Evaluation of Intrathecal ALN-APP Efficacy and Safety in Cerebral Amyloid Angiopathy: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-510137-29-01
- Protocol
- ALN-APP-002
- Sponsor
- Alnylam Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the effect of **ALN-APP** on the incidence of new lobar Cerebral Microbleeds (CMBs) in patients with Cerebral Amyloid Angiopathy (CAA). This is clinically relevant as CMBs are a significant marker of disease progression in CAA, a condition characterized by amyloid protein deposition in cerebral blood vessels, leading to increased risk of hemorrhagic events.
Secondary objectives include: - Evaluating the effect of ALN-APP on the clinical severity of new cerebral hemorrhagic lesions. - Assessing the effect of ALN-APP on changes in vascular reactivity. - Determining the effect of ALN-APP on the incidence of new cerebral hemorrhagic lesions and white matter hypersensitivity. - Evaluating the effect of ALN-APP on the progression of small vessel abnormalities. - Assessing the pharmacodynamic (PD) effect of ALN-APP.
Participants
The clinical trial involves a total of **150 participants** diagnosed with **Cerebral Amyloid Angiopathy (CAA)**, a neurological condition characterized by the accumulation of amyloid proteins in the cerebral blood vessels. The study population includes both male and female subjects, with an age range starting from 30 years for those with Dutch-type CAA and 50 years for those with sporadic CAA. Participants were selected based on specific inclusion criteria, including a confirmed diagnosis of CAA according to the Boston Criteria Version 2.0, and the presence of certain MRI findings. The trial does not involve a vulnerable population. Participants are required to have a **Body Mass Index (BMI)** between 18 and 34 kg/m² and must be able to undergo MRI scans. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The trial aims to evaluate the effect of ALN-APP on the incidence of new lobar cerebral microbleeds (CMBs) in this population.
Plans and Procedures
The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, safety, tolerability, and pharmacodynamics of intrathecally administered ALN-APP in patients with **Cerebral Amyloid Angiopathy (CAA)**. The primary objective is to assess the effect of ALN-APP on the incidence of new lobar cerebral microbleeds (CMBs) over an 18-month period. The trial will involve the administration of Mivelsiran, a solution for injection, and a placebo, with the active substance being a synthetic small interfering RNA. The trial is expected to conclude by February 25, 2030, with recruitment starting on March 31, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical presentation, and MRI findings. Follow-up visits will be scheduled to monitor the participants' health, assess the primary and secondary endpoints, and ensure compliance with the study protocol. The end-of-study visit will mark the completion of the trial for each participant, where final assessments will be conducted. The expected length of participant involvement is approximately 18 months, with conditions for early termination including loss of mental capacity to provide informed consent, as determined by the investigator, or if local regulations do not permit continued participation by a legally authorized representative.
Key elements of the research methodology include the use of MRI to detect new lobar CMBs and other hemorrhagic events, as well as the evaluation of changes in BOLD-fMRI parameters and CAA SVD scores. The study will also measure changes in sAPPα and sAPPβ concentrations in cerebrospinal fluid. Participants must meet specific inclusion criteria, such as having a probable diagnosis of CAA per the Boston Criteria Version 2.0, and must be able to comply with study requirements, including travel to the study center and undergoing MRI scans. The trial is not classified as a low-intervention study, and it involves a drug not currently authorized for the population involved in the trial.
Treatment
The clinical trial involves the administration of **Mivelsiran**, an investigational medication formulated as a **solution for injection**. Mivelsiran is designed for **intrathecal use** and is administered to patients with Cerebral Amyloid Angiopathy (CAA). The active substance in Mivelsiran is ALN-961583, a synthetic small interfering RNA (siRNA) of nucleic acid origin. The maximum daily dose of Mivelsiran is 75 mg, with a total maximum dose of 225 mg over a treatment period of 24 weeks. The dosing schedule and administration are carefully monitored to ensure participant compliance and safety throughout the study.
In addition to Mivelsiran, a **placebo** is used as a comparator treatment in this randomized, double-blind, placebo-controlled study. The placebo is administered in a manner consistent with the experimental treatment to maintain the study's blinding and integrity. The placebo does not contain any active pharmaceutical ingredients and serves as a control to evaluate the efficacy and safety of Mivelsiran. Compliance with the administration of the placebo is also monitored to ensure the reliability of the study results.
Efficacy
Efficacy in this clinical trial will be assessed primarily by evaluating the **annualized rate of new lobar Cerebral Microbleeds (CMBs)** as detected by MRI over an 18-month period in patients with Cerebral Amyloid Angiopathy (CAA). Secondary efficacy endpoints include changes from baseline over time in BOLD slope, amplitude, and time-to-peak detected by visual-evoked fMRI in a subset of patients. Additional secondary endpoints involve the total number of new lobar CMBs, new intracerebral hemorrhages (ICH), time to first ICH recurrence, new or extended cortical superficial siderosis (cSS) or new cortical subarachnoid hemorrhage (cSAH), and the proportion of patients with hemorrhagic disease progression, all detected by MRI. Furthermore, changes from baseline in white matter hyperintensity (WMH) volume, total CAA small vessel disease (SVD) score, and concentrations of sAPPα and sAPPβ in cerebrospinal fluid (CSF) will be measured.
These efficacy parameters will be collected and analyzed using MRI and fMRI at specified timepoints throughout the study. The trial is designed to ensure rigorous assessment of the therapeutic impact of ALN-APP, administered intrathecally, on the progression of CAA-related symptoms and biomarkers. The use of validated imaging techniques and biomarker analysis will provide comprehensive data on the drug's efficacy in reducing the incidence and progression of cerebral microbleeds and other related pathologies in the study population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Inclusion Criteria for Sporadic Cerebral Amyloid Angiopathy (sCAA) patients. Male or female aged ≥50 years at the time of informed consent
- 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. Presentation with spontaneous intracerebral hemorrhage, convexity subarachnoid hemorrhage, transient focal neurological episodes, or cognitive impairment or dementia b. At least 2 strictly lobar hemorrhagic lesions on MRI, in any combination (ICH, CMB, or foci of cSS or cSAH), or c. At least 1 lobar hemorrhagic lesion plus 1 white matter feature (severe PVS in the CSO PVS or WMH in a multispot pattern), and d. Absence of any spontaneous deep hemorrhagic lesions (ie, intracerebral hemorrhage or microbleeds in basal ganglia, thalamus, or brainstem) on MRI, and e. Absence 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.
- 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.
- Inclusion Criteria for Dutch-type Cerebral Amyloid Angiopathy (D-CAA) patients. Male or female aged ≥30 years at the time of informed consent
- Individuals with a known E693Q APP gene mutation for Dutch-type CAA
- 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.
- 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 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. Able 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. Body Mass Index (BMI) ≥18 and ≤40 kg/m2 at Screening visit d. Able to tolerate LP
- Evaluable brain MRI imaging at screening
- 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
- 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
- History of previous clinical ICH with onset less than 90 days prior to anticipated randomization in the study
- 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.
- Has any of the following laboratory parameter assessments at screening: a. Alanine aminotransferase or aspartate aminotransferase ≥ 3.0 x upper limit of normal (ULN) b. Total 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. International normalized ratio >1.4 d. Platelet count <100,000/microliter (μL) e. Estimated 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).
- 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.
- 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.
- 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.
- Treatment with amyloid-targeting antibody prior to Screening
- Treatment with another IT administered medication within the last 1 year prior to Screening
- Prior treatment with a CNS-targeted siRNA or antisense oligonucleotide (ASO)
- Any history of gene therapy or cell transplantation or experimental brain surgery
- Presence of an implanted shunt for the drainage of Cerebrospinal fluid (CSF) or an implanted CNS catheter
- 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).
- Has systolic blood pressure >150 mmHg and/or a diastolic blood pressure >90 mmHg after 10 minutes of rest at screening.
- 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
- 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.
- History of bleeding diathesis.
- 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.
- History of uncontrolled seizures within the last 6 months prior to screening.
- Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening.
- 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.
- Is not willing to comply with the contraceptive requirements during the study period, as described in Section 5.9.1 of the protocol.
- Female patient is pregnant, planning a pregnancy, or breast-feeding.
- History of alcohol abuse, within the last 12 months before Screening, in the opinion of the Investigator.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 The Netherlands | Not Recruiting | 31 Mar 2025 | — |
| Netherlands | — | — | 50 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Mivelsiran | Test | SOLUTION FOR INJECTION | INTRATHECAL USE | 0 | 24 | PRD10911714 |
Placebo | Placebo | N/A | — | — | — | N/A |