IRB Study Number 20-511
Phase Phase 3
Location Cleveland Clinic Lou Ruvo Center for Brain Health - Las Vegas
Institute Neurological Institute
The primary purpose of this study is to determine whether treatment with lecanemab is superior to placebo on change from baseline of the Preclinical Alzheimer Cognitive Composite 5 (PACC5) at 216 weeks of treatment (A45 Trial) and to determine whether treatment with lecanemab is superior to placebo in reducing brain amyloid accumulation as measured by amyloid positron emission tomography (PET) at 216 weeks of treatment (A3 Trial).
- Male or female, age 55 to 80 years inclusive at the time of informed consent
a. Those 55 to 64 must have 1 of the following additional risk factors, given the relatively low rates of amyloid positivity <65 years:
i. First degree relative diagnosed with dementia onset before age 80, or
ii. Known to possess at least 1 apolipoprotein є4 variant (APOE4) allele, or
iii. Known before screening to have elevated brain amyloid according to previous PET or CSF testing. Individuals with historical amyloid PET scans with Aβi (eg, from preclinical AD studies such as A4 or EARLY) are eligible to be screened provided the subject did not participate in any clinical studies involving anti-amyloid therapies subsequent to the PET assessment.
2.Global CDR score of 0 at Screening
3.Mini Mental State Examination (MMSE) score ≥27 (with educational adjustments) at Screening
4.Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II) score at Screening of ≥6
5.A45 Trial: Elevated brain amyloid pathology by amyloid PET: Elevated amyloid is defined as approximately >40 centiloids on Screening scan.
A3 Trial: Intermediate levels of brain amyloid pathology by amyloid PET: Intermediate amyloid is defined as approximately 20 to 40 centiloids on Screening scan.
6.Has a study partner that is willing to participate as a source of information and has approximately weekly contact with the participant (contact can be in-person, via telephone or electronic communication). The study partner must have sufficient contact such that the investigator feels the study partner can provide meaningful information about the subject’s daily function.
7.Provide written informed consent
8.Willing and able to comply with all aspects of the protocol
- Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test witha minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]). For women of childbearing potential, a separate baseline assessment is required if a negative Screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
- Females of childbearing potential who:
• Within 28 days before study entry, did not use a highly effective method of contraception,which includes any of the following:
o total abstinence (if it is their preferred and usual lifestyle)
o an intrauterine device or intrauterine hormone-releasing system
o a contraceptive implant
o an oral contraceptive (with additional barrier method) (Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation.)
o have a vasectomized partner with confirmed azoospermia
• Do not agree to use a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation
For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, ie, double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide.
NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age range, and without other known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
3.History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of Screening
4.Current or history within the past 2 years of psychiatric diagnosis or symptoms (eg, hallucinations, major depression, or delusions) that, in the opinion of the investigator, could interfere with study procedures
5.Contraindications to MRI scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (eg, in-skull and cardiac devices other than those approved as safe for use in MRIscanners), or exhibit other significant pathological findings on brain MRI at Screening, including but not limited to: more than 4 microhemorrhages (defined as 10 mm or less at the greatest diameter); a singlemacrohemorrhage greater than 10 mm at greatest diameter; an area of superficial siderosis; evidence of vasogenic edema; evidence of cerebral contusion, encephalomalacia, aneurysms, vascular malformations that are at high risk for hemorrhage, or infective lesions; evidence of multiple lacunar infarcts (that in the opinion of the investigator, may impact cognition) or stroke involving a major vascular territory, severe small vessel, or severe diffuse white matter disease; space occupying lesions; or brain tumors (however, lesions diagnosed as meningiomas or arachnoid cysts and less than 1 cm at their greatest diameter need not beexclusionary)
6.Hypersensitivity to any monoclonal antibodytreatment
7.Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the study
8.Bleeding disorder that is not under adequate control (including a platelet count <50,000 or international normalized ratio [INR] >1.5) at Screening
9.Results of laboratory tests conducted during Screening that are outside the following limits:
• Thyroid stimulating hormone (TSH) above normal range. Other tests of thyroid function with results outside the normal range should only be exclusionary if they are considered clinically significant by the investigator. This applies to all subjects whether or not they are taking thyroid supplements
• Abnormally low (below lower limit of normal [LLN]) serum vitamin B12 levels for the testing laboratory (if subject is taking vitamin B12 injections, level should be at or above the LLN for the testing laboratory). A low vitamin B12 is exclusionary, unless the required follow-up labs (homocysteine and methylmalonic acid [MMA]) indicate that it is not physiologically significant
10.Known to be human immunodeficiency virus (HIV) positive
11.Any other clinically significant abnormalities that in the opinion of the investigator require further investigation or treatment or may interfere with study procedures or safety, such as:
• Physical examination or vital signs at Screening
• Laboratory tests or ECG at Screening
• Other medical conditions (eg, cardiac, respiratory, gastrointestinal, psychiatric, renal disease), which are not adequately and stably controlled
• Severe visual or hearing impairment that would prevent the subject from performing psychometric tests accurately
12.Malignant neoplasms within 3 years of Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male subjects with treatment cycles completed at least 6 months before Screening). Subjects who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before Screening need not be excluded.
13.Answer “yes” to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before Screening, at Screening, or at Baseline, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening.
14.Known or suspected history of drug or alcohol abuse or dependence within 2 years before Screening or a positive urine drug test at Screening. Subjects who test positive for benzodiazepines, opioids, or tetrahydrocannabinol (THC) in urine drug testing need not be excluded unless in the clinical opinion of the investigator this is due to potential drug abuse
15.Taking prohibited medications
16.Participation in a clinical study involving:
• Any therapeutic monoclonal antibody, protein derived from a monoclonal antibody, immunoglobulin therapy, or vaccine within 6 months before Screening (anti-amyloid therapies within 1 year before Screening), unless it can be documented that the subject was randomized to placebo or never received study drug
• Any new chemical entities or investigational drug for AD within 6 months before Screening unless it can be documented that the subject received only placebo
• Any other investigational medication or device study in the 8 weeks or 5 half-lives (whichever is longer) of the medication before randomization unless it can be documented that the subject was in a placebo treatment arm
17.Planned surgery during the Prerandomization Phase or within 3 months of Randomization, which requires general anesthesia