ALN-961583 for Cerebral amyloid angiopathy | Dutch-type cerebral amyloid angiopathy

Inclusion criteria

• {"criterion_text":"- Inclusion Criteria for Sporadic Cerebral Amyloid Angiopathy (sCAA) patients. Male or female aged ≥50 years at the time of informed consent\n- Individuals with probable CAA per the Boston Criteria Version 2.0, characterized by the following history of clinical presentation and MRI findings at screening: a.\tPresentation with spontaneous intracerebral hemorrhage, convexity subarachnoid hemorrhage, transient focal neurological episodes, or cognitive impairment or dementia b.\tAt least 2 strictly lobar hemorrhagic lesions on MRI, in any combination (ICH, CMB, or foci of cSS or cSAH), or c.\tAt least 1 lobar hemorrhagic lesion plus 1 white matter feature (severe PVS in the CSO PVS or WMH in a multispot pattern), and d.\tAbsence of any spontaneous deep hemorrhagic lesions (ie, intracerebral hemorrhage or microbleeds in basal ganglia, thalamus, or brainstem) on MRI, and e.\tAbsence of other causes of the hemorrhagic lesions. Other causes of hemorrhagic lesions include antecedent head trauma, hemorrhagic transformation of an ischemic stroke, arteriovenous malformation, hemorrhagic tumor, CNS vasculitis. In addition, other causes of cSS and acute cSAH should also be excluded.\n- Individuals with probable CAA with supporting pathology per the Boston criteria version 2.0, with the following clinical data and pathological tissue (evacuated hematoma or cortical biopsy) at or prior to screening demonstrating: a. Presentation with spontaneous intracerebral hemorrhage, transient focal neurological episodes, convexity subarachnoid hemorrhage, or cognitive impairment or dementia. b. Some degree of CAA in specimen from evacuated hematoma or cortical biopsy. c. Absence of other diagnostic lesion.\n- Inclusion Criteria for Dutch-type Cerebral Amyloid Angiopathy (D-CAA) patients. Male or female aged ≥30 years at the time of informed consent\n- Individuals with a known E693Q APP gene mutation for Dutch-type CAA\n- Inclusion Criteria for both sCAA and D-CAA Patients. Corrected vision at 20/50 or better as measured per local procedures or sourced from documented medical history, for the subset of patients who will have BOLD-fMRI assessments. If otherwise eligible but without 20/50 or better corrected vision, omit BOLD-fMRI assessment.\n- 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.\tAdequately supportive psychosocial circumstances. Must have a study partner who in the Investigator’s judgement is able to provide accurate information regarding the patient’s cognitive and functional abilities, who agrees to provide information at applicable study visits which require informant input for scale completion. Selection criteria of the study partner is included in the ICF and can differ by regional standards. If a study partner becomes unable to participate, a new study partner is required. b.\tAble to undergo MRI scans and able to tolerate them (eg, no metal implants including MRI incompatible intrauterine devices, myoclonus of a severity that precludes MRI scans or any condition that renders testing intolerable for the patient) c.\tBody Mass Index (BMI) ≥18 and ≤40 kg/m2 at Screening visit d.\tAble to tolerate LP\n- Evaluable brain MRI imaging at screening\n- Patient is able to understand, is willing, and able to comply with the study requirements and to provide written informed consent. at Screening visit. If the patient is unable to provide informed consent, legally authorised representative (LAR) (s) is (are) willing and able to comply with the study requirements and to provide written informed consent, provided that the patient also assents to participation. In countries where local laws, regulations, and customs do not permit patients who lack capacity to consent to participate in this study, they will not be enrolled. Ongoing participation in the trial will be contingent upon the patient maintaining mental capacity to provide informed consent, unless LARs are allowed per local regulations. During the study, a patient’s mental capacity will be assessed regularly, eg, prior to each treatment and after clinical events that may affect capacity (eg, stroke), by the Investigator and the study team members with relevant expertise who interact with the patient according to sites’ established processes. This comprehensive evaluation may include assessments already performed during the study and will incorporate the patient’s general understanding of the study and its procedures and input from study partner and possibly others including family members or care givers. If the Investigator determines a loss in mental capacity, the Investigator will document this change and will terminate patient's participation in the study if local regulations do not allow consent for continued participation by a LAR. Otherwise, the patient will be assigned a LAR as allowed per local law. In the Netherlands, patients who are not capable of consent will be excluded and, if deemed during the course of the study by the investigator to no longer have mental capacity to provide informed consent, their participation will be terminated."}

Exclusion criteria

• {"criterion_text":"- Moderate or Severe Stage AD (defined as global clinical dementia rating [CDR] 2.0 or 3.0, respectively) or significant CI (Mini Mental State Examination [MMSE] <22) at screening\n- Prior treatment with a CNS-targeted siRNA or antisense oligonucleotide (ASO)\n- Any history of gene therapy or cell transplantation or experimental brain surgery\n- Presence of an implanted shunt for the drainage of Cerebrospinal fluid (CSF) or an implanted CNS catheter\n- Clinically significant electrocardiogram (ECG) abnormalities at Screening, in the opinion of the Investigator, or a Fridericia-corrected QT interval (QTcF) >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 (e.g., bundle branch blocks and ventricular paced rhythms).\n- Has systolic blood pressure >150 mmHg and/or a diastolic blood pressure >90 mmHg after 10 minutes of rest at screening.\n- Active fungal or bacterial systemic infection that will not be completely treated at least 7 days prior to the study drug dosing on Day 1\n- Attempted suicide, suicidal ideation with a plan that required hospital admission and/or change in level of care within 12 months prior to Screening. For patients with suicidal behaviors within the last 12 months, a risk assessment should be done by an appropriately qualified health professional to assess whether it is safe for the patient to participate in the study. In addition, patients deemed by the Investigator to be at significant risk of suicide, major depressive episode, psychosis, confusional state, or violent behavior should be excluded.\n- History of bleeding diathesis.\n- A medical history of brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment., Investigators should consider findings including but not limited to tumors or abnormalities visualized by MRI or computed tomography, suggestion of raised intracranial pressure on MRI or ophthalmic examination, spinal stenosis, or curvature, Chiari malformation, hydrocephalus, syringomyelia, tethered spinal cord syndrome and connective tissue disorders such as Ehlers-Danlos syndrome and Marfan syndrome.\n- History of uncontrolled seizures within the last 6 months prior to screening.\n- History of previous clinical ICH with onset less than 90 days prior to anticipated randomization in the study\n- Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening.\n- Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation; or, in the opinion of the Investigator, taking part in the study would jeopardize the safety of the patient.\n- Is not willing to comply with the contraceptive requirements during the study period, as described in Section 5.9.1 of the protocol.\n- Female patient is pregnant, planning a pregnancy, or breast-feeding.\n- History of alcohol abuse, within the last 12 months before Screening, in the opinion of the Investigator.\n- History of previous or contemporary diagnosis of CAA-related inflammation (CAA-ri) or amyloid beta related angiitis (ABRA) as defined by validated diagnostic criteria eg, [Auriel 2016] or on pathological examination.\n- Has any of the following laboratory parameter assessments at screening: a.\tAlanine aminotransferase or aspartate aminotransferase ≥ 3.0 x upper limit of normal (ULN) b.\tTotal bilirubin ≥ 1.5 x ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN. c.\tInternational normalized ratio >1.4 d.\tPlatelet count <100,000/microliter (μL) e.\tEstimated glomerular filtration (eGFR) of <30mL/min/1.73m2 (calculation will be based on the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine formula (2021) (refer to Section 10.1 of the protocol).\n- Treatment with another investigational drug, biological agent, or device within 6 months of Screening, or 5 half-lives of investigational agent, whichever is longer. Any agent that has received health agency authorization (including for emergency use) by local or regional regulatory authorities is not considered investigational.\n- Use of the following medications is prohibited unless the dose has been stable (prescribed dosing regimen is unchanged) for at least 12 weeks prior to Screening and the dosing regimen is not anticipated to change during the study: antidepressants, antipsychotics, anxiolytics, benzodiazepines (except when used for study imaging and procedures), acetylcholinesterase inhibitors, anticonvulsants, mood stabilizers, and memantine.\n- Antiplatelet or anticoagulant therapy within the 10 days prior to Screening or anticipated use during the study. This includes but is not limited to: clopidogrel, dipyridamole, warfarin, dabigatran, rivaroxaban and apixaban. Aspirin is allowed.\n- Treatment with amyloid-targeting antibody prior to Screening\n- Treatment with another IT administered medication within the last 1 year prior to Screening"}

Primary endpoints

• {"endpoint_text":"- Annualized rate of new lobar Cerebral Microbleeds as detected by MRI in patients with Cerebral Amyloid Angiopathy (sCAA)","definition_or_measurement_approach":"Annualized rate of new lobar cerebral microbleeds detected by MRI."}

Secondary endpoints

• {"endpoint_text":"- Global rank of patients based on clinical or MRI imaging outcomes by severity, count, presence of symptoms, and timing, and: ­\tNew ICH ­\tNew cSS or cSAH ­\tNew lobar CMBs","definition_or_measurement_approach":"Composite global ranking based on clinical and MRI imaging outcomes (severity, count, symptoms, timing) for new ICH, cSS/cSAH, and lobar CMBs."}
• {"endpoint_text":"- Change from baseline over time in BOLD slope (amplitude over time-to-peak), amplitude, and time-to-peak detected, in a subset of enrolled patients, by visual-evoked fMRI","definition_or_measurement_approach":"BOLD-fMRI metrics (slope, amplitude, time-to-peak) measured by visual-evoked fMRI in a subset of patients; change from baseline over time."}
• {"endpoint_text":"- •\tTotal number of new lobar CMBs over time detected by MRI •\tNew ICH over time as detected by MRI or clinical diagnosis •\tTime to first ICH recurrence •\tNew/extended cSS or new cSAH over time as detected by MRI or clinical diagnosis •\tProportion of patients with hemorrhagic disease progression over time detected by MRI or clinical diagnosis where appropriate. •\tTotal number of new symptomatic hemorrhages over time •\tChange from baseline over time in WMH volume","definition_or_measurement_approach":"MRI and clinical diagnosis used to detect new lobar CMBs, new ICH, cSS/cSAH; time-to-event analyses for ICH recurrence; MRI-based WMH volume change over time; proportion with hemorrhagic progression determined by MRI/clinical diagnosis."}
• {"endpoint_text":"- Change from baseline over time in total CAA SVD score as detected by MRI based on: ­\tLobar CMBs ­\tCSO PVS ­\tWMH ­\tcSS","definition_or_measurement_approach":"MRI-based total CAA small vessel disease (SVD) score composed of lobar CMBs, CSO PVS, WMH, and cSS; change from baseline over time."}
• {"endpoint_text":"- Change from baseline over time in sAPPα and in sAPPβ concentration in CSF","definition_or_measurement_approach":"Quantitative measurement of sAPPα and sAPPβ concentrations in cerebrospinal fluid (CSF) over time; change from baseline."}

Methods

• Recruitment Website (document: K2_ALN-APP-002_BRC Recruitment Website text_NLD) — digital site-level recruitment text for Netherlands (channel: website; target audience: potential patients in NL).
• Patient Information Brochure (document: K2_ALN-APP-002_Patient Information Brochure_Red_San) — printed/digital brochure for prospective participants.
• Study Partner Brochure and Study Partner ICF (documents: K2_ALN-APP-002_Study Partner Brochure_Red_San; L1_ALN-APP-002_Study Partner ICF_Red_San) — materials targeted to required study partners/informants.
• Lumbar Puncture Educational Fact Sheet (document: K2_ALN-APP-002_Lumbar Puncture Educational Fact Sheet_Red_San) — educational material addressing LP procedure for participants.
• Visual Talking Points (document: K2_ALN-APP-002_Visual Talking Points_Red_San) — site/staff-facing visual aids for recruitment conversations.
• Patient-facing study materials and questionnaires (multiple D4 patient-facing documents) — local-language patient materials and assessments for screening and enrollment.
• Home Health Care support (vendor duty: Illingworth Research Group Limited listed as 'Home Health Care') — home health services to support participants as needed.

Netherlands

Earliest CTIS Part Ii Submission Date

04-03-2025

Latest Decision Or Authorization Date

12-08-2025

Processing Time Days

161

Number Of Sites

3

Number Of Participants

50

Primary sponsor

Full Name

Alnylam Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

IQVIA Limited

Responsibilities

Start-Up, IRB submission, Site Budget/CTA Negotiations, Vendor Contracting, Site Payments, Medical Monitoring, Investigator Meeting; ECG delivery and central reading; other operational activities

Name

PPD Development LP

Responsibilities

Bioanalytical laboratory activities (sAPPα and sAPPβ in CSF and plasma)

Name

Syneos Health Inc.

Responsibilities

Safety Submissions

Name

Q Squared Solutions Limited

Responsibilities

Central labs, lab kit shipment

Name

Suvoda LLC

Responsibilities

Electronic data capture / eClinical support (role code present but not fully specified)

Third parties

• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"QP certification of IMP in the EU, Secondary packaging and labelling","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Medical Equipment Supplies And Management Limited","duties_or_roles":"Shipment of additional materials/equipment (if required by site)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"MRI qualification and central reading","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Illingworth Research Group Limited","duties_or_roles":"Home Health Care","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"code 3 (role not specified in supplied data)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Q Squared Solutions Limited","duties_or_roles":"Central Labs, Lab Kit Shipment","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Bbk Worldwide LLC","duties_or_roles":"Patient Reimbursement","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"PPD Development LP","duties_or_roles":"Bioanalytical Laboratory/sAPPa and sAPPb in CSFand Plasma","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Start-Up (SSQ, IRB submission), Site Budget/CTA Negotiations, Vendor Contracting, Site Payments, Medical Monitoring, Investigator Meeting; ECG delivery and central reading; other operational support (multiple duties listed)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"Safety Submissions","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Advanced Clinical LLC","duties_or_roles":"code 7 (role not specified in supplied data)","organisation_type":"Pharmaceutical company"}