Amyloid Lowering for Alzheimer's in Down's With Donanemab Investigation

Launched by MICHAEL RAFII, MD, PHD · Mar 28, 2025

Keywords

ClinConnect Summary

This clinical trial, called "Amyloid Lowering for Alzheimer's in Down's With Donanemab Investigation," is exploring whether a medication called donanemab can lower amyloid levels in the brain of people with Down syndrome who may also develop Alzheimer’s disease. The study aims to find out if donanemab is safe to use and whether it effectively reduces amyloid, a protein that can build up in the brain and is linked to Alzheimer’s. Participants will be between 35 and 50 years old and will take part in the study for a total of 24 months, with the first 12 months receiving either donanemab or a placebo (a non-active look-alike treatment), followed by a long-term extension where all participants will receive donanemab.

To be eligible for this study, participants must have a confirmed diagnosis of Down syndrome, be in good health without dementia, and have elevated amyloid levels in their brain. They will receive an intravenous infusion of either donanemab or placebo every four weeks and will have regular checkups that include brain scans, blood tests, and memory assessments. A study partner, such as a family member or friend, is required to help provide information and support during study visits. This trial is not yet recruiting participants, but it aims to gather important information to help improve treatments for individuals with Down syndrome and Alzheimer’s disease.

Gender

ALL

Eligibility criteria

• Inclusion Criteria:
• • 1. Documentation of the participant's informed consent to study procedures
• • 2. Ages 35-50 years (inclusive).
• • 3. Plasma Phosphorylated tau (pTau) 217 levels at screening that confers amyloid PET eligibility.
• • 4. Diagnosis of Down syndrome (including trisomy 21, mosaic trisomy 21, Robertsonian translocation trisomy 21, or partial trisomy 21) as confirmed by medical record review or Karyotype genetic testing.
• • 5. Intelligence quotient (IQ) equal to or greater than 40 based on Kaufman Brief Intelligence Test, Second Edition.
• • 6. Participants must be in good general health as evidenced by medical history with no diagnosis of dementia.
• • 7. Elevated brain amyloid (\>18 centiloids) at screening.
• • 8. Participants must achieve a performance score greater than 23 on the modified Cued Recall Test (mCRT)
• • 9. Stable dose of permitted medications as described protocol for 4 weeks prior to screening.
• • 10. In the opinion of the site PI, has a study partner able and willing to provide accurate information (including clinical symptoms and medical history) about the participant and participate in study visits and informant-based assessments (usually requires at least 5 hours of contact per week) for the duration of the study.
• • 11. As assessed by the site PI, participant is likely to be able to comply with the protocol for the duration of the study, and has adequate vision, hearing (hearing aid permitted), and literacy sufficient for compliance with required testing procedures.
• • 12. Must complete all screening evaluations as outlined in protocol
• Exclusion Criteria:
• • 1. Females who are lactating or pregnant (as confirmed by a urine pregnancy test) during screening, or plan to become pregnant during the study.
• • 2. Females of childbearing potential who did not use a highly effective method of contraception within 28 days of screening and/or are not willing to use highly effective method of contraception for the duration of their participation in the study. Males who are sexually active with a female of childbearing potential and do not agree to use barrier methods of contraception (condoms with spermicide) during the trial and for 3 months after the last dose of study drug unless the female is using a highly effective method of contraception.
• • 3. Weight less than 40kg at screening.
• • 4. Lack of good venous access such that intravenous (IV) drug delivery or multiple blood draws would be precluded.
• • 5. Suspected or known allergic reactions, adverse reactions, or hypersensitivity to humanized monoclonal antibodies or any components of the study treatments (donanemab or placebo).
• • 6. Previous treatment with donanemab unless there is firm evidence that the participant received placebo only.
• • 7. Prior or current treatment with a prohibited medication as described in protocol.
• • 8. Enrollment in another investigational study, or intake of investigational drug, within 30 days prior to screening or five half-lives of the investigational drug, whichever is longer.
• • 9. Magnetic Resonance Imaging (MRI) scan at screening showing a single area of cerebral vasogenic edema, superficial siderosis, or evidence of a prior macro-hemorrhage, or showing more than four (4) cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as "possible" or "definite"), evidence of space occupying lesions, more than two (2) lacunar infarcts, or one (1) infarct larger than 1 centimeter (cm) in diameter, and structural evidence of alternative pathology not consistent with Alzheimer's Disease (AD) and considered to be at the origin of participant's symptoms.
• • NOTE: Small incidental meningiomas (\<1cm in diameter) may be permitted with Medical Monitor review and approval.
• • 10. Contraindication(s) to MRI studies, including metal (ferromagnetic) implants, a cardiac pacemaker or other devices that are not compatible with MRI, and/or severe claustrophobia.
• • 11. Contraindications to amyloid positron emission tomography (PET) imaging and/or use of florbetapir.
• • 12. Any unstable and/or clinically significant medical condition likely to hamper the evaluation of safety and/or efficacy of study drug (e.g., moderate and/or severe untreated obstructive sleep apnea, clinically significant reduction in serum B12 or folate levels, clinically significant abnormalities of thyroid function, stroke, or other cerebrovascular conditions), as per the site PI's judgement.
• • 13. History of severe allergic reaction (e.g., anaphylaxis) including, but not limited to: severe allergic reaction to previous vaccines, foods, and/or medications.
• • 14. Hospitalization within 30 days prior to screening or baseline.
• • 15. Clinically significant infections or major surgical operation within 3 months prior to screening.
• • 16. History of chronic or recurrent infections judged to be clinically significant by the site PI and which would potentially hamper the evaluation of efficacy and safety assessments.
• • 17. Myocardial infarction within one (1) year prior to baseline, unstable angina pectoris, or significant coronary artery disease.
• • 18. History of cancer within the past five (5) years other than treated squamous cell carcinoma, basal cell carcinoma and melanoma in-situ, in-situ prostate cancer, or in-situ breast cancer, which have been fully removed and are considered cured.
• • 19. History or presence of immunological or inflammatory conditions, including neurological disorders, judged to be clinically significant by the site PI.
• • 20. History of meningitis or meningoencephalitis.
• • 21. History of moderate or severe traumatic brain injury.
• • 22. History or presence of uncontrolled seizures. If history of seizures, they must be well controlled with no occurrence of seizures in the 2 years prior to study screening. The use of antiepileptic medications is permitted.
• • 23. Concomitant or past history of psychiatric or neurologic disorder (e.g., head injury with loss of consciousness, symptomatic stroke, Parkinson's disease, severe carotid occlusive disease, transient ischemic attacks, hemorrhagic and/or non-hemorrhagic stroke) other than those considered to be related to AD.
• • 24. Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) criteria for drug or alcohol abuse or dependence currently met within the past 5 years.
• • 25. Significant risk of suicide defined, using the Columbia-Suicide Severity Rating Scale (C-SSRS) (Child Version), as the participant answering "yes" to suicidal ideation questions 4 or 5 or answering "yes" to suicidal behavior within the past 12 months.
• • 26. Clinically significant abnormal vital signs including sustained sitting blood pressure \>160/90 millimeters of mercury (mmHg).
• • 27. Participants with diabetes mellitus with hemoglobin A1c (HbA1c) levels of ≥8.0%.
• • 28. In the opinion of the site PI, clinically significant deviations from normal values for hematologic parameters, liver function tests, and other biochemical measures.
• • 29. Participants with a known history of human immunodeficiency virus (HIV-1 and 2).
• • 30. Participants with known history of acute/chronic hepatitis B or C.
• • 31. Clinically significant arrhythmias or other clinically significant abnormalities on electrocardiogram (ECG) at screening (minor abnormalities documented as clinically insignificant by the site PI are allowed).
• • 32. Residing in a continuous care nursing facility.
• • 33. For participants undergoing Lumbar Puncture (LP) as part of the optional longitudinal cerebrospinal fluid (CSF) biomarker sub-study, any contraindication to LP including, but not limited to: inability to tolerate an appropriately flexed position for the time necessary to perform an LP; international normalized ratio (INR) \>1.4 or other metrics indicating coagulopathy; platelet count of \<120,000/microliter(μL); infection at the desired lumbar puncture site; taking anti-coagulant medication within 90 days of LP (Note: low dose (up to 81 milligram (mg)) aspirin is permitted); degenerative arthritis of the lumbar spine; suspected non-communicating hydrocephalus or intracranial mass; prior history of spinal mass or trauma.
• • 35. Participants who are apolipoprotein E ε4 (APOE ε4) homozygotes. 36. Participants who receive anti-coagulants or thrombolytics within 30 days prior to baseline. Any use of anticoagulants or thrombolytics during the study will lead to discontinuation of the study drug.
• • 37. Participants with clotting disorders. 38. Any condition, which in the opinion of the site PI, Coordinating Center, regulatory sponsor, or Project Lead/Protocol PI, makes the participant unsuitable for inclusion.