Mild Alzheimer's Disease

This study will evaluate the efficacy, safety, and pharmacokinetics of crenezumab compared with placebo in patients with prodromal to mild AD. Primary Efficacy Objective: • To evaluate the efficacy of crenezumab compared with placebo

Crenezumab

Crenezumab

IVT

720 mg/ 4 ml

Primary Efficacy Endpoint:
• Change from baseline to Week 105 in global outcomes as assessed by CDR-SB

Secondary Efficacy Endpoints:
• Change from baseline to Week 105 on cognition as
measured by ADAS-Cog-13
• Time to clinically evident decline as defined by
Confirmed decline (at two consecutive visits) on the MMSE of
≥ 2 points; and either
Loss of ≥ 1 point on ≥ 1 basic ADL on the ADCS-ADL (not
including a decline from 0 to 1); or
Loss of ≥ 2 points on ≥ 1 instrumental ADL on the ADCS-ADL
(not including a decline from 0 to 1)
• Change from baseline to Week 105 on severity of dementia,
assessed using the CDR-GS
Change from baseline to Week 105 on the following:
• Effect on cognition, assessed using the MMSE
• Effect on cognition, assessed using the ADAS-Cog-12
• Effect on cognition, assessed by time to an increase of
≥ 4 points from baseline at any time before or on Week 105
(i.e., worsening) in the ADAS-Cog-13
Function secondary endpoints:
• Effect on function, assessed using the ADCS-iADL
• Effect on function, assessed using the ADCS-ADL total score
• Effect on dependence level derived from the ADCS-ADL score
• Effect of function, assessed using the FAQ total score
Behavioral secondary endpoint:
• Effect on behavioral and neuropsychological symptoms of
AD, assessed using the NPI-Q
Other secondary endpoints:
• Effect of crenezumab on HRQOL, assessed using the QOL-AD scale
• Effect of crenezumab on caregiver burden, assessed using the ZCI-AD scale
• Effect of crenezumab on health outcomes in patient and caregiver as measured by EQ-5D

INCLUSION CRITERIA
Patients must meet the following criteria for study entry:
• Able to provide written consent signed by the patient (co-signed by the patient’s
legally authorized representative, if required by the local regulations, guidelines, and
independent ethics committee or institutional review board [IRB])
• Aged between 50 and 85 years at screening, inclusive
• Weight between 40 and 120 kg, inclusive
• Availability of a person (referred to as the “caregiver” throughout this protocol) who
in the investigator's judgment:
– Has frequent and sufficient contact with the patient to be able to provide
accurate information regarding the patient’s cognitive and functional abilities,
agrees to provide information at clinic visits (which require partner input for
scale completion), signs the necessary consent form, and has sufficient
cognitive capacity to accurately report upon the patient’s behavior and cognitive
and functional abilities.
– Is in sufficiently good general health to have a high likelihood of maintaining the
same level of interaction with the patient and participation in study procedures
throughout the study duration.
Every effort should be made to have same caregiver participate throughout the
duration of the study.
• Fluency in the language used at the study site
• Willingness and ability to complete all aspects of the study (including MRI, lumbar
puncture [if applicable], clinical genotyping, and PET imaging [if applicable]); the
patient should be capable of completing assessments either alone or with the help
of the caregiver
• Adequate visual and auditory acuity, in the investigator’s judgment, sufficient to
perform the neuropsychological testing (eye glasses and hearing aids are permitted)
• For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use contraceptive methods that result in a failure rate
of < 1% per year during the treatment period and for at least 8 weeks after the last
dose of study drug.
– A woman is considered to be of childbearing potential if she is postmenarcheal,
has not reached a postmenopausal state (≥ 12 continuous months of
amenorrhea with no identified cause other than menopause), and has not
undergone surgical sterilization (removal of ovaries and/or uterus).
– Examples of contraceptive methods with a failure rate of < 1% per year include
bilateral tubal ligation, male sterilization, established proper use of hormonal
contraceptives that inhibit ovulation, hormone-releasing intrauterine devices,
and copper intrauterine devices.
– The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation
methods) and withdrawal are not acceptable methods of contraception.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or
use contraceptive measures, and agreement to refrain from donating sperm, as
defined below:
– With female partners of childbearing potential or pregnant female partners, men
must remain abstinent or use a condom during the treatment period and for at
least 8 weeks after the last dose of study drug to avoid exposing the embryo.
Men must refrain from donating sperm during this same period.
– The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and the preferred and usual lifestyle of the patient.
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation
methods) and withdrawal are not acceptable methods of contraception.
• Evidence of the AD pathological process, by a positive amyloid assessment either
on CSF Aβ1−42 levels as measured on the Elecsys β-Amyloid(1-42) Test System OR
amyloid PET scan by qualitative read by the core/central PET laboratory.
• Demonstrated abnormal memory function at early screening (up to 4 weeks before
screening begins) or at screening [FCSRT cueing index ≤ 0.67 AND free recall ≤ 27]
• Evidence of retrospective decline confirmed by a diagnosis verification form (see
Appendix 4)
• Mild symptomatology, as defined by a screening MMSE score of ≥ 22 points and
CDR-GS of 0.5 or 1.0. MMSE may be performed at early screening (up to 4 weeks
before screening begins) or screening.
• Meets NIAAA core clinical criteria for probable AD dementia (see Appendix 2;
McKhann et al. 2011) or pAD (consistent with the NIAAA diagnostic criteria and
guidelines for MCI; Appendix 3; Albert et al. 2011)
• If the patient is receiving symptomatic AD medications, the dosing regimen must
have been stable for 3 months prior to screening.
• Inclusion is subject to review of clinical criteria at screening (diagnostic verification
form – see Appendix 4).
• Patient must have completed at least 6 years of formal education after the age of
5 years
• For enrollment into the China Extension Phase, patients must have residence in the
People’s Republic of China.

EXCLUSION CRITERIA
Patients who meet any of the following criteria will be excluded from study entry:
• Any evidence of a condition other than AD that may affect cognition, including but
not limited to, frontotemporal dementia, dementia with Lewy bodies, vascular
dementia, Parkinson’s disease, corticobasal degeneration, Creutzfeldt-Jakob
disease, progressive supranuclear palsy, frontotemporal degeneration, Huntington’s
disease, normal pressure hydrocephalus, seizure disorder, or hypoxia.
• History or presence of clinically evident vascular disease that could potentially affect
the brain (e.g., clinically significant carotid, vertebral stenosis or plaque; aortic
aneurysm; intracranial aneurysm; cerebral hemorrhage; arterio-venous
malformation) and that in the opinion of the investigator has the potential to affect
cognitive function.
• History or presence of any stroke with clinical symptoms within the past 2 years, or
documented history within the last 6 months of an acute event consistent, in the
opinion of the investigator, with a transient ischemic attack.
• History of severe, clinically significant (persistent neurologic deficit or structural brain
damage) CNS trauma (e.g., cerebral contusion)
• History or presence of intracranial tumor (e.g., glioma). History or presence of
meningioma that, in the opinion of the investigator, is not clinically significant and is
unlikely to result in cognitive impairment is not excluded.
• Presence of infections that affect brain function or history of infections that resulted
in neurologic sequelae (e.g., HIV, syphilis, neuroborreliosis, viral or bacterial
meningitis/encephalitis)
• History or presence of systemic autoimmune disorders that potentially cause
progressive neurologic disease with associated cognitive deficits (e.g., multiple
sclerosis, lupus erythematosus, anti-phospholipid antibody syndrome, Behçet
disease)
• History of schizophrenia, schizoaffective disorder, major depression, or bipolar
disorder
– A history of major depression is acceptable if patient had no episode within the
past year or is considered in remission or depression is controlled by treatment.
• At risk of suicide in the opinion of the investigator
• Alcohol and/or substance abuse or dependence (according to Diagnostic and
Statistical Manual of Mental Disorders v5 criteria) within the past 2 years
– Nicotine use is allowed.
– Marijuana use is not allowed and must be discontinued 3 months before screening.
• According to the MRI central reader, MRI evidence of a) > 2 lacunar infarcts, b) any
territorial infarct > 1 cm3
, or c) any white matter lesion that corresponds to an overall
Fazekas score of 3 that requires at least 1 confluent hyperintense lesion on the
FLAIR sequence, which is ≥ 20 mm in any dimension.
• Evidence of more than 4 microbleeds and/or areas of leptomeningeal hemosiderosis
(ARIA-H) as assessed by central review of T2* GRE MRI (see MRI Charter for further details).
• Presence of significant cerebral vascular pathology as assessed by MRI central
reader (see MRI Charter for further details).
• Presence on MRI of any cortical stroke regardless of age.
• 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
The following cardiovascular disorders:
• History or presence of atrial fibrillation except if only one episode that resolved
> 1 year ago and for which treatment is no longer indicated
• Within the last 2 years, unstable or clinically significant cardiovascular disease
(e.g., myocardial infarction, angina pectoris, or New York Heart Association Class II
or higher cardiac failure)
• Uncontrolled hypertension (e.g., blood pressure generally > 160 mmHg systolic or
> 95 mmHg diastolic)
The following hepatic/renal disorders:
• Chronic kidney disease of Stage ≥ 4, according to the National Kidney Foundation
Kidney Disease Outcomes Quality Initiative guidelines for chronic kidney disease
• Confirmed and unexplained impaired hepatic function as indicated by screening
AST or ALT≥ 3 the upper limit of normal (ULN) or total bilirubin ≥ 2ULN
The following infections and immune disorders:
• History of or known to currently have hepatitis B or hepatitis C infection that has not
been adequately treated in the opinion of the investigator
• Systemically, clinically significantly immunocompromised patients, owing to
continuing effects of immune-suppressing medication
• Corticosteroids are permitted as long as the dose is < 7.5 mg/day prednisolone
equivalent and the condition being treated is not expected to deteriorate significantly
during the study period.
The following metabolic/endocrine disorders:
• Abnormal thyroid function as indicated by abnormal screening tests that are judged
to be clinically significant by the investigator, or abnormal thyroid function that
requires a new treatment or an adjustment of current treatment
– A patient may be rescreened if there is no improvement in cognition in the
investigator's judgment after 3 months of adequate treatment for thyroid
function.
History of cancer except:
• If considered to be cured
• If not being actively treated with anti-cancer therapy or radiotherapy and, in the
opinion of the investigator, not likely to require treatment in the ensuing 5 years
• For prostate cancer or basal cell carcinoma, no significant progression over the
previous 2 years
Other exclusion criteria:
• Screening folic acid or vitamin B12 levels that are sufficiently low or remain low on
retest such that deficiency may be contributing to cognitive impairment
– A patient may be rescreened if there is no improvement in cognition after
3 months of adequate treatment for folic acid or vitamin B12 deficiency.
• Screening hemoglobin A1c (HbA1C) > 8% (retesting is permitted if slightly elevated)
or poorly controlled insulin-dependent diabetes (including hypoglycemic episodes).
– A patient may be rescreened after 3 months to allow optimization of diabetic
control.
• Pregnant or lactating, or intending to become pregnant during the study
• Poor peripheral venous access
• Other causes of intellectual disability that may account for cognitive deficits
observed at screening (e.g., static encephalopathy, closed brain injury, mental
retardation).
– This may be based on, for example, patient’s sufficient education or work experience.
• Sleep apnea that requires treatment (e.g., continuous positive airway pressure) or
other significant respiratory diseases (e.g., severe COPD – Global Initiative for
Obstructive Lung Disease criteria Stage IV) likely to result in cognitive impairment.
• Deformity of the lumbosacral region of the spine that in the opinion of the
investigator would contraindicate lumbar puncture in those who can only be
CSF-eligible due to regional lack of availability of PET ligands.
• Clinically significantly abnormal screening blood or urine that remain abnormal at retest
• Impaired coagulation (screening PT> 1.2 × the ULN that remains abnormal on retest).
• Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric, human, or humanized antibodies or fusion proteins
• 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, interfere with the patient’s
ability to complete the study assessments, or would require the equivalent of
institutional or hospital care
• Residence in a skilled nursing facility such as a convalescent home or long-term
care facility: Patients who subsequently require residence in these facilities during
the study may continue in the study and be followed for efficacy and safety provided
that they have a caregiver who meets the minimum requirement (refer to Section 4.1).
The following medications are prohibited for a pre-specified duration prior to study start,
as indicated, and during the entire period of study participation (patients who start these
medications during the study may be withdrawn from study treatment):
• Any previous administration of crenezumab or any other therapeutic that targets Aβ
• Any investigational active immunotherapy (vaccine) that is under evaluation to
prevent or postpone cognitive decline
• Any passive immunotherapy (immunoglobulin) or other long−acting biologic agent
that is under evaluation to prevent or postpone cognitive decline within 1 year of screening
• Any other investigational treatment within 5 half-lives or 3 months of screening,
whichever is longer
• Any previous treatment with medications specifically intended to treat Parkinsonian
symptoms or any other neurodegenerative disorder within 1 year of screening
– Certain medications are acceptable if the patient is taking the medicine for a
non-neurodegenerative disorder, such as restless leg disorder
(e.g., pramipexole)
• Typical antipsychotic or neuroleptic medication within 6 months of screening except
as brief treatment for a non-psychiatric indication (e.g., emesis)
• Atypical antipsychotics except with intermittent short-term use which is permitted
except within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive assessment
• Anti-coagulation medications within 3 months of screening
– Anti-platelet treatments (e.g., aspirin, clopidigrel, dipyridamol) are permitted.
Short-term, peri-operative use of anti-coagulants will not result in
discontinuation from the study; however, any such use must be discussed with
the Sponsor (see section 4.5.1 for further details).
• Chronic use of opiates or opioids (including long-acting opioid medication) within
3 months of screening
• Intermittent short-term use of short−acting opioid medications for pain is permitted
except within 2 days or 5 half-lives (whichever is longer) prior to any neurocognitive
assessment
• Stimulant medications (amphetamine, methylphenidate preparations, or modafinil)
within 1 month of screening and throughout the study
• Chronic use of benzodiazepines, barbiturates, or hypnotics from 3 months before screening
– Intermittent short-term use of benzodiazepines, buspirone, or short−acting
hypnotic medication for sleep or anxiety is allowed except within 2 days or
5 half-lives (whichever is longer) prior to any neurocognitive assessment.
However, intermittent use of barbiturates is not permitted.
• Permitted medications are described in Section 4.5.1