A double-blind study to evaluate the effectiveness and safety of CAEL-101 in patients with AL amyloidosis.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alexion Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

Trial duration

13 Feb 2021 → ongoing

Decision date (initial)

2024-06-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Alexion Pharmaceuticals, Inc.

External identifiers

EU CT number

2022-503072-84-00

EudraCT number

2020-000713-32

ClinicalTrials.gov

NCT04512235

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy

The primary objectives are:
- To determine if CAEL-101 and treatment for plasma cell dyscrasia (PCD) improves overall survival and/or decreases the frequency of cardiovascular hospitalizations in Mayo stage IIIa AL amyloidosis
patients who are treatment naïve compared to treatment for PCD and placebo;
- To evaluate the safety and tolerability of CAEL-101 in combination with treatment for PCD and placebo

Secondary objectives 7

1. To determine if CAEL-101 and treatment for PCD improves survival post- initiation of study treatment in Mayo stage IIIa amyloid light chain (AL) amyloidosis patients who are treatment naïve compared to treatment for PCD and placebo
2. To determine if CAEL-101 and treatment for PCD decreases cardiovascular-related hospitalizations (CVH) post-initiation of study treatment in Mayo stage IIIa amyloid light chain (AL) amyloidosis patients who are treatment naïve compared to treatment for PCD and placebo
3. To assess improvement in cardiomyopathy as measured by NTproBNP
4. To assess quality of life (QoL) as measured by the Kansas City Cardiomyopathy Questionnaire Overall Score (KCCQ-OS)
5. To assess cardiac improvement as measured by global longitudinal strain (GLS%).
6. To assess functional improvement as measured by the distance walked in the six-minute walk test (6MWT).
7. To assess quality of life as measured by the Short Form 36 Health Survey Physical Component Score (SF-36v2® PCS).

Conditions and MedDRA coding

stage IIIa cardiac AL amyloidosis

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

Yes

IPD plan description

Each patient will be assigned a unique identifier after signing the Informed Consent Form (ICF). Patient numbers will not be reassigned. Any patient records or datasets transferred to the Sponsor must contain only the unique identifier and must not include patient names or any information which would make the patient identifiable. Patients will be informed that their personal study-related data will be used by the Sponsor in accordance with local data protection laws and that their medical records may be examined by representatives of the Sponsor, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) members and by inspectors from regulatory authorities. Study monitors will inspect all documents and records that are required to be maintained by the Investigator for this study.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. AL amyloidosis stage IIIa based on the European Modification of the 2004 Standard Mayo Clinic Staging who also have NT-proBNP ≥ 650 ng/L at the time of Screening
2. Measurable hematologic disease at Screening as defined by at least one of the following: a. Involved/uninvolved free light chain difference (dFLC) > 4 mg/dL OR b. Involved free light chain (iFLC) > 4 mg/dL with abnormal Kappa/Lambda ratio OR c. Serum protein electrophoresis (SPEP) m-spike > 0.5 g/dL
3. Histopathological diagnosis of amyloidosis based on polarizing light microscopy of green bi-refringent material in Congo red stained tissue specimens AND confirmation of AL derived amyloid deposits by at least one of the following: a. Immunohistochemistry/Immunofluorescence OR b. Mass spectrometry OR c. Characteristic electron microscopy appearance/Immunoelectron microscopy
4. Cardiac involvement as defined by: a. Documented clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure AND b. At least one of the following: I. Endomyocardial biopsy demonstrating AL cardiac amyloidosis OR ii. Echocardiogram demonstrating a mean left ventricular wall thickness (calculated as [IVSd+LPWd]/2) of > 12 mm at diastole in the absence of other causes (e.g., severe hypertension, aortic stenosis), which would adequately explain the degree of wall thickening OR iii. Cardiac magnetic resonance imaging (MRI) with gadolinium contrast agent diagnostic of cardiac amyloidosis
5. Planned first-line treatment for plasma cell dyscrasia is cyclophosphamide-bortezomib-dexamethasone (CyBorD)-based regimen administered as SoC.
6. Women of childbearing potential must have a negative pregnancy test during Screening and must agree to use highly effective contraception from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of her PCD therapy, whichever is longer
7. Men must be surgically sterile or must agree to use highly effective contraception and refrain from donating sperm from Screening to at least 5 months following the last study drug administration or 12 months following the last dose of their PCD therapy, whichever is longer

Exclusion criteria 4

1. Have any other form of amyloidosis other than AL amyloidosis
2. Received prior therapy for AL amyloidosis or multiple myeloma. A maximum exposure of 2 weeks of a CyBorD-based PCD treatment after Screening laboratory samples are obtained and prior to randomization is allowed.
3. Has POEMS syndrome OR multiple myeloma defined as clonal bone marrow plasma cells > 10% from a bone marrow biopsy (performed ≤ 3 months prior to signing the ICF or during Screening) OR biopsy-proven (performed ≤ 3 months prior to signing the ICF or during Screening) bony or extramedullary plasmacytoma AND any one or more of the following CRAB features: a. Evidence of end organ damage that can be attributed to the underlying plasma cell proliferative disorder, (eg, multiple myeloma and POEMS syndrome), specifically: i. Hypercalcemia: serum calcium > 0.25 mmol/L (> 1 mg/dL) higher than the ULN or > 2.75 mmol/L (> 11 mg/dL) OR ii. Renal insufficiency: creatinine clearance < 40 mL per minute or serum creatinine > 177 μmol/L (> 2 mg/dL) OR iii. Anemia: hemoglobin value of > 20 g/L below the lowest limit of normal, or a hemoglobin value < 100 g/L OR iv. Bone lesions: one or more osteolytic lesion on imaging tests (performed ≤ 3 months prior to signing the ICF or during Screening): skeletal radiography, CT, or PET/CT, or MRI. If bone marrow has < 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with minimal marrow involvement OR b. Any one of the following biomarkers of malignancy: i. 60% or greater clonal plasma cells on bone marrow examination OR ii. More than one focal lesion on MRI that is at least 5mm or greater in size
4. Have supine systolic blood pressure < 90 mmHg or symptomatic orthostatic hypotension, defined as a decrease in systolic blood pressure upon standing of > 30 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the absence of volume depletion

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. A hierarchical combination of time to all-cause Mortality (ACM) and the frequency of cardiovascular hospitalizations (CVH). Incidence of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs). Changes from baseline in vital signs, weight, clinical laboratory tests, and 12lead electrocardiograms (ECGs).

Secondary endpoints 7

1. Time to ACM in Primary Evaluation Treatment Period (PETP)
2. Frequency of CVH in PETP
3. Changes from baseline to Week 50 in the KCCQ-OS.
4. Change from baseline to Week 50 in NTproBNP
5. Changes from baseline to Week 50 in GLS%.
6. Changes from baseline to Week 50 in the 6MWT
7. Change from baseline to Week 50 in the SF-36v2 PCS

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alexion Pharmaceuticals Inc.

Sponsor organisation

Alexion Pharmaceuticals Inc.

Address

121 Seaport Boulevard

City

Boston

Postcode

02210-2050

Country

United States

Scientific contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Public contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Third parties 11

Locations

8 EU/EEA countries · 37 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 81 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications