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

NCT06911944 | Not Yet Recruiting Phase 4 DMC FDA Drug

• 2 other identifiers: ATRI-0165R33AG066543
• Study Type: interventional
• Target: 60
• Locations: 0 countries
• Sites: N/A

Brief Summary

The goal of this clinical trial is to learn if donanemab can reduce levels of amyloid in the brain, and if donanemab is safe and well-tolerated in participants with Down syndrome. The main questions it aims to answer are: Does donanemab reduce amyloid in the brain? Is donanemab safe and well-tolerated in people with Down syndrome? Researchers will compare donanemab to a placebo (a look-alike substance that contains no drug) to see if donanemab works to reduce levels of amyloid in the brain. Participants in the study will be 35-50 years old and will be in the study for 12 months. Participants will then stay in the study for an additional 12 months in an long-term extension where all participants will receive donanemab. Participants who had a reduction in amyloid (measured by amyloid brain scan) by the end of the first 12 months will receive placebo for the long-term extension, while participants who did not have an amyloid reduction will receive study donanemab for the long-term extension. Everyone (participants and study staff) will remain blinded to treatment for the duration of the study. Participants will:

• Have intravenous (IV) infusions of donanemab (or placebo) every 4 weeks
• Visit the clinic once every other month for checkups and tests. These tests will include brain scans (magnetic resonance imaging \[MRI\] and positron emission tomography \[PET\] ), blood draws and memory tests.
• Have a study partner who who can provide information about the participant and can join participant for some of the study visits.

Conditions

Down Syndrome (DS); Down Syndrome (Trisomy 21); Alzheimer Disease; Amyloid Beta Protein

Outcome Measures

Primary Outcomes (1)

• Change from baseline on brain amyloid levels

  Change in brain amyloid measured by amyloid PET imaging (amyloid centiloid levels) from baseline to 12 months. An increase indicates a worsening.

  12 months

Secondary Outcomes (3)

• Change from baseline to 12 months in the Modified Cued Recall Test (mCRT)

  From baseline to 12 months

• Change from baseline in whole brain volume

  From baseline to 12 months

• Change from baseline in brain hippocampal volume

  From baseline to 12 months

Study Arms (2)

donanemab

EXPERIMENTAL

Donanemab will be administered per label instructions and the pharmacy manual as an IV infusion every 4 weeks using an up-titration regimen that will allow participants to reach a target dose of 1400 mg within 12 weeks

Drug: Donanemab

placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Donanemab DRUG

Donanemab will be administered as an IV infusion every 4 weeks using an up-titration regimen that will allow participants to reach a target dose of 1400 mg within 24 weeks.

Also known as: Kisunla

donanemab

Placebo DRUG

The control product (placebo) will be supplied in vials containing 350 mg/20 mL of donanemab Placebo for donanemab is supplied to the clinical site to match the active study intervention and contains only inactive ingredients. Normal sterile saline solution (0.9% sodium chloride) will be used for dilution.

placebo

Eligibility Criteria

• Age: 35 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Documentation of the participant's informed consent to study procedures
• Ages 35-50 years (inclusive).
• Plasma Phosphorylated tau (pTau) 217 levels at screening consistent with amyloid PET eligibility.
• 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.
• Intelligence quotient (IQ) equal to or greater than 40 based on Kaufman Brief Intelligence Test, Second Edition.
• Participants must be in good general health as evidenced by medical history with no diagnosis of dementia.
• Elevated brain amyloid (\>18 centiloids) at screening.
• Stable dose of permitted medications as described protocol for 4 weeks prior to screening.
• 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.
• 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.
• Must complete all screening evaluations as outlined in protocol

You may not qualify if:

• Females who are lactating or pregnant (as confirmed by a urine pregnancy test) during screening, or plan to become pregnant during the study.
• Females of childbearing potential or males with a female partner of childbearing potential who did not use a highly effective method of contraception within 28 days of screening alongside with a suitable barrier method (e.g., male condom) and/or are not willing to use both methods for the duration of their participation in the study and for 3 months after the last dose of study drug.
• Weight less than 40kg at screening.
• Lack of good venous access such that intravenous (IV) drug delivery or multiple blood draws would be precluded.
• Suspected or known allergic reactions, adverse reactions, or hypersensitivity to humanized monoclonal antibodies or any components of the study treatments (donanemab or placebo).
• Previous treatment with donanemab unless there is firm evidence that the participant received placebo only.
• Prior or current treatment with a prohibited medication as described in protocol.
• 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.
• 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 one (1) cerebral microhemorrhage (regardless of their anatomical location with a diagnostic characterization as "definite"), evidence of space occupying lesions, more than two (2) lacunar infarcts, or one (1) infarct larger than 1cm in diameter, severe white matter disease, and structural evidence of alternative pathology not consistent with AD and considered to be at the origin of participant's symptoms.
• NOTE: Small incidental meningiomas and arachnoid cysts (\<1cm in diameter) may be permitted with Medical Monitor review and approval.
• 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.
• Contraindications to amyloid positron emission tomography (PET) imaging and/or use of florbetapir.
• 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.
• History of severe allergic reaction (e.g., anaphylaxis) including, but not limited to: severe allergic reaction to previous vaccines, foods, and/or medications.
• Hospitalization within 30 days prior to screening or baseline.

Sponsors & Collaborators

• Michael Rafii, MD, PhD: lead
• National Institute on Aging (NIA): collaborator
• Eli Lilly and Company: collaborator
• Alzheimer's Clinical Trials Consortium: collaborator
• Alzheimer's Therapeutic Research Institute: collaborator

Related Links

• Alzheimer's Clinical Trials Consortium - Down Syndrome

MeSH Terms

Conditions

Down Syndrome; Alzheimer Disease; Plaque, Amyloid

Interventions

donanemab

Condition Hierarchy (Ancestors)

Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Chromosome Disorders; Genetic Diseases, Inborn; Dementia; Brain Diseases; Central Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Study Officials

• Michael Rafii, MD, PhD

  University of Southern California (USC) Keck School of Medicine, Alzheimer's Therapeutic Research Institute (ATRI)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

ATRI Recruitment and Retention (RER) Unit

CONTACT

213-821-0569; atri-recruit@usc.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Medical Director of the Alzheimer's Therapeutic Research Institute (ATRI) and Professor of Clinical Neurology at the Keck School of Medicine

Study Record Dates

• First Submitted: March 28, 2025
• First Posted: April 4, 2025
• Study Start (Estimated): August 1, 2026
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2028
• Last Updated: November 24, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL