11 tasks that assess orientation, word recall, attention and calculation, language abilities, and visuospatial functions. The scores from the 11 tests are combined to obtain the total score, which ranges from 0 to 30, with lower scores over time indicating increasing cognitive impairment. MMRM analysis was used to analyze change from baseline in MMSE. A negative change from baseline indicates clinical decline.

Group	Value	95% CI
Placebo (PC Period)	-3.5	± 0.21
BIIB037 Low Dose (PC Period)	-3.3	± 0.21
BIIB037 High Dose (PC Period)	-3.6	± 0.21

Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale (13 Items) (ADAS-Cog 13) Score at Week 78 Secondary · Baseline, Week 78

ADAS-Cog13 comprises both cognitive tasks and clinical ratings of cognitive performance. The scale items capture word recall, ability to follow commands, the ability to correctly copy or draw an image, naming, the ability to interact with everyday objects, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure for delayed word recall and concentration/distractibility. The total score ranges from 0 to 85. An increase in score over time indicates increasing cognitive impairment. MMRM analysis was used to analyze change from bas

Group	Value	95% CI
Placebo (PC Period)	5.140	± 0.3783
BIIB037 Low Dose (PC Period)	4.558	± 0.3780
BIIB037 High Dose (PC Period)	4.552	± 0.3872

Change From Baseline in Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment Version) (ADCS-ADL-MCI) Score at Week 78 Secondary · Baseline, Week 78

The ADCS-ADL-MCI consists of 17 instrumental items (e.g., shopping, preparing meals, using household appliances) and 1 basic item (getting dressed). Ratings reflect caregiver observations about the patient's actual functioning over the previous month and provide an assessment of change in the functional state of the participant over time. The total score ranges from 0 to 53, with lower values over time reflecting functional deterioration. MMRM analysis was used to analyze change from baseline in ADAS-ADL-MCI. A negative change from baseline indicates clinical decline.

Group	Value	95% CI
Placebo (PC Period)	-3.8	± 0.35
BIIB037 Low Dose (PC Period)	-3.1	± 0.35
BIIB037 High Dose (PC Period)	-3.1	± 0.35

Adverse events — posted to ClinicalTrials.gov

Time frame: From First Dose to End of Study (up to 4 years). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo (PC Period)

Serious: 70/540 (13%)

Deaths: 0/540

BIIB037 Low Dose (PC Period)

Serious: 76/549 (14%)

Deaths: 3/549

BIIB037 High Dose (PC Period)

Serious: 79/558 (14%)

Deaths: 2/558

BIIB037 Late Start: Low Dose (LTE Period)

Serious: 19/150 (13%)

Deaths: 1/150

BIIB037 Late Start: High Dose (LTE Period)

Serious: 14/152 (9%)

Deaths: 1/152

BIIB037 Early Start: Low Dose (LTE Period)

Serious: 35/299 (12%)

Deaths: 1/299

BIIB037 Early Start: High Dose (LTE Period)

Serious: 25/251 (10%)

Deaths: 2/251

Serious adverse events (264 terms)

Reaction	System	Placebo (PC Period)	BIIB037 Low Dose (PC Period)	BIIB037 High Dose (PC Peri…	BIIB037 Late Start: Low Do…	BIIB037 Late Start: High D…	BIIB037 Early Start: Low D…	BIIB037 Early Start: High …
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Amyloid related imaging abnormality-oedema/effusion	Nervous system disorders	—	—	—	—	—	—	—
Atrial fibrillation	Cardiac disorders	—	—	—	—	—	—	—
Syncope	Nervous system disorders	—	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—	—
Deep vein thrombosis	Vascular disorders	—	—	—	—	—	—	—
Non-cardiac chest pain	General disorders	—	—	—	—	—	—	—
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Acute myocardial infarction	Cardiac disorders	—	—	—	—	—	—	—
Cardiac arrest	Cardiac disorders	—	—	—	—	—	—	—
Cataract	Eye disorders	—	—	—	—	—	—	—
Inguinal hernia	Gastrointestinal disorders	—	—	—	—	—	—	—
Obstructive pancreatitis	Gastrointestinal disorders	—	—	—	—	—	—	—
Chest pain	General disorders	—	—	—	—	—	—	—
Gait disturbance	General disorders	—	—	—	—	—	—	—
Cellulitis	Infections and infestations	—	—	—	—	—	—	—
Diverticulitis	Infections and infestations	—	—	—	—	—	—	—
Gastroenteritis	Infections and infestations	—	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—	—
Cervical vertebral fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Femoral neck fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Femur fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Hand fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Humerus fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Joint dislocation	Injury, poisoning and procedural complications	—	—	—	—	—	—	—

Other adverse events (19 terms — click to expand)

Reaction	System	Placebo (PC Period)	BIIB037 Low Dose (PC Period)	BIIB037 High Dose (PC Peri…	BIIB037 Late Start: Low Do…	BIIB037 Late Start: High D…	BIIB037 Early Start: Low D…	BIIB037 Early Start: High …
Amyloid related imaging abnormality-oedema/effusion	Nervous system disorders	—	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—	—
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits	Nervous system disorders	—	—	—	—	—	—	—
Superficial siderosis of central nervous system	Nervous system disorders	—	—	—	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Nasopharyngitis	Infections and infestations	—	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—	—
Depression	Psychiatric disorders	—	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—	—
Anxiety	Psychiatric disorders	—	—	—	—	—	—	—
Confusional state	Psychiatric disorders	—	—	—	—	—	—	—

Most-reported serious reactions: Fall, Amyloid related imaging abnormality-oedema/effusion, Atrial fibrillation, Syncope, Pneumonia, Deep vein thrombosis, Non-cardiac chest pain, Pulmonary embolism.

Data from ClinicalTrials.gov NCT02477800 adverse events section.

Sponsor's own description

The primary objective of the study is to evaluate the efficacy of monthly doses of aducanumab in slowing cognitive and functional impairment as measured by changes in the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score as compared with placebo in participants with early AD. Secondary objectives are to assess the effect of monthly doses of aducanumab as compared with placebo on clinical progression as measured by Mini-Mental State Examination (MMSE), AD Assessment Scale-Cognitive Subscale (13 items) \[ADAS-Cog 13\], and AD Cooperative Study-Activities of Daily Living Inventory (Mild Cognitive Impairment version) \[ADCS-ADL-MCI\].

Publications & conference data

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

1. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments.
   Guo J, Huang X, Dou L, Yan M, et al · · 2022 · cited 1019× · PMID 36522308 · DOI 10.1038/s41392-022-01251-0
2. 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
3. Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease.
   Salloway S, Chalkias S, Barkhof F, Burkett P, et al · · 2022 · cited 437× · PMID 34807243 · DOI 10.1001/jamaneurol.2021.4161
4. 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
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. Antibodies to watch in 2020.
   Kaplon H, Muralidharan M, Schneider Z, Reichert JM. · · 2020 · cited 332× · PMID 31847708 · DOI 10.1080/19420862.2019.1703531
8. 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