A Long-Term Safety Extension of Studies ABE4869g and ABE4955g in Participants With Mild to Moderate Alzheimer's Disease Treated With Crenezumab

A Multicenter, Open-Label, Long-Term Safety Extension of Phase II Studies ABE4869g and ABE4955g in Patients With Mild to Moderate Alzheimer's Disease

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01723826

Enrollment

360

Registered

2012-11-08

Start date

2012-12-07

Completion date

2017-02-08

Last updated

2020-02-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alzheimer's Disease

Brief summary

This Phase II, open-label extension (OLE), multicenter study will evaluate the long-term safety and tolerability of crenezumab in participants with mild to moderate Alzheimer's disease who have participated in and completed the treatment period of the Phase II Study ABE4869g (NCT01343966) or ABE4955g (NCT01397578). Participants who received placebo in Study ABE4869g (NCT01343966) or ABE4955g (NCT01397578) will receive crenezumab. Anticipated time on study treatment is 144 weeks.

Interventions

DRUGCrenezumab

Participants will receive intravenous infusion of crenezumab every 4 weeks for 144 weeks.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

50 Years to No maximum

Healthy volunteers

Inclusion criteria

* Previous participation in Study ABE4869g or ABE4955g and completion of the Week 73 visit * Adequate visual and auditory acuity, in the investigator's judgment, to allow for neuropsychological testing * Availability of a person (caregiver) who can provide information on activities of daily living and behavior in order to complete the study-specific assessments * Diagnosis of probable Alzheimer's disease according to the National Institute on Neurological and Communication Disease and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria (McKhann et al. 1984) * Mini-Mental State Examination (MMSE) score of 10 or more at screening (Folstein et al. 1975) * For male participants with partners with reproductive potential, agreement to use a reliable means of contraception (e.g., condoms) during the study and for at least 8 weeks following the last dose of study drug * For female participants, a negative pregnancy test at screening

Exclusion criteria

* Early treatment and/or study discontinuation prior to completion of the Week 73 visit of Genentech Study ABE4869g or ABE4955g * Early discontinuation from the treatment schedule of a prior version of Study GN28525 for safety reasons. If treatment discontinuation occurred for safety reasons, participants may not re-start dosing on extended treatment schedules offered in amendments to Study GN28525 * Inability to tolerate Magnetic Resonance Imaging (MRI) procedures or contraindication to MRI * Female participants with reproductive potential: Female participants must either have undergone documented surgical sterilization or have not experienced menstruation for at least 12 consecutive months * Severe or unstable medical condition that, in the opinion of the investigator or Sponsor, would interfere with the participant's ability to complete the study assessments or would require the equivalent of institutional or hospital care * History or presence of clinically evident vascular disease potentially affecting the brain * History of severe, clinically significant central nervous system trauma * History or presence of clinically relevant intracranial tumor * Presence of infections that affect the brain function or history of infections that resulted in neurologic sequelae * History or presence of systemic autoimmune disorders potentially causing progressive neurologic disease * History or presence of a neurologic disease other than Alzheimer's disease that may affect cognition * History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins * Evidence of malignancies (except squamous cell cancer or basal cell cancer of the skin), acute infections, renal failure that requires dialysis, or other unstable medical disease not related to Alzheimer's disease that, in the investigator's opinion, would preclude participant's participation. Cancer that is not being actively treated with anti-cancer therapy or radiotherapy as well as cancers which are considered to have low probability of recurrence are allowed * History or presence of atrial fibrillation that, in the investigator's judgment, poses a risk for future stroke * Chronic kidney disease of Stage greater than or equal to (\>=) 4, according to the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) guidelines for chronic kidney disease (CKD) * Impaired hepatic function * Impaired coagulation (activated partial thromboplastin time \[aPTT\] greater than \[\>\] 1.2 times upper limit of normal \[ULN\]) * Platelet count less than (\<) 100,000 per microliter (mcL) * Presence at screening of superficial siderosis of central nervous system, more than 8 cerebral microhemorrhages, or evidence of a prior cerebral macrohemorrhage * Presence at screening of any other significant cerebral abnormalities, including ARIA-E * Treatment with anticoagulation medications within 2 weeks prior to enrollment. Clopidogrel, dipyridamole, and aspirin are permitted * Treatment with anticholinergic antidepressants, typical antipsychotics, or barbiturates within 2 weeks prior to enrollment. All other antidepressants and atypical antipsychotics are allowed with certain restrictions as defined in the protocol * Chronic use of opiates, opioids, or benzodiazepines * Any biologic therapy within 75 weeks prior to enrollment * Any investigational agent (other than crenezumab) within 75 weeks prior to enrollment * Treatment with anticholinergic antidepressants, typical antipsychotics, barbiturates, or narcotics within 5 half-lives or 3 months prior to screening, whichever is longer. All other antidepressants and atypical antipsychotics are allowed. Chronic use of benzodiazepines is not allowed; however, the intermittent use of benzodiazepines is allowed, except within 2 days prior to any neurocognitive assessment

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Adverse Events (AEs)	Up to 50 months	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product which does not necessarily 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.
Percentage of Participants by Nature of AEs	Up to 50 months	A serious adverse event (SAE) is any AE that meets any of the following criteria: fatal, life threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect in a neonate/infant. Non-SAE of special interest for this study include the following: cerebral vascular edema, Superficial siderosis of central nervous system, cerebral micro-hemorrhages or macro-hemorrhages, pneumonia, liver injury.
Percentage of Participants by Severity of AEs	Up to 50 months	AE severity grading scale for the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 was used for assessing adverse event severity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on the following general guideline: Grade 1) mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated, Grade 2) moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL), Grade 3) severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL, Grade 4) life-threatening consequences; urgent intervention indicated, Grade 5) death related to AE.
Percentage of Participants With Human Anti-Therapeutic Antibody (ATA) Formation	Pre-dose (Day-14), predose at Week 25, 49, 97, Follow-up Week 8 (Week 153) and 12 (Week 157)	ATA is a measurement to explore the potential relationship of immunogenicity response with pharmacokinetics, safety and efficacy. Percentage of participants at post-baseline with positive results for ATA against crenezumab are reported.
Percentage of Participants With Amyloid-Related Imaging Abnormalities Edema/Effusions (ARIA-E)	Baseline, Weeks 23, 47, 71, 97, 121 and 153	Alzheimer's disease (AD) is associated with ARIA. The occurrence of imaging abnormalities believed to represent cerebral vasogenic edema, has been reported in association with the investigational use of compounds that are intended to treat Alzheimer's disease by reducing Abeta in the brain. Here, the percentage of participants with symptomatic and asymptomatic ARIA-E were reported.
Percentage of Participants With Amyloid-Related Imaging Abnormalities-Hemorrhage (ARIA-H)	Baseline, Weeks 23, 47, 71, 97, 121 and 153	AD is associated with ARIA. Cerebral micro-hemorrhages (microbleeds \[MBs\]) are radiologically defined as small dot-like foci of signal loss observed on magnetic resonance imaging (MRI) sequences sensitive for paramagnetic tissue properties. The occurrence of MBs has also been identified as an adverse event in anti-amyloid vaccination trials, and together with superficial siderosis, they have been termed ARIA-H.

Countries

Canada, France, Germany, Spain, United Kingdom, United States

Participant flow

Recruitment details

A total of 360 participants were enrolled at 83 sites across 6 countries.

Pre-assignment details

Participants who completed either Phase II Study NCT01343966 (ABE4869g) or NCT01397578 (ABE4955g) and had Mini-Mental State Examination (MMSE) score of 10 or more at the time of screening were included. Participant flow is represented based on the safety population by treatment received.

Participants by arm

Arm	Count
PCP PL - OLE CREN SC - OLE CREN IV Participants who on their placebo-controlled portion \[PCP\]/parent study received placebo (PL) and who on this open-label extension (OLE) study initially received crenezumab (CREN) subcutaneously (SC) and after the protocol amendment received CREN intravenously (IV).	47
PCP PL - OLE CREN IV Participants who on their PCP/parent study received placebo and who on this OLE study received CREN IV.	63
PCP CREN SC - OLE CREN SC - OLE CREN IV Participants who on their PCP/parent study received CREN and who on this OLE study initially received CREN SC and after the protocol amendment received CREN IV.	101
PCP CREN IV - OLE CREN IV Participants who on their PCP/parent study received CREN IV and who on this OLE study received CREN IV.	149
Total	360

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Adverse Event	4	1	4	5
Overall Study	Death according to AE eCRF	2	3	3	7
Overall Study	Lost to Follow-up	1	3	1	1
Overall Study	Non-compliance	0	1	3	3
Overall Study	Non-compliance With Study Drug	0	1	0	0
Overall Study	Other Reason	8	6	12	14
Overall Study	Physician Decision	1	3	4	11
Overall Study	Protocol Violation	1	1	3	1
Overall Study	Withdrawal by Subject	10	17	27	48

Baseline characteristics

Characteristic	PCP PL - OLE CREN SC - OLE CREN IV	Total	PCP CREN IV - OLE CREN IV	PCP CREN SC - OLE CREN SC - OLE CREN IV	PCP PL - OLE CREN IV
Age, Continuous	70.9 Years STANDARD_DEVIATION 7.4	72.0 Years STANDARD_DEVIATION 7	72.2 Years STANDARD_DEVIATION 6.7	72.3 Years STANDARD_DEVIATION 7.2	71.9 Years STANDARD_DEVIATION 7.4
Race/Ethnicity, Customized Hispanic or Latino	2 Participants	10 Participants	4 Participants	2 Participants	2 Participants
Race/Ethnicity, Customized Not Hispanic or Latino	45 Participants	349 Participants	145 Participants	98 Participants	61 Participants
Race/Ethnicity, Customized Not Stated	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Asian	0 Participants	4 Participants	4 Participants	0 Participants	0 Participants
Race/Ethnicity, Customized Black or African American	0 Participants	5 Participants	1 Participants	4 Participants	0 Participants
Race/Ethnicity, Customized White	47 Participants	351 Participants	144 Participants	97 Participants	63 Participants
Sex: Female, Male Female	26 Participants	199 Participants	79 Participants	58 Participants	36 Participants
Sex: Female, Male Male	21 Participants	161 Participants	70 Participants	43 Participants	27 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	2 / 47	3 / 63	3 / 101	7 / 149
other Total, other adverse events	37 / 47	51 / 63	80 / 101	97 / 149
serious Total, serious adverse events	9 / 47	14 / 63	22 / 101	35 / 149

Outcome results

Primary

Percentage of Participants by Nature of AEs

A serious adverse event (SAE) is any AE that meets any of the following criteria: fatal, life threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect in a neonate/infant. Non-SAE of special interest for this study include the following: cerebral vascular edema, Superficial siderosis of central nervous system, cerebral micro-hemorrhages or macro-hemorrhages, pneumonia, liver injury.

Time frame: Up to 50 months