ALN-APP for Cerebral Amyloid Angiopathy (cAPPricorn-1 Trial)
Palo Alto (17 mi)Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Alnylam Pharmaceuticals
Prior Safety Data
Trial Summary
What is the purpose of this trial?The purpose of the study is to evaluate the effect of ALN-APP on measures of CAA disease progression and to characterize the safety, tolerability, and pharmacodynamics (PD) of ALN-APP in adult patients with sporadic CAA (sCAA) and Dutch-type CAA (D-CAA). The study will be conducted over 2 periods: a 24-month double-blind treatment period and an optional 18-month open-label extension (OLE) period. The estimated duration of study participation, inclusive of screening, treatment, and additional safety follow-up, is up to 50 months.
What safety data exists for ALN-APP treatment for Cerebral Amyloid Angiopathy?The provided research does not directly mention ALN-APP or its safety data. However, it discusses the safety concerns related to amyloid β immunotherapy, which may be relevant. Haemorrhagic amyloid-related imaging abnormalities, such as microbleeds and cortical superficial siderosis, are noted as adverse events in amyloid β immunotherapy trials. These abnormalities are associated with severe cerebral amyloid angiopathy. The research highlights the need for further studies to confirm these findings in patients who received passive immunotherapy against amyloid β. Therefore, while specific safety data for ALN-APP is not available, related treatments have shown potential risks of haemorrhagic lesions.5791012
Do I have to stop taking my current medications?The trial information does not specify if you need to stop taking your current medications. However, if you have recently received an investigational agent or have been treated with an amyloid-targeting antibody, you may not be eligible to participate.
Is the drug ALN-APP a promising treatment for Cerebral Amyloid Angiopathy?ALN-APP is a promising drug because it targets the amyloid deposits in the brain, which are linked to Cerebral Amyloid Angiopathy. This condition often leads to symptoms like cognitive decline and seizures, and currently, there are no effective treatments. ALN-APP offers hope by potentially addressing the root cause of these symptoms.267813
What data supports the idea that ALN-APP for Cerebral Amyloid Angiopathy is an effective treatment?The available research does not provide specific data supporting the effectiveness of ALN-APP for treating Cerebral Amyloid Angiopathy. Instead, it discusses challenges in measuring treatment effectiveness and the potential impact of other treatments like aducanumab, which is used for Alzheimer's disease and may affect patients with Cerebral Amyloid Angiopathy. Without direct evidence or comparisons, it's unclear how ALN-APP performs as a treatment for this condition.134611
Eligibility Criteria
This trial is for adults aged 50 or older with probable Cerebral Amyloid Angiopathy (CAA) as per Boston Criteria, or those 30 and above with a known E693Q amyloid precursor protein gene mutation linked to Dutch-type CAA. It's not suitable for individuals who don't meet these specific conditions.Inclusion Criteria
I am 50 years old or older.
I am 30 years old or older.
I have a specific genetic mutation known as E693Q.
Treatment Details
The study tests the effects of ALN-APP on slowing down CAA disease progression compared to a placebo. Participants will be randomly assigned to receive either ALN-APP or placebo over a period of up to 50 months, including an optional extension phase.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: ALN-APPExperimental Treatment1 Intervention
Participants will be administered multiple doses of ALN-APP during the double-blind treatment period and optional open-label extension period.
Group II: Placebo/ALN-APPPlacebo Group2 Interventions
Participants will be administered multiple doses of placebo during the double-blind treatment period. Participants who continue into the optional open-label extension period will be administered multiple doses of ALN-APP.
Find a clinic near you
Research locations nearbySelect from list below to view details:
Clinical Trial SiteNew York, NY
Clinical Trial SitePlymouth, MA
Clinical Trial SiteAbington, PA
Clinical Trial SiteOttawa, Canada
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Who is running the clinical trial?
Alnylam PharmaceuticalsLead Sponsor
References
Progression of white matter lesions and hemorrhages in cerebral amyloid angiopathy. [2022]To determine the rate of progression of white matter lesions and hemorrhages in a cohort with cerebral amyloid angiopathy (CAA).
Course of cerebral amyloid angiopathy-related inflammation. [2016]A subset of patients with cerebral amyloid angiopathy (CAA) present with cognitive symptoms, seizures, headaches, T2-hyperintense MRI lesions, and neuropathologic evidence of CAA-associated vascular inflammation.
Aβ-related angiitis: comparison with CAA without inflammation and primary CNS vasculitis. [2022]To analyze the clinical findings, response to therapy, and outcomes of patients with cerebral vascular amyloid-β (Aβ) deposition with and without inflammatory vascular infiltration.
Outcome markers for clinical trials in cerebral amyloid angiopathy. [2022]Efforts are underway for early-phase trials of candidate treatments for cerebral amyloid angiopathy, an untreatable cause of haemorrhagic stroke and vascular cognitive impairment. A major barrier to these trials is the absence of consensus on measurement of treatment effectiveness. A range of potential outcome markers for cerebral amyloid angiopathy can be measured against the ideal criteria of being clinically meaningful, closely representative of biological progression, efficient for small or short trials, reliably measurable, and cost effective. In practice, outcomes tend either to have high clinical salience but low statistical efficiency, and thus more applicability for late-phase studies, or greater statistical efficiency but more limited clinical meaning. The most statistically efficient markers might be those that are potentially reversible with treatment, although their clinical significance remains unproven. Many of the candidate outcomes for cerebral amyloid angiopathy trials are probably applicable also to other small-vessel brain diseases.
APP Mutations in Cerebral Amyloid Angiopathy with or without Cortical Calcifications: Report of Three Families and a Literature Review. [2018]Specific APP mutations cause cerebral amyloid angiopathy (CAA) with or without Alzheimer's disease (AD).
Emerging concepts in sporadic cerebral amyloid angiopathy. [2022]Sporadic cerebral amyloid angiopathy is a common, well-defined small vessel disease and a largely untreatable cause of intracerebral haemorrhage and contributor to age-related cognitive decline. The term 'cerebral amyloid angiopathy' now encompasses not only a specific cerebrovascular pathological finding, but also different clinical syndromes (both acute and progressive), brain parenchymal lesions seen on neuroimaging and a set of diagnostic criteria-the Boston criteria, which have resulted in increasingly detected disease during life. Over the past few years, it has become clear that, at the pathophysiological level, cerebral amyloid angiopathy appears to be in part a protein elimination failure angiopathy and that this dysfunction is a feed-forward process, which potentially leads to worsening vascular amyloid-β accumulation, activation of vascular injury pathways and impaired vascular physiology. From a clinical standpoint, cerebral amyloid angiopathy is characterized by individual focal lesions (microbleeds, cortical superficial siderosis, microinfarcts) and large-scale alterations (white matter hyperintensities, structural connectivity, cortical thickness), both cortical and subcortical. This review provides an interdisciplinary critical outlook on various emerging and changing concepts in the field, illustrating mechanisms associated with amyloid cerebrovascular pathology and neurological dysfunction.
Cerebral amyloid angiopathy associated with inflammation: A systematic review of clinical and imaging features and outcome. [2019]Background Cerebral amyloid angiopathy associated with inflammation is an increasingly recognized condition, characterized by an inflammatory response to the vascular deposits of β-amyloid within the brain that are the hallmark of cerebral amyloid angiopathy. Two main patterns of this inflammatory response have been identified to date: one involving a perivascular inflammatory cell infiltrate (cerebral amyloid angiopathy-related inflammation); the other a transmural vasculitic process (A-beta related angiitis). Unlike cerebral amyloid angiopathy itself, which predisposes to intracerebral hemorrhage and has no known treatment, cerebral amyloid angiopathy associated with inflammation typically presents in diverse ways and diagnosis may be challenging and delayed. Aims We sought to summarize the clinical features, imaging appearances and available data on outcome and treatment responses, using information derived from a systematic review of pathologically proven cases of cerebral amyloid angiopathy associated with inflammation. Summary of review We identified 213 distinct pathologically proven cases of cerebral amyloid angiopathy-related inflammation/A-beta related angiitis, from 104 publications. The clinical presentation, imaging features, pathology, treatment, and outcomes of cerebral amyloid angiopathy associated with inflammation are described. Conclusions Cerebral amyloid angiopathy associated with inflammation is an important and increasingly recognized clinical condition, which affects the older patient population and presents most commonly with cognitive decline, seizures, and headaches. Future research is required to develop and validate diagnostic criteria and determine optimum treatment strategies.
Atypical Clinical Manifestations of Cerebral Amyloid Angiopathy. [2020]Cerebral amyloid angiopathy is a vasculopathy caused by β-amyloid deposition in cerebral arterioles and capillaries. It is closely linked to Alzheimer's disease and predisposes elderly patients to intracerebral hemorrhage, transient focal neurological episodes, and cognitive impairment. Because of a predilection for symptomatic hemorrhage, particularly in the frontal lobes, cerebral amyloid angiopathy may also cause a dysexecutive syndrome.
A practical approach to the management of cerebral amyloid angiopathy. [2022]Cerebral amyloid angiopathy is a common small vessel disease in the elderly involving vascular amyloid-β deposition. Cerebral amyloid angiopathy is one of the leading causes of intracerebral hemorrhage and a significant contributor to age-related cognitive decline. The awareness of a diagnosis of cerebral amyloid angiopathy is important in clinical practice as it impacts decisions to use lifelong anticoagulation or nonpharmacological alternatives to anticoagulation such as left atrial appendage closure in patients who have concurrent atrial fibrillation, another common condition in older adults. This review summarizes the latest literature regarding the management of patients with sporadic cerebral amyloid angiopathy, including diagnostic criteria, imaging biomarkers for cerebral amyloid angiopathy severity, and management strategies to decrease intracerebral hemorrhage risk. In a minority of patients, the presence of cerebral amyloid angiopathy triggers an autoimmune inflammatory reaction, referred to as cerebral amyloid angiopathy-related inflammation, which is often responsive to immunosuppressive treatment in the acute phase. Diagnosis and management of cerebral amyloid angiopathy-related inflammation will be presented separately. While there are currently no effective therapeutics available to cure or halt the progression of cerebral amyloid angiopathy, we discuss emerging avenues for potential future interventions.
[Intracerebral hemorrhage under platelet inhibition and oral anticoagulation in patients with cerebral amyloid angiopathy]. [2022]Oral anticoagulation in patients with cerebral amyloid angiopathy is a therapeutic challenge. The association of cerebral amyloid angiopathy with intracerebral hemorrhage, a high mortality of intracerebral hemorrhage especially under oral anticoagulation and the high risk of recurrent bleeding require a multidisciplinary approach and a thorough risk-benefit analysis. Vitamin K antagonists increase the risk of intracerebral bleeding and the accompanying mortality by 60% and should be avoided if possible or reserved for special clinical situations (e.g. mechanical aortic valve replacement). Treatment with novel oral anticoagulants and antiplatelet drugs also increases the risk of cerebral bleeding and therefore needs a thorough risk-benefit evaluation. An interventional left atrial appendage closure is a promising therapeutic option especially in patients with an absolute arrythmia with atrial fibrillation. Furthermore, other clinical implications in patients with cerebral amyloid angiopathy are the subject of this review of the literature, such as special characteristics after acute ischemic stroke and the necessary secondary prophylaxis, with previous intracerebral hemorrhage and in patients with cognitive deficits.
Vessels Sing Their ARIAs: The Role of Vascular Amyloid in the Age of Aducanumab. [2022]We review the implications of the recently approved aducanumab amyloid-β immunotherapy for treating Alzheimer disease with comorbid cerebral amyloid angiopathy. In clinical trials, amyloid-β immunotherapy has been associated with a high rate of amyloid-related imaging abnormalities, potentially driven by coexisting cerebral amyloid angiopathy. Therefore, immunotherapy's efficacy in patients may be modified by coexisting cerebrovascular pathology. We discuss the contributions of cerebral amyloid angiopathy on the development of amyloid-related imaging abnormalities and propose strategies to identify cerebral amyloid angiopathy in patients considered for immunotherapy.
Histopathological correlates of haemorrhagic lesions on ex vivo magnetic resonance imaging in immunized Alzheimer's disease cases. [2023]Haemorrhagic amyloid-related imaging abnormalities on MRI are frequently observed adverse events in the context of amyloid β immunotherapy trials in patients with Alzheimer's disease. The underlying histopathology and pathophysiological mechanisms of haemorrhagic amyloid-related imaging abnormalities remain largely unknown, although coexisting cerebral amyloid angiopathy may play a key role. Here, we used ex vivo MRI in cases that underwent amyloid β immunotherapy during life to screen for haemorrhagic lesions and assess underlying tissue and vascular alterations. We hypothesized that these lesions would be associated with severe cerebral amyloid angiopathy. Ten cases were selected from the long-term follow-up study of patients who enrolled in the first clinical trial of active amyloid β immunization with AN1792 for Alzheimer's disease. Eleven matched non-immunized Alzheimer's disease cases from an independent brain brank were used as 'controls'. Formalin-fixed occipital brain slices were imaged at 7 T MRI to screen for haemorrhagic lesions (i.e. microbleeds and cortical superficial siderosis). Samples with and without haemorrhagic lesions were cut and stained. Artificial intelligence-assisted quantification of amyloid β plaque area, cortical and leptomeningeal cerebral amyloid angiopathy area, the density of iron and calcium positive cells and reactive astrocytes and activated microglia was performed. On ex vivo MRI, cortical superficial siderosis was observed in 5/10 immunized Alzheimer's disease cases compared with 1/11 control Alzheimer's disease cases (κ = 0.5). On histopathology, these areas revealed iron and calcium positive deposits in the cortex. Within the immunized Alzheimer's disease group, areas with siderosis on MRI revealed greater leptomeningeal cerebral amyloid angiopathy and concentric splitting of the vessel walls compared with areas without siderosis. Moreover, greater density of iron-positive cells in the cortex was associated with lower amyloid β plaque area and a trend towards increased post-vaccination antibody titres. This work highlights the use of ex vivo MRI to investigate the neuropathological correlates of haemorrhagic lesions observed in the context of amyloid β immunotherapy. These findings suggest a possible role for cerebral amyloid angiopathy in the formation of haemorrhagic amyloid-related imaging abnormalities, awaiting confirmation in future studies that include brain tissue of patients who received passive immunotherapy against amyloid β with available in vivo MRI during life.
Inflammatory Cerebral Amyloid Angiopathy: A Broad Clinical Spectrum. [2023]Cerebral amyloid angiopathy (CAA) is a common central nervous system (CNS) vasculopathy, which in some cases is associated with subacute encephalopathy, seizures, headaches, or strokes due to vascular inflammation directed against vascular amyloid accumulation. The pathological subtypes of inflammatory CAA include CAA-related inflammation (CAAri) with mostly perivascular lymphocytic infiltrates, or amyloid-beta (Aβ)-related angiitis (ABRA) with transmural granulomatous inflammation. CAAri and ABRA probably represent part of the spectrum of CNS vasculopathies, intermediate between CAA and primary CNS vasculitis, and they are closely related to Aβ-related imaging abnormalities and other manifestations of an inflammatory response directed against Aβ in the leptomeninges and cerebral parenchyma. As treatment strategies in Alzheimer's disease shift toward potentially effective antiamyloid immunotherapy, the incidence rate of inflammatory CAA (which is probably an underrecognized condition) is likely to increase. Its clinical features are varied and include subacute encephalopathy, behavioral symptoms, headaches, seizures, and focal neurological deficits, which necessitate a high degree of suspicion for this disorder that often responds to treatment. The recent definition of the typical clinical and radiological syndrome has increased its recognition and may eliminate the need for invasive histological sampling in at least some affected patients. Here we review the pathophysiology, clinical spectrum, and approach to diagnosis, and discuss illustrative cases that highlight the wide range of clinical presentations.