APPlauDS · ALN-APP-003

Public study eligibility criteria

Inclusion

• Male or female, aged 40 to 55 years at the time of informed consent with early-stage DS-AD
• Clinical diagnosis of DS associated with trisomy 21.
• Cognitively stable in the opinion of the investigator, and as determined by clinical consensus case conference (Section 6.2.2) and a National Task Group-Early Detection Screen for Dementia (NTG-EDSD ≤2 combined for memory and language domains)
• Amyloid PET burden of ≥18 CLs
• Able and willing to meet all study requirements in the opinion of the Investigator, including travel to study center, procedures, measurements, and visits, including: a. Adequately supportive psychosocial circumstances. Must have a study partner who, in the Investigator’s judgement, is able to provide accurate information regarding the participant’s cognitive and functional abilities, who agrees to provide information at applicable study visits which require informant input for scale completion.
• When applicable, seizures must be well controlled (antiepileptic medication is permitted) with no occurrence of seizures in the 6 months prior to screening.
• Informed consent will follow country-specific regulations outlined in the individual country and site consent forms. Participant is able to understand and is willing and able to comply with all study requirements and procedures and able to provide written informed consent or assent (where allowed). Legally authorized representative(s) [LAR(s)] is (are) willing and able to comply with the study requirements and to provide written informed consent (where allowed). In the event that a participant loses mental capacity to consent or assent, informed consent must be obtained from the LAR prior to continuation of study procedures, and the participant’s assent should be sought where feasible and allowed. When in accordance with local regulation, participants for whom a loss of decision‑making capacity is foreseeable during the course of the study (eg, due to a neurodegenerative disease) may provide written advance consent. This advance consent must be study‑specific and may only be obtained while the participant is still capable of giving informed consent. If the participant chooses to remain in the study in the event they become incapacitated continued participation in the study will only proceed if a LAR is designated.

Exclusion

• Severe ID [as defined as Kaufman Brief Intelligence Test, Second Edition (KBIT-2) intelligence quotient composite standard score ≤40 and verbal and nonverbal mental age equivalents of 460 msec for males or >480 msec for females at Screening unless the QTcF measurement is not clinically significant in the judgement of the investigator in the presence of depolarization abnormalities (eg, bundle branch blocks and ventricular paced rhythms).
• Has systolic blood pressure >150 mmHg and/or a diastolic blood pressure >90 mmHg after 10 minutes of rest at Screening
• Has active infection that in the opinion of the investigator would prevent full participation in the study (eg, influenza, severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2])
• A medical history of brain or spinal disease that per Investigator would interfere with the LP process, CSF circulation or safety assessments. These conditions may include, but are not limited to, tumors or abnormalities visualized by magnetic resonance imaging (MRI) or computed tomography, hydrocephalus, myelopathy, prior spinal surgeries, atlanto axial instability
• Antiplatelet or anticoagulant therapy that is contraindicated for LP per local standard of care are not allowed. Therapies that can be managed per local standard of care by the Investigator to perform LP are allowed.
• History of bleeding diathesis or coagulopathy.
• History of intolerance to IT injection(s).
• Any condition that increases risk of meningitis (eg, immunodeficient state).
• History of DS regression disorder.
• Other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation.
• Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of or during Screening or planned during the trial.
• Comorbidities such as obstructive sleep apnea and hypothyroidism that are not well controlled and in the opinion of the Investigator confound the ability to follow a participant's functional status
• Attempted suicide, suicidal ideation with a plan that required hospital admission and/or change in level of care within 12 months prior to Screening. a. Participants deemed by the Investigator to be at significant risk of suicide, major depressive episode(s), psychosis, confusional state, or violent behavior should be excluded.
• Is not willing to comply with the contraceptive requirements during the study period, as described in Section 5.9.1.
• Female participant is pregnant, planning a pregnancy or breastfeeding.
• History of alcohol use disorder, within the last 12 months before screening, in the opinion of the Investigator.
• Has any of the following laboratory parameter assessments at screening: a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2×upper limit of normal (ULN). b. Total bilirubin >1.5×ULN. Participants with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if the total bilirubin is 1.4 d. Platelet count <100,000/microliter (μL) e. Absolute neutrophil count less than lower limit of normal (LLN) cells/μL or absolute lymphocyte count less than LLN cells/μL f. Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 at Screening (calculation will be based on the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine formula [2021], refer to Section 10.1)
• Treatment with another investigational drug, biological agent, or device during study or prior to Screening - within 6 months or 5 half-lives of investigational agent, whichever is longer.
• Treatment with an anti-amyloid antibody before or during the study.
• Treatment with an IT administered medication with a genetic target such as siRNA or antisense oligonucleotide (ASO) within 3 years of Screening.
• History of treatment with or tau targeting antibody within 3 years of Screening.
• Any history of gene therapy or cell transplantation or experimental brain surgery
• Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter