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Phase 2 Randomized Study of Mivelsiran in Adults with Early-Stage Down Syndrome-Associated Alzheimer’s Disease

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on adults who have early-stage Down Syndrome-Associated Alzheimer’s Disease, a condition in which the brain changes typical of Alzheimer’s appear at a younger age in people with Down syndrome. The investigational drug Mivelsiran (code name ALN-961583) is administered by an intrathecal injection, meaning it is delivered directly into the fluid surrounding the spinal cord, and a matching placebo solution is used for comparison.

The purpose of the study is to determine whether the drug can reduce brain amyloid, a protein that accumulates in Alzheimer’s, as measured by a brain scan called PET. Participants will receive a series of injections over about two years and will attend regular visits that include simple blood draws, a spinal fluid sample (CSF), and brief cognitive tests to monitor safety and any changes.

The research process

The trial runs in 7 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Enrollment

    You have joined the study after providing consent and confirming eligibility for early‑stage down syndrome‑associated alzheimer’s disease.

    Baseline information is recorded before any study medication is given.

  2. Step 2

    Randomization

    You are randomly assigned to receive either mivelsiran or a placebo (isotonic aqueous buffer).

    The assignment is double‑blind, meaning you and the study staff do not know which product you receive.

  3. Step 3

    First intrathecal injection

    You receive a single intrathecal injection (injection into the spinal fluid) of the assigned product.

    The injection is a solution for injection; the dose listed in the protocol is 0 mg, administered by trained personnel.

  4. Step 4

    Baseline assessments

    You undergo an amyloid PET scan to measure brain amyloid levels.

    Cerebrospinal fluid (csf) is collected to measure sAPPβ, sAPPα, and Aβ42 concentrations.

    A blood sample is taken to measure p‑tau217 levels in plasma.

    You complete the modified cognitive rating test (mcrt) to assess cognition.

  5. Step 5

    Ongoing treatment period

    You continue to receive intrathecal injections of the same product according to the study schedule for up to 24 months.

    Each injection uses the same dose and route as the first injection; the exact frequency is defined by the study protocol.

  6. Step 6

    Month‑24 follow‑up assessments

    At the end of month 24 you repeat the amyloid PET scan.

    Csf and blood samples are collected again to measure the same biomarkers (sAPPβ, sAPPα, Aβ42, p‑tau217).

    You complete the mcrt again to evaluate any change in cognition.

  7. Step 7

    Study completion

    After the month‑24 assessments the study medication is stopped and the trial ends for you.

    The collected data will be used to evaluate the safety and effect of mivelsiran compared with placebo.

Who can join the trial?

7 criteria

  • Be a man or woman between 40 and 55 years old when you sign the consent form and have early‑stage Down Syndrome‑Associated Alzheimer’s Disease (DS‑AD), which is a form of Alzheimer’s that can appear in people with Down syndrome.
  • Have a confirmed diagnosis of Down syndrome, meaning you have an extra copy of chromosome 21 (called trisomy 21).
  • Be judged by the study doctor to be cognitively stable (your thinking and memory are not rapidly getting worse), as shown by a team review and a score of 2 or less on the National Task Group‑Early Detection Screen for Dementia (NTG‑EDSD) for memory and language.
  • Show a level of brain amyloid that is at least 18 centiloid (CL) units on an Amyloid PET scan, which is an imaging test that measures the amount of amyloid protein in the brain.
  • Be able and willing to follow all study visits, travel to the study center, and complete required procedures, and have supportive living circumstances. You must also have a study partner (a family member or caregiver) who can give accurate information about your daily abilities and agree to take part in the study visits.
  • If you have a history of seizures, they must be well‑controlled with medication, and you must not have had a seizure in the six months before screening.
  • Be able to understand the study, agree to follow all requirements, and sign a written informed consent form (or have a legally authorized representative sign for you). If you might lose the ability to decide later, you can give an advance consent while you are still able.

Who cannot join the trial?

31 criteria

  • Severe intellectual disability (IQ ≤ 40 or mental age < 4 years) as measured by a standard test.
  • Use of antidepressants, antipsychotics, anxiolytics, benzodiazepines (except for study imaging), acetylcholinesterase inhibitors, anticonvulsants, mood stabilizers, or memantine unless the dose has been stable for at least 12 weeks before screening.
  • Taking any systemic antiviral or antimicrobial medication for an active infection within 7 days before the first study dose.
  • Having a significant electrocardiogram (ECG) abnormality or a corrected QT interval (QTcF) longer than 460 ms for males or 480 ms for females, unless the doctor judges it not clinically important.
  • Having a resting systolic blood pressure over 150 mm Hg or diastolic blood pressure over 90 mm Hg after 10 minutes of rest.
  • Having an active infection (such as flu or COVID‑19) that the doctor believes would stop you from completing the study.
  • Having a history of brain or spinal problems (tumors, abnormal scans, fluid buildup, spinal cord disease, previous spinal surgery, or instability of the neck vertebrae) that could interfere with a lumbar puncture or safety assessments.
  • Using antiplatelet or anticoagulant medicines that make a lumbar puncture unsafe, unless the doctor can manage the risk safely.
  • Having a personal history of easy bleeding (known as bleeding diathesis) or a blood clotting disorder (coagulopathy).
  • Having ever been intolerant to an intrathecal (IT) injection (injection into the spinal fluid).
  • Having any condition that raises the risk of meningitis (infection of the brain lining), such as a weakened immune system.
  • Having a history of Down syndrome regression disorder (a sudden loss of skills).
  • Any other medical problem that the doctor feels would make it hard to follow the study plan or affect the results.
  • Being hospitalized for a major surgery or medical procedure with general anesthesia within the past 12 weeks or planned during the trial.
  • Having poorly controlled obstructive sleep apnea or hypothyroidism that could affect the ability to track functional status.
  • Having attempted suicide, having serious suicidal thoughts with a plan that required hospital care, or being judged at high risk for suicide, severe depression, psychosis, confusion, or violent behavior within the past year.
  • Not agreeing to use birth control as required by the study.
  • Being pregnant, trying to become pregnant, or breastfeeding.
  • Having a recent (within the last 12 months) problem with alcohol misuse (known as alcohol use disorder).
  • Having any of the following abnormal lab results at screening:
    • High liver enzymes (ALT or AST) more than twice the normal limit.
    • Total bilirubin greater than 1.5 times normal (unless due to Gilbert’s syndrome and still under 2 × normal).
    • International Normalized Ratio (INR) over 1.4 (a measure of blood clotting).
    • Platelet count lower than 100,000 per microliter (low platelets).
    • Very low white blood cell counts (neutrophils or lymphocytes) below the normal range.
    • Kidney function (estimated glomerular filtration rate, eGFR) less than 45 mL/min/1.73 m².
    • Receiving any other experimental drug, biologic, or device within the past 6 months or five drug half‑lives (whichever is longer).
    • Having taken an anti‑amyloid antibody before or during the study.
    • Having received an intrathecal medication that targets genes (such as siRNA or antisense oligonucleotide (ASO)) within the past 3 years.
    • Having received a medication that targets the protein tau within the past 3 years.
    • Having any history of gene therapy, cell transplantation, or experimental brain surgery.
    • Having an implanted shunt or catheter that drains cerebrospinal fluid (CSF) from the brain or spine.
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Investigated drugs

  • Mivelsiran

    is an experimental medicine being tested for the first time in people with early‑stage Down syndrome‑associated Alzheimer’s disease. It is given as a very small amount of liquid that is injected directly into the spinal fluid (intrathecal administration). The goal of the study is to see whether this medicine can reduce the amount of amyloid protein that builds up in the brain, which is thought to help slow the disease.

  • WATER FOR INJECTION

    is a sterile, pure water solution that is also injected into the spinal fluid. In the trial it is used as a comparison to help researchers understand the effects of the injection itself and to make sure any changes seen are due to the active medicine, not just the procedure.

What is already known about the treatment

  • Mivelsiran

    This medication is given as a sterile solution that is injected directly into the spinal fluid (intrathecal injection). It is still experimental and is being studied in clinical trials for safety and effectiveness. The drug is intended for adults with early‑stage Down syndrome‑associated Alzheimer’s disease, aiming to lower the buildup of amyloid protein in the brain. It works as an antisense oligonucleotide that binds to a specific genetic target to reduce production of a protein involved in amyloid formation, and it is classified as a disease‑modifying antisense therapy for neurodegenerative disorders.

  • Water for injection

    This product is a sterile, purified water used as a liquid to dissolve or dilute medicines for injection into the spinal fluid (intrathecal use). It is an approved medical ingredient that has been used for many years as a safe carrier for injectable drugs. The water itself has no therapeutic effect and is simply a vehicle to help deliver the active medication. It is classified as a sterile diluent or solvent for parenteral (injectable) preparations.

Investigated diseases

Early-Stage Down Syndrome-Associated Alzheimer’s Disease (DS-AD) - It is a neurodegenerative condition that appears in individuals with Down syndrome, characterized by the early buildup of amyloid proteins in the brain. The disease starts with subtle changes in thinking and memory, which gradually become more noticeable over months and years. As the amyloid accumulates, brain cells begin to lose connections, leading to increasing difficulty with daily tasks. The condition progresses with worsening of language, problem‑solving, and spatial abilities. Over time, the decline spreads to other cognitive functions, reflecting the spread of disease pathology across brain regions.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-523390-42-00Protocol codeALN-APP-003Estimated enrolment58 patientsSponsorAlnylam Pharmaceuticals Inc.

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