The objectives of the study are to: • Assess the efficacy of 2 dose levels of COR388 HCl in Alzheimer*s disease (AD) subjects; and• Assess the safety and tolerability of 2 dose levels of COR388 HCl in AD subjects.
ID
Source
Brief title
Condition
- Other condition
- Dementia and amnestic conditions
Synonym
Health condition
Alzheimer's disease
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The 2 primary endpoints are:
• Mean change in Alzheimer*s Disease Assessment Scale-Cognitive Subscale 11
(ADAS-Cog 11) from baseline to the end of treatment period.
• Mean change in Alzheimer*s Disease Cooperative Study Group- Activities of
Daily Living (ADCS-ADL) from baseline to the end of treatment period.
Secondary outcome
Secondary endpoints in all subjects include:
• Change in Clinical Dementia Rating-Sum of Boxes (CDR-SB).
•* Change in Mini-Mental State Examination (MMSE)
•* Change in Neuropsychiatric Inventory (NPI)
Exploratory endpoints in all participating subjects include change from
screening/baseline and/or Visit 2 to the end of treatment period in the
following measures:
• Blood-based biomarkers in serum and peripheral blood mononuclear cells
(PBMCs); and
• Saliva biomarkers of P. gingivalis infection and inflammation.
• Cerebrospinal fluid:
o CSF Aβ42, total Tau, and phosphorylated Tau;
o Bacterial DNA in the CSF based on quantitative polymerase chain reaction
(qPCR) and sequencing; and
o CSF biomarkers.
Exploratory endpoints in subjects participating in sub-studies include change
from screening/baseline to the end of treatment period in the following
measures:
• Winterlight Speech Assessment (only in English speaking (primary language)
subjects and only in the US and UK);
• Magnetic resonance imaging sub-study (subjects who have MRIs done in
conjunction with the study):
o Hippocampal volume; and
o Cortical thickness.
• Clinical periodontitis sub-study (subjects enrolled at selected sites):
o Pocket Depth (PD);
o Clinical Attachment Level (CAL) at 6 sites per tooth (distobuccal [DB],
buccal [B], mesiobuccal [MB], distolingual [DL], lingual [L], and mesiolingual
[ML]);
o The percentage of sites with Bleeding on Probing (BOP); and
o Biomarkers of P. gingivalis infection and inflammation in subgingival plaque
(SGP) and buccal cell swabs.
Safety Endpoints Safety endpoints include:
• The incidence and severity of TEAEs;
• Vital signs and physical examinations;
• Laboratory values;
• MRI scans;
• 12-lead ECGs; and
• C-SSRS.
Background summary
This is a randomized, double-blind, placebo-controlled study that will assess
the efficacy, safety, and tolerability of 2 dose levels of COR388 HCl in
subjects with probable AD dementia according to the National Institute on
Aging-Alzheimer*s Association (NIA-AA) criteria (McKhann 2011). The study will
enroll approximately 573 generally healthy male and female subjects >=55 and <=80
years of age. Enrolled subjects must have a documented diagnosis of probable AD
dementia with clinical evidence of progressive cognitive decline in the last
year. Clinical decline will be defined as the evidence of progressive cognitive
decline on sequential evaluations based on information from informants and/or
cognitive testing in the context of either formal neuropsychological evaluation
or standardized mental status examinations for probable AD dementia (McKhann
2011).
Study objective
The objectives of the study are to:
• Assess the efficacy of 2 dose levels of COR388 HCl in Alzheimer*s disease
(AD) subjects; and
• Assess the safety and tolerability of 2 dose levels of COR388 HCl in AD
subjects.
Study design
This is a randomized, double-blind, placebo-controlled study that will assess
the efficacy, safety, and tolerability of 2 dose levels of COR388 HCl in
subjects with probable AD dementia according to the National Institute on
Aging-Alzheimer*s Association (NIA-AA) criteria (McKhann 2011). The study will
enroll approximately 573 generally healthy male and female subjects *55 and *80
years of age. Enrolled subjects must have a documented diagnosis of probable AD
dementia with clinical evidence of progressive cognitive decline in the last
year. Clinical decline will be defined as the evidence of progressive cognitive
decline on sequential evaluations based on information from informants and/or
cognitive testing in the context of either formal neuropsychological evaluation
or standardized mental status examinations for probable AD dementia (McKhann
2011). The subject should not have other conditions or brain imaging
abnormalities that can explain the symptoms of dementia. All subjects will have
lumbar punctures (LPs) performed at baseline (Visit 2) and at end of treatment
Week 48 (Visit 10) or early termination visit (ET). Cerebrospinal fluid (CSF)
will be tested for measurement of bacterial DNA (Pg) using quantitative
polymerase chain reaction (qPCR), biomarkers of AD, and gingipain activity.
Saliva and blood will be analyzed for biomarkers of AD and neuroinflammation,
and for the presence of bacterial deoxyribonucleic acid (DNA) of Porphyromonas
gingivalis (P. gingivalis [Pg]) using qPCR.
A subset of sites will be selected to monitor subjects for clinical evidence of
periodontitis in addition to AD. An oral examination will be conducted by a
study dentist/hygienist at these sites to assess for the presence of clinical
evidence of periodontitis at screening, 24 and 48 weeks. Subgingival plaque
(SGP) and buccal cell swabs will be collected at these sites and analyzed for
measurements of biomarkers associated with P. gingivalis DNA, proteins, and
inflammation.
Due to the nature of AD, subjects must identify a primary caregiver prior to
enrollment in the study who will assist the subject with study participation.
The primary caregiver must sign a caregiver informed consent.
The safety of study participants will be evaluated throughout the study by
repeated physical examinations, vital signs, safety laboratory tests,12 lead
electrocardiograms (ECGs), Columbia-Suicide Severity Rating Scale (C SSRS),
magnetic resonance imaging (MRI), and assessments of treatment-emergent adverse
events (TEAEs). Periodic safety reviews will be conducted during the study.
Following the Data Monitoring Committee (DMC) recommendation after the November
16, 2020 meeting, increased frequency of liver safety
monitoring has been implemented, which increased the frequency of safety
laboratory analyte collections (see Table 1, Schedule of Evaluations).
The study will consist of 3 periods: a screening period of up to 6 weeks, a
treatment period of up to 48 weeks, and a safety follow-up period of 6 weeks.
An interim analysis may be conducted to reassess the sample size and evaluate
for efficacy after 24 weeks of treatment on key outcome measures.
Screening
During the screening period, the eligibility of subjects will be confirmed
according to the Schedule of Evaluations in this protocol. The Mini-Mental
State Examination (MMSE) will be administered by a trained rater to assess the
level of cognitive impairment. MMSE will be assessed as early in the screening
period as possible. Subjects with MMSE score of 12-24, inclusive, will have the
rest of their screening procedures performed or scheduled. Magnetic resonance
imaging (MRI) of the brain will be performed in all subjects at screening,
except subjects with an absolute contraindication for MRI, who can have a
Computed Tomography (CT) scan of the brain instead. Screening procedures can be
done on multiple days if needed, with more invasive procedures done after less
invasive screening procedures are completed. A screen failure is any subject
who signs the informed consent but does not qualify for the study or
discontinues the study prior to randomization. A subject can be rescreened if
the Principal Investigator thinks the subject may qualify for the study upon
rescreening, and if the Medical Monitor agrees.
Treatment Period
Subjects who meet all eligibility criteria will enter the treatment period and
will be randomized 1:1:1 to receive 40 mg COR388 HCl, 80 mg COR388 HCl, or
placebo twice a day. Randomization will be stratified by baseline MMSE (MMSE
>=12 and <=18, and MMSE >=19 and <=24) and Apolipoprotein E (ApoE4 positive either
homozygous or heterozygous vs. all others) genotype to assure balanced
distribution of mild and moderate AD and a balanced distribution of ApoE4
subjects, across treatment arms. Subjects will receive their assigned blinded
study treatment orally twice a day for up to 48 weeks and will come back to the
investigative site periodically for scheduled efficacy and safety evaluations.
Blood samples for pharmacokinetics levels and biomarkers will be collected
during selected visits. Baseline LP will be performed prior to the first dose
of study drug, and follow-up LP will be done at the end of the treatment
period. Subjects will continue to receive the study drug for 48 weeks, unless
the Investigator determines that treatment of a given subject should be stopped
or interrupted for safety or tolerability reasons, the subject withdraws
consent, or the Sponsor decides to stop the study.
Safety Follow-up Period
After completion of study treatment, subjects will continue to be monitored on
the study for 6 weeks and will have a phone call to assess safety at Weeks 49
and 51 and will return for the Safety Follow-up Visit (Week 54).
For subjects with early termination, end of study procedures (Week 48) will be
performed, and subjects will be encouraged to return to the clinic for the
Safety Follow-up Visit after 6 weeks. Phone calls will be performed to assess
safety at Week 1 and Week 3 after end of study procedures are performed.
Intervention
Eligible subjects will be randomized 1:1:1 to receive one of the following
treatments:
• 80 mg COR388 HCl, twice daily (bid);
• 40 mg COR388 HCl, bid; or
• Placebo, bid
Study burden and risks
Side Effects of COR388
The study drug is in a research stage, so it may have adverse effects (side
effects) that are not known at this time. As with any new drug there is a risk
that unexpected adverse effects may occur. Almost all drugs, both old and new,
can cause severe reactions. In previous clinical studies of COR388 in humans,
subjects received COR388 at doses up to 250 mg. The study drug was well
tolerated and had an acceptable safety profile with no evidence of any
clinically significant adverse or serious reactions. No serious adverse events
related to COR388 treatment were reported during 2 previous clinical studies of
COR388 in humans.
However, the possible mild to moderate side effects you may experience when
having treatment with COR388 may include:
• Dizziness
• Headaches
• Nausea
• Diarrhea
Abnormal liver blood tests were seen in subjects receiving study drug (observed
in approximately 10% of the study patients). The abnormalities generally
returned to normal or improved over time. However, there is a very small chance
you may experience liver injury or failure. Though a potential trend in
transaminase elevations was identified, there have been no reported cases of
persistent liver injury or failure to date. Your study doctor will monitor for
any signs of liver damage or injury.
If you experience any of the following symptoms, then call your doctor
immediately:
• Loss of appetite
• Nausea
• Vomiting
• Fever
• Weakness
• Tiredness
• Abdominal (stomach) pain
• Tenderness
• Itching
• Yellowing of the skin or eyes
• Light colored bowel movements
• Dark colored urine
As the safety and effectiveness of COR388 is still being researched, if you are
in a group that receives COR388, there is no guarantee that it will be
effective for you. Your symptoms may not improve or may even worsen.
Placebo Risks
If you are in the group that is assigned to placebo (the medically inactive
substance), your symptoms may not improve or may even worsen.
Allergic Reactions
As with taking any drug, there is a risk of allergic reaction. If you have a
very serious allergic reaction, you may be at risk of death. Some symptoms of
allergic reactions include an itchy rash (hives) or swelling of the throat
making it difficult to breathe.
Please seek treatment immediately and tell the study doctor and study staff if
you have any of these symptoms, or any other side effects, during the study.
You may experience additional discomforts during the procedures in this study.
These are described in Attachment 2.
Risks to an Unborn Child
Women
You may not take part in this study if you are breastfeeding, are pregnant,
think that you may be pregnant, or are trying to get pregnant. If you are
pregnant or breastfeeding, there may be risks to you and the baby that are not
known at this time. Women who can get pregnant will be tested for pregnancy
during the study.
You must avoid getting pregnant in order to take part in this research study.
You should not have heterosexual intercourse, or you should use one of the
following highly effective methods of birth control that is acceptable to you,
the study doctor, and the Sponsor; to prevent pregnancy throughout this
research study:
• Surgical sterilization (eg, hysterectomy, bilateral oophorectomy, or tubal
ligation) for at least 6 months.
• Use of a hormonal contraceptive or a double barrier method of contraception
(eg, intrauterine device plus condom) or true abstinence from 30 days before
receiving your first dose of study drug through 30 days after receiving the
final dose of study drug.
It is important for you to tell the study doctor at once if you get pregnant or
think that you might be pregnant while you are in the research study. If this
happens, the study doctor will discuss with you what you should do.
Men
COR388 may harm an unborn child. You should not have heterosexual intercourse
with a woman who is able to get pregnant, or you must inform your partner of
your participation in the study. If you have not had a vasectomy and have
heterosexual intercourse with a woman who is able to get pregnant, you must use
contraception (barrier method or true abstinence) from 30 days before receiving
your first dose of study drug through 90 days after receiving the final dose of
study drug. Your partner must then also use an effective contraceptive method.
If you think that your partner has become pregnant, you, in agreement with your
partner, must tell the study doctor at once.
Unknown Risks
There may be risks to you that are currently not known or cannot be predicted.
Your condition may worsen, remain the same, or improve as a result of
participating in this research study.
Please tell the study doctor or staff about all problems, illnesses, or
injuries that happen to you during the study, even if you think they are not
related to your taking part in this study.
You might have side effects or discomforts that are not listed in this form.
Some side effects may not be known yet. New ones could happen to you. Tell
the study doctor or study staff right away if you have any problems.
In the case of incidental findings (eg, from clinical tests or genetic
analysis), that could contribute towards preventing, confirming, and treating
an existing illness, or one that could be expected in the future, you may
choose, (a) to be directly informed of these findings; (b) to not be informed
of the findings, if that is your wish; or (c) to leave the decision with your
attending physician (see statement of consent).
You may or may not receive any benefit from being in the study. It is possible
that you may get better, stay the same, or get worse. If you take part in this
study, other people with AD may be helped by the research.
East Grand Ave. 269
South San Francisco CA 94080
US
East Grand Ave. 269
South San Francisco CA 94080
US
Listed location countries
Age
Inclusion criteria
1. Subject has provided full written informed consent prior to the performance
of any protocol-specified procedure; or if unable to provide informed consent
due to cognitive status, subject has provided assent and a legally authorized
representative has provided full written informed consent on behalf of the
subject.
2. Caregiver has provided full written informed consent, on a separate informed
consent form (ICF), on his/her own behalf prior to the performance of any
protocol-specified procedure.
3. Male and female subjects must be 55 years to 80 years of age, at the time of
consent.
4. Subject has probable AD dementia according to the NIA-AA criteria (McKhann
2011) with clinical evidence of progressive cognitive decline in the last year.
Clinical decline will be determined based on serial cognitive test scores, if
available, or subject/caregiver report as documented by the Investigator.
5. Subject has an MMSE score between 12 and 24 inclusive at both screening and
Visit 2 and a <=3-point difference between these visits.
6. Subject has a Modified Hachinski score <=4 at screening.
7. Subject has brain MRI scan consistent with the diagnosis of AD performed
during the screening period. Computed Tomography scan can be used only if the
subject has an absolute contraindication for MRI.
8. Subject has a primary caregiver willing to accept responsibility for
supervising the treatment (e.g., administering study drug), accompanying the
study subject to clinic visits and assessing the condition of the subject
throughout the study in accordance with all protocol requirements.
9. Subject is not likely to experience a change in living conditions (e.g.,
institutionalization, moving to a different city, etc.), or change in primary
caregiver, during participation in the trial.
10. Subjects with background symptomatic therapy with acetylcholinesterase
inhibitors, and/or memantine, are allowed as long as the dose has been stable
for 90 days prior to screening and no changes are planned during the study.
11. Subjects who have occasional use of sedative agents are acceptable, but
these agents should not be given within 48 hours prior to cognitive assessments.
12. Subjects who have background medications used for stable chronic illnesses
that are not prohibited by the protocol are allowed. The dose of psychoactive
drugs must be stable for 30 days prior to screening, and no changes must be
planned during the study unless for safety reasons.
13. Subject has body mass index <38 kg/m2 at Screening.
14. Subject must be able to ingest oral medications and can swallow the study
drug without breaking or crushing.
15. Subject must be willing to undergo Apolipoprotein E genotype (ApoE) genetic
testing (ApoE results may be disclosed after trial completion).
16. Subjects participating in the study must meet one of the following criteria:
a. Females: Surgically sterilized (e.g., hysterectomy, bilateral oophorectomy
or tubal ligation) for at least 6 months or postmenopausal (postmenopausal
females must have no menstrual bleeding for at least 1 year). If not
postmenopausal, agree to use a highly effective method of contraception, that
can achieve a failure rate of less than 1% per year when used consistently and
correctly, such as hormonal contraception or a double barrier method (e.g.,
intrauterine device plus condom or true abstinence defined as in line with the
preferred and usual lifestyle of the subject. Periodic abstinence e.g.
calendar, ovulation, symptothermal, post-ovulation methods are not acceptable.
Declaration of abstinence for the duration of a trial, and withdrawal are not
acceptable methods of contraception) from 30 days prior to dosing until 30 days
after last dose and have negative human chorionic gonadotropin (β hCG) test for
pregnancy at screening.
b. Males who have not had a vasectomy must use appropriate contraception
methods (barrier or true abstinence defined as in line with the preferred and
usual lifestyle of the subject. Periodic abstinence e.g. calendar, ovulation,
symptothermal, post-ovulation methods are not acceptable. Declaration of
abstinence for the duration of a trial, and withdrawal are not acceptable
methods of contraception) from 30 days prior to dosing until 90days after last
dose.
Exclusion criteria
Subjects will not be eligible to participate in this study if they meet any of
the following exclusion criteria:
1. Subject has imaging consistent with other differential dementia diagnoses
other than the diagnosis of AD. For example, any suggestion of vascular disease
including multiple infarction involving large blood vessels or localized single
infarction (angular gyrus, thalamus, anterior cerebral artery and posterior
cerebral artery region), multiple lacunae of the basal nuclei or white matter
or extensive lesions of the periventricular white matter or combination of
several lesions are considered exclusionary. Additionally, any single lacune
in an area known to impact cognition such as the hippocampus will also be
exclusionary. Finally, Probable CAA with/without supporting pathological
evidence according to the modified Boston criteria, if in the opinion of the
investigator this may be contributing to symptoms overlapping with those of AD
or confound neuropsychological assessments, would be exclusionary.
Importantly, should there be any evidence of neurologic symptoms between
scanning and baseline visits, rescanning is necessary to ensure proper patient
selection.
2. Subject has had an increase or restoration of cognition based on medical
history.
3. Subjects who meet the following imaging exclusion criteria will not be
included in this study:
a. Claustrophobia that will result in significant anxiety and difficulty lying
still for brain imaging (MRI or CT scan).
b. Severe motor problems or chronic pain indication that prevents the subject
from lying still for brain imaging.
4. Subject with history of cancer requiring systemic therapy in the last 5
years; except for localized cancer of the skin and in-situ cervical cancer
successfully treated with surgical excision. Stable (for at least 90 days)
prostate cancer is allowed.
5. Subject has a contraindication for LP, such as infected skin over the needle
entry site, possible increased intracranial pressure, severe thrombocytopenia
or coagulopathy, suspected spinal epidural abscess, or spinal structural
abnormalities that would interfere with LP procedures.
6. Subject has evidence of clinically significant unstable cardiovascular,
pulmonary, renal, hepatic, gastrointestinal, neurologic or metabolic disease
within 6 months prior to Screening.
7. Subject has any of the following cardiovascular conditions:
a. Unstable angina, uncompensated and/or symptomatic congestive heart failure
(Grade 2 or higher on the New York Heart Association scale) or myocardial
infarction within 6 months.
b. Acute or poorly controlled blood pressure >180 mmHg systolic or >100 mmHg
diastolic.
c. Current, or recent history of, any of the following that are clinically
significant in the investigator's judgment: arrhythmia, hypotension, heart
block (1st, 2nd or 3rd degree AV block), ANY bundle branch block, ventricular
pacing, symptomatic ectopy, unstable arrhythmias including atrial fibrillation;
stable atrial fibrillation is allowed.
d. History of prolonged QT or prolonged QT on screening ECG (QTcF *480 msec).
e. History of prolonged PR interval or prolonged PR interval on screening ECG
(PR >210 msec).
f. History of prolonged QRS interval or prolonged QRS interval on screening ECG
(QRS >120 msec).
g. Supraventricular or ventricular ectopy on the screening ECG or Brugada
pattern on the ECG.
8. Subject with major stroke, uncontrolled seizure disorder, or other medical
illnesses that in the Investigator*s opinion will increase the subject*s risk
of participation in the study or confound study assessments.
9. Subject with history or current evidence of major neurological or
psychiatric illness such as schizophrenia, bipolar disorder, Parkinson*s
Disease, etc. Subjects with major depressive disorder that may interfere with
the patient*s ability to perform the study and all assessments. NOTE: Mild
depression or depressive mood arising in the context of AD are not criteria for
exclusion. The use of anti-depressants or the use of anti epileptic medication
for non seizure-related treatment is allowed if the dose has remained stable
for at least 60 days prior to enrollment.
10. Subject with history of violent or aggressive behavior that requires
medication to control.
11. Subjects with active suicidal thoughts (Type 4 or 5 on the C SSRS) in the 6
months preceding screening or at baseline; or have a history of a suicide
attempt in the previous 2 years, or more than 1 lifetime suicide attempt; or
are at serious suicide risk in the Investigator*s clinical judgment.
12. Subject with history of alcohol or drug use disorder within 12 months of
screening as defined by the Diagnostic and Statistical Manual of Mental
Disorders-5.
13. Subject with previous treatment with investigational vaccine therapy for AD.
14. Subject has participated in another Investigational New Drug (IND) research
study involving small molecule drugs within 60 days or biological drugs within
90 days prior to the first dose of study drug or 5 half-lives of the
investigational drug, whichever is longer.
15. Subject has a history of epilepsy or seizure disorder requiring ongoing
treatment, or any seizure or loss of consciousness within 6 months prior to
enrollment.
16. Subject has any of the following laboratory findings at screening:
a. Alanine aminotransferase >3 x upper limit of normal (ULN), aspartate
aminotransferase >3 x ULN, or history of clinically significant liver disease
in the Investigator*s judgment.
b. Hemoglobin *10 g/dl.
c. International Normalized Ratio (INR) >1.5 or total bilirubin >1.5 x ULN
(unless subject has evidence of Gilbert*s disease).
d. Creatinine clearance (CL) of <45 ml/min.
e. Poorly controlled diabetes as defined by hemoglobin A1C (HbA1C) >8.
f. Positive blood screen for Human Immunodeficiency Virus (HIV 1 and 2),
Hepatitis B surface antigen (HBsAg), or Hepatitis C virus antibodies (HCV-Ab)
at Screening.
g. Positive urine screen for drugs of abuse that include opiates, cocaine,
amphetamines, or barbiturates.
17. Subject has abnormal laboratory tests that suggest an alternate etiology
for dementia, such as serum vitamin B12 deficiency, thyroid function
abnormality, severe anemia, electrolyte abnormality, or positive syphilis
serology. In these cases, the patient should be re-evaluated to determine if
these potential causes of dementia have been addressed. Only if these causes
have been ruled out as the cause of the dementia can the patient be enrolled.
18. Use of systemic (i.e., oral, intravenous, etc., but not topical)
antibiotics in the last 60 days or history of recurrent infection that requires
chronic or repeated courses of antibiotics.
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 | EUCTR2019-000370-27-NL |
| ClinicalTrials.gov | NCT03823404 |
| CCMO | NL69958.041.19 |