ALN-APP-002: A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacodynamics of Intrathecally Administered ALN-APP in Patients with Cerebral Amyloid Angiopathy (CAA)
Overview
HELP CONTRIBUTE TO CAA RESEARCH
Introducing the cAPPricorn-1 clinical trial for people living with cerebral amyloid angiopathy (CAA)
cAPPricorn-1 is researching an investigational medication called mivelsiran to see if it could be safe and effective.
Participating in this trial may be an opportunity to contribute to CAA research.
WHO CAN JOIN?
Participants with sporadic CAA:
• 50 years of age or older
• Have received a diagnosis of CAA from their doctor
Participants with Dutch-type CAA:
• 30 years of age or older
• Have a known gene mutation for Dutch-type CAA
Additional criteria will be assessed by the study team to determine your eligibility.
For more information, reach out to the study team.
Planned end date
31 Dec 2029 17:20Conditions
Neurological DisordersInclusion Criteria
Inclusion Criteria for sCAA Patients:
1. Male or female aged ≥ 50 years at the time of informed consent Patient and Disease Characteristics.
2. 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 haemorrhage, transient focal neurological episodes or cognitive impairment or dementia
b. At least 2 strictly lobar haemorrhagic lesions on MRI, in any combination (ICH, CMB, or foci of cSS or cSAH), or
c. At least 1 lobar haemorrhagic lesion plus 1 white matter feature (severe PVS in the CSO-PVS or WMH in a multispot pattern), and
d. Absence of any deep haemorrhagic lesions (ie, intracerebral haemorrhage or microbleeds in basal ganglia, thalamus, or brainstem) on MRI, and
e. Absence of other cause of the haemorrhagic lesions. Other causes of haemorrhagic lesion: antecedent head trauma, haemorrhagic transformation of an ischaemic stroke, arteriovenous malformation, haemorrhagic tumour, CNS vasculitis. In addition, other causes of cSS and acute cSAH should also be excluded.
3. A minimum of 4 lobar CMBs confirmed by MRI; or multifocal cSS (as defined in [Charidimou 2017] with 2 or more lobar CMBs confirmed by MRI; or multiple lobar ICH with 2 or more lobar CMBs confirmed by MRI.
Inclusion Criteria for D-CAA Patients:
4. Male or female aged ≥ 30 years at the time of informed consent.
Patient and Disease Characteristics
5. Individuals with a known E693Q APP gene mutation for Dutch-type CAA.
Inclusion Criteria for Both sCAA and D-CAA Patients
Patients are eligible to be included in the study if all the following criteria apply during the screening period:
Patient and Disease Characteristics
6. 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.
7. Able and willing to meet all study requirements in the opinion of the Investigator, including travel to study centre, 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
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 ≤ 34 kg/m2 at Screening visit
d. Able to tolerate LP.
8. Evaluable brain MRI imaging at screening Informed Consent.
9. Patient is able to understand, is willing and able to comply with the study requirements and to provide written informed consent.
Exclusion Criteria
Exclusion Criteria for Both sCAA and D-CAA Patients:
Disease-specific Conditions
1. 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.
2. History of previous clinical ICH with onset less than 90 days prior to anticipated randomization in the study.
Laboratory Assessments
3. 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 ≥ 2.0 x ULN.
c. International normalized ratio > 1.4
d. Platelet count < 100,000/microliter (μL)
e. Estimated glomerular filtration (eGFR) of < 30mL/min/1.73m 2 (calculation will be based on the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] creatinine formula (2021) (refer to Section 10.1).
Prior/Concomitant Therapy
4. 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.
5. 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, acetylcholinesterase inhibitors, anticonvulsants, mood stabilizers, and memantine.
6. 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.
7. Treatment with amyloid-targeting antibody prior to Screening.
8. Treatment with another IT administered medication within the last 1 year prior to Screening.
9. Prior treatment with a CNS-targeted siRNA or antisense oligonucleotide (ASO).
10. Any history of gene therapy or cell transplantation or experimental brain surgery.
11. Presence of an implanted shunt for the drainage of CSF or an implanted CNS catheter.
Medical Conditions
12. Clinically significant electrocardiogram (ECG) abnormalities at Screening, in the opinion of the Investigator, or a Fridericia-corrected QT interval (QTcF) > 450 msec for males or > 470 msec for females at Screening.
13. Has systolic blood pressure > 150 mmHg and/or a diastolic blood pressure > 90 mmHg after 10 minutes of rest at screening.
14. 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.
15. 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 behaviours 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.
16. History of bleeding diathesis.
17. A medical history of brain or spinal disease that would interfere with the LP process, CSF circulation or safety assessment, 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.
18. History of uncontrolled seizures within the last 6 months prior to screening.
19. Hospitalization for any major medical or surgical procedure involving general anaesthesia within 12 weeks of Screening.
20. 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.
Contraception, Pregnancy, and Breastfeeding
21. Is not willing to comply with the contraceptive requirements during the study period, as described in the protocol.
22. Female patient is pregnant, planning a pregnancy, or breast-feeding.
Alcohol Use
23. History of alcohol abuse, within the last 12 months before Screening, in the opinion of the Investigator.