The objectives are to evaluate the long-term safety and tolerability profile of aducanumab in subjects with early AD, and to evaluate the long-term efficacy of aducanumab treatment as measured by clinical, radiological and additional assessments…
ID
Source
Brief title
Condition
- Mental impairment disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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 CDR-SB score as compared with placebo in subjects with early AD.
The primary endpoint that relates to this objective is the change from baseline
in CDR-SB score at Week 78.
Secondary outcome
To assess the effect of monthly doses of aducanumab as compared with placebo on
clinical progression as measured by
- MMSE
* + Change from baseline in MMSE score at Week 78
- Alzheimer*s Disease Assessment Scale-Cognitive Subscale (13 items) [ADAS-Cog
13]
* + Change from baseline in ADAS-Cog 13 at Week 78
- Alzheimer*s Disease Cooperative Study-Activities of Daily Living Inventory
(Mild Cognitive Impairment version) [ADCS-ADL-MCI]
* + Change from baseline in ADCS-ADL-MCI score at Week 78
Background summary
The purpose of this Phase 3 study is to assess the efficacy and safety of
aducanumab compared with placebo in subjects with early Alzheimer*s Disease
(AD), including mild cognitive impairment (MCI) due to AD and a subset of mild
AD. Aducanumab is a human monoclonal antibody that recognizes aggregated forms
of *-amyloid (A*), including soluble A* oligomers and deposited fibrillar A*.
Interim analyses of the ongoing multiple dose study (Study 221AD103) have
demonstrated target engagement, a pharmacodynamic effect on amyloid reduction,
and an effect on the Clinical Dementia Rating (CDR)-Sum of Boxes (SB) and
Mini-Mental State Examination (MMSE) suggestive of a reduction in the
progression of clinical impairment for aducanumab-treated subjects. These
results along with the observed safety and tolerability profile warrant further
Phase 3 investigation of aducanumab in a patient population spanning the early
stages of the AD continuum.
Study objective
The objectives are to evaluate the long-term safety and tolerability profile of
aducanumab in subjects with early AD, and to evaluate the long-term efficacy of
aducanumab treatment as measured by clinical, radiological and additional
assessments reported by the subject and informant/care partner.
Study design
Multicenter, randomized study with an 18-month double-blind, placebo-controlled
period followed by an optional up to 5 year dose-blind, LTE period.
Intervention
For the 18-month placebo-controlled period of the study and based upon their
ApoE *4 carrier status, subjects will be assigned to 1 of 3 treatment groups
(450 subjects each) in a 1:1:1 ratio (aducanumab low dose: aducanumab high
dose: placebo) as follows:
- ApoE *4 carrier
+ Low dose (3 mg/kg)
+ High dose (6 mg/kg)
+ Placebo
- ApoE *4 non-carrier
+ Low dose (6 mg/kg)
+ High dose (10 mg/kg)
+ Placebo
After completion of the placebo-controlled period, subjects may enter a 5 year
dose-blind LTE study during which all subjects will receive aducanumab.
Study burden and risks
TREATMENT RISKS
Possible Side Effects
The most common side effect in the 185 people with AD who received aducanumab
each month during their participation in the ongoing clinical study, for which
detailed safety information is available, was transient (temporary) swelling of
the brain and/or small spots of bleeding in or around the brain; as of 25 May
2017, 32% of the people had this side effect. Also, some people had iron
deposits from small spots of bleeding around the brain (6%). These side effects
are observed on magnetic resonance imaging (MRI) of the brain and are generally
known as amyloid-related imaging abnormalities (ARIA). Some of the people also
had symptoms, most being mild and temporary, while others did not have
symptoms. For further details on ARIA, see *Additional Information on ARIA Side
Effects* and *Serious Side Effects* sections below.
Other common side effects observed in at least 11 of the 185 (more than 5%)
people with AD who received aducanumab during the placebo-controlled period
and/or the long-term extension period of the ongoing clinical study were as
follows:
- Headache (26%)
- Fall (23%)
- Urinary tract infection (18%)
- Upper respiratory tract infection (15%)
- Diarrhea (14%)
- Viral upper respiratory tract infection (14%)
- Joint pain (arthralgia) (11%)
- Back pain (11%)
- Bruising (contusion) (10%)
- Dizziness (10%)
- Anxiety (10%)
- Confused state (9%)
- Nausea (9%)
- Cough (8%)
- Agitation (8%)
- Depression (8%)
- Scraped skin (abrasion) (8%)
- Fatigue (7%)
- Constipation (6%)
- Iron deposits in the brain (superficial siderosis of central nervous system)
[6%]
- Syncope (6%)
- Cut (laceration) (6%)
- Vomiting (6%)
- Decrease in weight (6%)
Serious Side Effects
Transient swelling (also known as edema) of the brain or the area around the
brain, or small spots of bleeding in the brain or around the brain (also known
as superficial siderosis or hemosiderosis) have been observed in some patients
receiving aducanumab, placebo, or some products that may work in a similar way
to aducanumab. To date, this transient swelling or small spots of bleeding have
been observed in 13% to 47 % of patients taking multiple doses of aducanumab at
doses similar to what you might receive. The higher percentage (47%) is in
patients with a specific genetic marker called ApoE *4 and who are taking the
higher doses. Small spots of bleeding have also been seen in patients taking
placebo. Some patients with edema or small spots of bleeding have symptoms that
can include headache, confusion or difficulty concentrating, seizures (also
known as fits or convulsions), unsteadiness, visual disturbances, and/or
vomiting. In the multiple-dose study, 1 patient with edema or small spots of
bleeding had a seizure with a brief loss of pulse. Some patients with edema or
small spots of bleeding have no symptoms. Stroke has been observed in some
patients receiving aducanumab, placebo, or some products that may work in a
similar way to aducanumab.
Other Possible Side Effects
Antibodies may be formed against aducanumab. These antibodies might prevent
aducanumab from working or might cause an allergic reaction to aducanumab.
RISKS OF STUDY TESTS
The examinations and IV administration of study treatment may cause discomfort.
IV administration of study treatment may cause pain, redness, swelling,
tenderness, and/or bruising at the IV site.
Taking blood from a vein may cause bruising, localized bleeding, infection,
faintness, or a small amount of pain from the needle stick.
Norden Road Innovation House, 70
Maidenhead Berkshire SL6 4AY
GB
Norden Road Innovation House, 70
Maidenhead Berkshire SL6 4AY
GB
Listed location countries
Age
Inclusion criteria
- Must meet all of the following clinical criteria for MCI due to AD or mild AD and must have:
- A Clinical Dementia Rating (CDR)-Global Score of 0.5.
- A Repeatable Battery for Assessment of Neuropsychological Status (RBANS) score of 85 or lower indicative of objective cognitiveimpairment
- An MMSE score between 24 and 30 (inclusive)
- Must have a positive amyloid Positron Emission Tomography (PET) scan
- Must consent to apolipoprotein E (ApoE) genotyping
- Must have stable symptomatic AD medications
- Must have a reliable informant or caregiver;LTE specific Criteria at week 78:
- Must have completed the placebo-controlled period of the study.
- Must (or the subject's legally authorized representative) understand the purpose and risks of the study and provide signed consent (or assent)
- Apart from a clinical diagnosis of AD, subject must be in good health as determined by the Investigator, based on medical history.
- Must have the ability to comply with procedures for protocol-related tests.
- Must have reliable informant or caregiver
Exclusion criteria
- Any medical or neurological condition (other than Alzheimer's Disease) that might be a contributing cause of the subject's cognitive impairment
- Have had a stroke or Transient Ischemic Attack (TIA) or unexplained loss of consciousness in the past 1 year
- Clinically significant psychiatric illness in past 6 months
- History of unstable angina, myocardial infarction, chronic heart failure, or clinical significant conduction abnormalities within 1 year prior to Screening
- Indication of impaired renal or liver function
- Have human immunodeficiency virus (HIV) infection
- Have a significant systematic illness or infection in past 30 days
- Relevant brain hemorrhage, bleeding disorder and cardiovascular abnormalities
- Any contraindications to brain magnetic resonance imaging (MRI) or PET scans
- Alcohol or substance abuse in past 1 year
- Taking blood thinners (except for aspirin at a prophylactic dose or less)
- Use of AD medications at doses that have not been stable for at least 8 weeks prior to Screening Visit 1;Subjects will be excluded from entering the LTE if at Week 78 they have:
any medical or psychiatric contraindication or clinically significant abnormality that will substantially increase the risk associated with the subject's participation in and completion of the study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-000967-15-NL |
| CCMO | NL53598.072.15 |