To assess the efficacy of GV-971 compared with placebo on cognition and global function in participants with mild to moderate Alzheimer's disease (AD).
ID
Source
Brief title
Condition
- Mental impairment disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1 Change from baseline to End of Double-blind Study (EODB) in Alzheimer's
Disease Assessments Scale * cognitive subscale/11-item (ADAS-cog/11) score.
2 Alzheimer's Disease Cooperative Study - Clinical Global Impression of Change
(ADCS-CGIC) scale total score at EODB.
Secondary outcome
1. Change from baseline to Weeks 36, and 52 in Neuropsychiatric
Inventory (NPI) score.
2. Change from baseline to EODB in Mini Mental State Examination
(MMSE) score.
3. End point
* Change from baseline to Weeks 36 and 52 in Alzheimer's Disease
Cooperative Study * Activities of Daily Living; 23-item Scale (ADCSADL23).
* Change from baseline to Weeks 36 and 52 in Amsterdam Instrumental
Activities of Daily Living scale (A-IADL).
4. Change from baseline to Weeks 12, 24, and 36 in ADAS-cog/11 and
ADCS-CGIC scores.
5. end point
* Incidence of treatment emergent adverse events (TEAEs) and SAEs
* Vital signs
* Clinical laboratory values
* Physical exam findings
* Electrocardiogram (ECG)
* Brain magnetic resonance imaging (MRI)
* Columbia-Suicide Severity Rating Scale (C-SSRS)
* Change from baseline in Zarit Burden Interview (ZBI).
* Change from baseline in NPI caregiver items.
6. End point
* Change from baseline in the primary and secondary caregiver time
components of the Resource Utilization in Dementia (RUD) * Lite Version
* The change from baseline in the RUD-Lite total score
7. Changes from baseline through End of Study (EOS) and from Week 52
to Week 78 in:
o ADAS-cog/11,
o ADCS-CGIC,
o NPI,
o MMSE,
o ADCS-ADL23,
o A-IADL,
o Incidence of adverse events (AEs),
o Vital signs,
o Clinical laboratory values,
o Physical exam findings,
o Electrocardiogram (ECG),
oMRI - for safety,
o Columbia-Suicide Severity Rating Scale (C-SSRS).
Background summary
This is a 52-week, multi-center, randomized, double-blind, 2-arm,
parallel-group, placebo-controlled, monotherapy Phase 3 study, to evaluate the
efficacy and safety of GV-971 in the treatment of mild to moderate Alzheimer*s
disease dementia participants (Mini Mental State Examination [MMSE] score 11 to
24, inclusive; with regional stratification [North America, China,
Europe/Australia/rest of world] and at least 75% of participants with MMSE
scores < 20). Participants who successfully complete the double-blind treatment
period may continue in the 26-week open-label extension (OLE) period.
Alzheimer*s disease (AD) represents both one of the greatest development
challenges as well as an area of urgent and rapidly increasing unmet need.
Symptomatic therapies available for the last 20 years for the treatment of AD
include acetylcholinesterase inhibitors (AChEI) and memantine. Because of the
limited duration of efficacy associated with current standard of care and
safety, there is an urgent unmet need for drugs that demonstrate long-term
efficacy, good tolerability, and safety in patients with mild to moderate AD.
GV-971 in a Phase 3 study conducted in China (Study 971-III) showed a pattern
of rapid initial gains with sustained improvement over the 36-week study
period. This study is designed to provide further data including biomarkers and
long-term efficacy and safety analyses that will show GV-971 effect on AD
progression.
The proposed study will involve 2046 subjects with mild to moderate Alzheimer*s
disease. The recruitment will take place globally across approximately 200
investigative sites. All eligible subjects will be randomized in a 1:1 ratio to
receive GV-971 or placebo capsules at a dose of 900 mg per day orally. The
clinical study design has taken into consideration the recommendations included
in the scientific advice documents requested by the sponsor from the European
Medicines Agency (EMA).
Study objective
To assess the efficacy of GV-971 compared with placebo on cognition and global
function in participants with mild to moderate Alzheimer's disease (AD).
Study design
This is a 52-week, multi-center, randomized, double-blind, 2-arm,
parallel-group, placebo-controlled, monotherapy Phase 3 study, to evaluate the
efficacy and safety of GV-971 in the treatment of mild to moderate AD dementia
participants (Mini Mental State Examination [MMSE] score 11 to 24, inclusive;
with regional stratification [North America, China, Europe/Australia/rest of
world] and at least 75% of participants with MMSE scores < 20). Participants
who successfully complete the double-blind treatment period may continue in the
26-week open-label extension (OLE) period.
Intervention
All eligible participants will be randomized in a 1:1 ratio to GV-971 and
placebo groups.
Both GV-971 and placebo will be administered orally, twice a day.
The dose of the product will be 450mg twice a day.
Study burden and risks
Subject*s participation in this study will last 1 year and 10 months and
consists of 4 periods: a screening period (8 weeks), double blind treatment
period (52 weeks), open label treatment period (26 weeks) and a safety
follow-up period (4 weeks). During the treatment periods, subjects will need to
visit the study site every 12 weeks.
4 weeks after discontinuation of treatment subjects will visit the study site 1
time.
Aside from the intervention described above, participation in this study
involves blood draws at multiple visits and might involve radiation exposure
through CT, in case MRI is contraindicated for medical reasons. Participants
will be subjected to:
- ECG 7 times
- MRI 3 times
Taking into account the study drug's tolerability close to placebo, the
measures taken to minimize any risk to study participants, the potential risks
identified in association with the study drug are justified by the anticipated
benefits that may be afforded to participants with mild to moderate AD.
Based on 9 clinical studies performed, the safety and tolerability profile of
the study drug strongly suggests a favorable risk/benefit profile given the
promising efficacy results of the Phase 2 and 3 studies.
Room 203, Section 102, Building 6 , Nuidun Road, Pilot Free Trade ZOne 393.421
Shanghai 200031
CN
Room 203, Section 102, Building 6 , Nuidun Road, Pilot Free Trade ZOne 393.421
Shanghai 200031
CN
Listed location countries
Age
Inclusion criteria
1. Male and female participants aged 50 to 85 years (inclusive) at the time of
screening.
2. Willing and able to give informed consent by GCP and local guidance. If the
study participant is not competent to give informed consent, in the opinion of
the principal investigator, a legally authorized representative (per applicable
laws, rules, and regulations) must provide informed consent on his/her behalf,
and the participant must provide assent (or local equivalent).
3. Mild to moderate AD as characterized by the following clinical, cognitive,
and functional criteria per National Institute on Aging - Alzheimer's
Association (NIA-AA) diagnostic criteria (refer to Section 11.5 for additional
details).
a. Clear history of cognitive and functional decline over at least 1 year that
is either (1) documented in medical records or (2) documented by history taken
from a study partner or other person who knows the participant well (eg,
personal physician).
b. MMSE scores between 11 and 24, inclusive, at screening and at baseline.
Note: Screening MMSE must be performed after obtaining consent.
4. Have a study partner/caregiver who has known the participant for at least 1
year and assists the participant regularly at least 3 times per week and has
intimate knowledge of the participant's cognitive, functional, and emotional
states and of the participant's personal care. The study partner must be
willing to accompany the participant to all study visits, assure that all of
the participant's medications and the
study drug are stored and dispensed safely, and report adverse events. The
study partner must be willing and able to give informed consent for their own
participation, be able to read and write, and be capable of providing partner
responses to scales such as ADL scales, ADCS-CGIC, and NPI.
Note: Use of the same study partner/caregiver during the study period is
encouraged. Any change in study partner/caregiver should be recorded with
reasons detailed in the medical chart and case report form (CRF). Informed
consent must be obtained from the new study partner/caregiver.
5. Investigator confirmation of participant's ability to complete efficacy
assessments and have physical, cognitive, hearing, speech, literacy, and
language capacity to participate in all testing.
6. A brain magnetic resonance imaging (MRI) scan during screening. All imaging
is evaluated by a central reader vendor (refer to imaging manual for details).
MRI will have oblique coronal hippocampus scan and must show the highest
possibility of AD, including:
a. Medial temporal lobe atrophy visual rating scale (MTA) * grade 2 by central
read;
b. Fazekas scale for white matter lesions grade < 3;
NOTE: Computerized tomography (CT) may be substituted with similar review by
central reading when there are MRI contraindications such as heart valve
replacement, pacemaker or implants, if medical monitor approves. CT unlike MRI
would not be repeated in double-blind or OLE period (see Section 8.2.7.4).
7. Female participants should be postmenopausal (menopause > 24 months),
surgically sterilized, or of childbearing potential who agree to take highly
effective contraceptive measures throughout the study (see Section 9 for
details regarding contraception).
Women of childbearing potential (WOCBP) must undergo a urine pregnancy test at
screening and baseline and result must be negative.
8. May use allowed/permitted concomitant medications at screening and during
the study (see Table 6-1). These medications must keep stable dosing at least
30 days before randomization and the regimens must be planned to remain
constant throughout the study.
9. Participants previously enrolled in an AD clinical study involving a disease
modifying or symptomatic therapeutic agent may enroll in this study if:
(1) AD vaccine last dose > 12 months before baseline visit;
(2) monoclonal antibodies last dose > 6 months before baseline visit; and
(3) last symptomatic therapeutic agent ended > 4 weeks or 5 half-lives
(whichever is longer) before baseline visit.
These restrictions do not apply if the participant was assigned to placebo
treatment, which is documented in the source documents.
Exclusion criteria
1. Diagnosis of a dementia-related central nervous system disease other than AD
(eg, Parkinson's Disease, Huntington's Disease, frontotemporal dementia,
multi-infarct dementia, dementia with Lewy bodies, normal pressure
hydrocephalus).
2. Abnormally low folate, thyroid, and/or vitamin B12 values or evidence of
hypothyroidism thought to be the cause of or to contribute to the severity of
the participant's dementia.
3. Abnormalities found on brain MRI, including ischemic and hemorrhagic
infarctions, hydrocephalus, and brain tumors will be flagged for discussion
with the Medical Monitor. The NIA-AA criteria will be applied to determine if
vascular lesions are exclusionary.
NOTE: CT scan may be substituted, with similar review by central reading when
there are MRI contraindications such as heart valve replacement, pacemaker, or
implants, if medical monitor approves. CT, unlike MRI, would not be repeated in
double-blind or OLE period (see Section 8.2.7.4).
4. Mental/psychiatric illness determined by Diagnostic and Statistical Manual
of Mental Disorders (DSM) V criteria, that is unstable within 12 months, or
would interfere with study assessments, including schizophrenia or other
psychotic disorders, bipolar disorder, severe depression, or delirium.
5. History of suicidal actions within the past 12 months or current suicide
risk determined by a positive response ('Yes') to either Question 4 or Question
5 on the suicidal ideation portion of the Columbia-Suicide Severity Rating
Scale (C-SSRS) at Screening.
6. DSM V diagnosis of alcohol or other substance abuse dependence within the
last 12 months.
7. Gastrointestinal illness that may substantially impact absorption such as
gastric bypass or recurrent diarrhea.
8. History within the last 12 months or current diagnosis of clinically
significant cardiovascular or cerebrovascular diseases/disorders such as
serious cardiac arrhythmias, heart rate abnormalities, myocardial infarction,
well-documented transient ischemic attack, or cerebrovascular accident,
uncompensated congestive heart failure New York Heart Association class III and
IV.
9. A resting heart rate of < 50 beats per minute (bpm) by pulse or ECG, after 5
minutes of rest in sitting or supine position unless deemed not clinically
significant by the Principal Investigator.
10. Major medical illness or unstable medical condition within 6 months of
screening that in the opinion of the investigator may interfere with the
participant's ability to comply with study procedures and abide by study
restrictions, or with the ability to interpret safety data, including any
physical disability (eg, blindness, deafness, non-AD-related speech impairment,
sensory or motor dysfunction) that would prevent completion of study procedures
or assessments.
11. Cancer except:
a. Cancer that has been in remission (no evidence of recurrence) for > 3 years
from the screening.
b. Basal cell or stage 1 squamous cell carcinoma of the skin or stable
untreated cancer such as prostate or meningioma.
c. Chronic carcinomas that do not require treatment (eg, prostate carcinoma
restricted to the prostate).
12. Any participants who have previously been treated with GV-971 but
discontinued due to safety issues or lack of efficacy.
13. Any participants who have taken any dose of GV-971 within 6 months prior to
screening.
14. Use of antibiotics
a. For more than 10 consecutive days in the last 12 weeks prior to baseline
b. When it is expected that participant will receive a treatment for more than
10 days.
c. Extended frequent use (eg, chronic every other day use), unless approved by
Medical Monitor.
Note: This refers to those antibiotics which are expected to act in the GI
tract, blood system, or an internal organ system and excludes topical agents,
which may not be absorbed systemically or come in contact with the GI tract.
15. Use of AChEI, memantine or aducanumab within 4 weeks prior to the first day
of screening, within 8 weeks prior to baseline and throughout the study.
16. Use of over-the-counter or prescription medication (including herbal
medications) not in compliance with Table 6-1
17. Participants are excluded if they:
a. have participated in any other clinical study (excluding non-drug
interventional clinical study) within 4 weeks prior to screening visit
b. have participated in another GV-971 clinical study at any time
c. plan to take part in another clinical study during this study.
18. Geriatric Depression Scale-15 (GDS-15) total score > 7 at screening
19. Inadequate hepatic function, defined in protocol
20. Substantial laboratory abnormalities, defined in protocol
21. After resting for at least 5 minutes in the supine position, 3 averaged ECG
shows clinically significant abnormalities or QTcF > 450 ms for male
participants and > 470 ms female participants. Exclusion applies if the average
of the 3 exceeds these limits.
22. After at least 5 minutes of rest in sitting or supine position (unless
deemed not clinically significant by the Principal Investigator):
a. systolic blood pressure (BP) > 180 mmHg
b. diastolic BP > 100 mmHg or < 50 mmHg
23. Poor venous access for blood samples
24. Female participants who are pregnant or lactating. NOTE: Does not apply to
female partners of male participants.
25. Wherever residing, participants who do not have a reliable caregiver/study
partner and are not able to perform basic ADL (eg, washing and eating) without
nursing supervision.
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 | EUCTR2020-001755-41-NL |
| ClinicalTrials.gov | NCT04520412 |
| CCMO | NL75788.056.21 |