REscue of Nephrons With ALe.F02 (RENAL-F02)

Study Overview
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Brief Summary
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The goal of this clinical trial is to learn if a new drug that might help protect and preserve kidney function in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). AAV is a type of autoimmune disease where the body's own immune system attacks itself, and in the case of AAV the body attacks its own small blood vessels. There are many small blood vessels in the kidneys meaning the kidneys are commonly affected in AAV. The main questions it aims to answer are: Is the new drug well tolerated and safe? Can the new drug protect and preserve kidney functions when is added to standard therapy? Researchers will compare the following groups to see how the new drug is tolerated and what effect to preserve kidney tissue has: Group A: Standard treatment + ALE.F02 lower dose infusions Group B: Standard treatment + ALE.F02 higher dose infusions Group C: Standard treatment + placebo infusions (inactive substance) The Treatment period will consist of 24 weeks beginning on Day 1, during which time participants will receive 13 infusions of the study medicine, along with standard therapy for kidney inflammation due to AAV. During the treatment period, participants will have the following assessments: A brief physical examination focusing on their skin any pre-existing medical conditions that you have. Collection of blood and urine samples for routine safety tests and to assess renal function. Collection of blood samples: To measure the amount of study medicine in their blood. This is called pharmacokinetics (PK) and it is tested to see how study medicine enters, moves through, and exits the body. To test for antidrug antibodies (ADA). To check if their body create antibodies against the study medicine, as this could reduce its effect. To measure biomarkers. Biomarkers are specific compounds in the body (can be protein, hormones, or genetic molecules) that indicate normal or abnormal processes taking place in your body and may be a sign of an underlying condition or disease (for example glucose levels are used as biomarker in managing diabetes). They are used to see how well the body responds to a treatment for a disease or condition. Collection of urine to measure urine markers of vasculitis/inflammation called biomarkers. Urine pregnancy test. A urine pregnancy test is a quick medical test that can tell if a woman is pregnant or not by checking for a hormone which is produced during pregnancy, usually in the urine. Chest High Resolution Computed Tomography (HRCT) scan to check whether they have vasculitis affecting their lungs. A CT scan uses special x-ray equipment to take detailed pictures of body tissues and organs to diagnose and monitor conditions in various parts of the body. For the CT scan, they will need to lie still on a table. At Week 24 a second lung CT scan will be performed for participants whose initial scan showed lung vasculitis to see whether your lung vasculitis is getting better or ongoing/worse.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study of Intravenously Administered ALE.F02 to Evaluate the Safety, Tolerability, Pharmacokinetics, and Renal Sparing in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Rapidly Progressive Glomerulonephritis

Conditions
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Glomerulonephritis Rapidly Progressive

Intervention / Treatment
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* Biological: ALE.F02
* Drug: Rituximab
* Drug: GlucoCorticoid
* Drug: Cyclophosphamid
* Drug: Placebo
* Drug: Immunosuppressive Agents


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are male or female patients ≥18 years of age of any race or ethnicity with a score of <7 on the Clinical Frailty Scale in the 3 months preceding the onset of RPGN attributed to AAV; Note: The PI should assess the Clinical Frailty Scale based on medical history and interview with the patient Must be willing and able to comply with the study requirements and give informed consent for participation in the study; Must be willing to have a renal biopsy procedure performed no later than prior to study drug administration at the Week 6 Visit; Have been newly diagnosed with RPGN within 30 days prior to the initiation of study drug treatment, as demonstrated by the following: - Evidence of loss of renal function with an eGFR of ≤50 mL/min/1.73 m2 and ≥15 mL/min/1.73 m2; and - History of proteinuria of any degree AND/OR hematuria that is temporally associated with the presenting episode of illness and supports the diagnosis of RPGN. Note: The hematuria may be represented by the presence of eumorphic or dysmorphic red blood cells (RBCs) and/or RBC casts. Are suspected of having RPGN attributed to AAV at Screening based on clinical laboratory diagnostic criteria, including a positive test for an ANCA, ie, anti-myeloperoxidase (MPO) or anti-proteinase 3 (PR3); Female patients must not be pregnant or lactating at Screening and 1 of the following conditions must apply: - Is a female of childbearing potential and agrees to use a highly effective method of birth control during their participation in the study and for at least 5 half-lives or a minimum of 30 days after the last dose of study drug, or as recommended in the Summary of Product Characteristics (SmPC) of any authorized AxMP given as part of background standard of care (SOC) therapy, whichever is longer; or - Is a female of nonchildbearing potential. Female patients must agree not to donate ova for 6 months after the last dose of study drug or as recommended in the SmPC of any authorized AxMP given as part of background SOC therapy, whichever is longer; Male patients must agree to use contraception, in the form of either sexual abstinence or a condom, during their participation in the study and for 90 days after the last dose of study drug or as recommended in the SmPC of any authorized auxiliary medicinal product (AxMP) given as part of background SOC therapy, whichever is longer; and Male patients must agree to abstain from sperm donation during their participation in the study and for 90 days after the last dose of study drug or as recommended in the SmPC of any authorized AxMP given as part of background SOC therapy, whichever is longer. Exclusion Criteria: Have a history of previous RPGN that resolved or ameliorated (ie, the patient had a documented case of RPGN and has suffered a relapse); Have a positive serology test for anti-glomerular basement membrane antibodies; Have evidence of active or latent tuberculosis (TB) determined by a positive (not indeterminate) QuantiFERON®-TB Gold test (or equivalent). Radiological criteria, including chest X-ray or computed tomography scan, must not be used to exclude TB; Have a chronic infection that could be exacerbated by RPGN or SOC therapy for RPGN; Have active hepatitis B, hepatitis C, or HIV infection; Have taken any prohibited medications, including >3000 mg of IV methylprednisolone equipotent glucocorticoids, or >40 mg/day oral glucocorticoids (prednisone equivalent) for >14 days, as part of acute RPGN care within 14 days prior to Screening; Have been treated or planned to be treated with protocol prohibited medications. Have poor venous access; Have participated in an investigational drug or device study and received investigational therapy <30 days or 5 half lives, whichever is the greater, prior to the first dose of study drug. For biological investigational drugs, the exclusionary period may not be <90 days prior to the first dose of study drug; Have a history of psoriasis, AD, excessively dry skin or recurrent conjunctivitis that has required treatment prescribed by a physician, scleroderma, vitiligo, or any other active autoimmune dermatological disorder, with the exception of dermatological disorders or skin rashes that are attributable to, or known to be associated with, the underlying diagnosis of AAV, which shall not be exclusionary; Have a diagnosis of systemic lupus erythematosus-AAV overlap syndrome; Have a diagnosis of eosinophilic granulomatosis with polyangiitis; Have evidence of uncontrolled respiratory, cardiac, hepatic, endocrine, central nervous system, or renal disease, unrelated to RPGN or AAV, that the PI believes cannot be readily brought under control, or any other medical condition that in the opinion of the PI renders the patient unsuitable for enrollment and could prevent the successful completion of the study; Have received a live vaccine within 30 days prior to Screening; Have received any vaccine within 7 days of the first dose of study drug other than against influenza or pneumococcal infection; Are employed by the PI or the study site, have direct involvement in the proposed study or other studies under the direction of that PI, or are a family member of the PI or study site personnel; Have not recovered from AEs and/or complications from major surgery prior to the first dose of study drug; Note: The PI should consult with the Medical Monitor and Sponsor to determine if ongoing, significant complications from major surgery are exclusionary. Have active or known history of alcohol or substance abuse within 1 year prior to Day 1/Randomization or have a positive urine drug screen for drugs of abuse at Screening; Have been diagnosed within the preceding 5 years with a malignant neoplastic disease, other than locally invasive cutaneous squamous or basal cell carcinoma; Have alveolar haemorrhage with hypoxia defined by an oxygen saturation <85% or that requires the use of invasive or noninvasive ventilatory support; Have undergone dialysis within 14 days prior to Screening; Have undergone therapeutic plasma exchange within 14 days prior to the first dose of study drug; or Have known hypersensitivity to the study drug or any of the excipients used in the formulation of the study drug.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard treatment + ALE.F02 lower dose infusions<br>Standard treatment + ALE.F02 lower dose infusions | Biological: ALE.F02<br>* ALE.F02 is an anti-Claudin-1 (CLDN1) monoclonal antibody (mAb) to selectively target the non-tight junctions (TJ), exposed form of CLDN1. CLDN1 is an integral component of the TJs between cells.<br>Drug: Rituximab<br>* Rituximab is a monoclonal antibody that targets cluster of differentiation antigen 20 (CD20), an antigen expressed on the surface of pre-B and mature B-lymphocytes<br>Drug: GlucoCorticoid<br>* Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones that bind to the glucocorticoid receptor. Glucocorticoid effects may be broadly classified into two major categories: immunological and metabolic.<br>Drug: Cyclophosphamid<br>* Cyclophosphamid is a medication used as chemotherapy and to suppress the immune system<br>Drug: Immunosuppressive Agents<br>* Immunosuppressants are drugs that prevent your immune system from attacking healthy cells and tissues by mistake.<br>|
| Experimental: Standard treatment + ALE.F02 higher dose infusions<br>Standard treatment + ALE.F02 higher dose infusions | Biological: ALE.F02<br>* ALE.F02 is an anti-Claudin-1 (CLDN1) monoclonal antibody (mAb) to selectively target the non-tight junctions (TJ), exposed form of CLDN1. CLDN1 is an integral component of the TJs between cells.<br>Drug: Rituximab<br>* Rituximab is a monoclonal antibody that targets cluster of differentiation antigen 20 (CD20), an antigen expressed on the surface of pre-B and mature B-lymphocytes<br>Drug: GlucoCorticoid<br>* Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones that bind to the glucocorticoid receptor. Glucocorticoid effects may be broadly classified into two major categories: immunological and metabolic.<br>Drug: Cyclophosphamid<br>* Cyclophosphamid is a medication used as chemotherapy and to suppress the immune system<br>Drug: Immunosuppressive Agents<br>* Immunosuppressants are drugs that prevent your immune system from attacking healthy cells and tissues by mistake.<br>|
| Placebo Comparator: Standard treatment + placebo infusions (inactive substance)<br>Standard treatment + placebo infusions (inactive substance) | Drug: Rituximab<br>* Rituximab is a monoclonal antibody that targets cluster of differentiation antigen 20 (CD20), an antigen expressed on the surface of pre-B and mature B-lymphocytes<br>Drug: GlucoCorticoid<br>* Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones that bind to the glucocorticoid receptor. Glucocorticoid effects may be broadly classified into two major categories: immunological and metabolic.<br>Drug: Cyclophosphamid<br>* Cyclophosphamid is a medication used as chemotherapy and to suppress the immune system<br>Drug: Placebo<br>* Drug product that will contain no active ingredient<br>Drug: Immunosuppressive Agents<br>* Immunosuppressants are drugs that prevent your immune system from attacking healthy cells and tissues by mistake.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint for this study is the safety and tolerability of ALE.F02 when administered as a continuous IV infusion in patients with rapidly progressive glomerulonephritis (RPGN) attributed to AAV. | Safety endpoints are the following: All adverse events (AEs); All serious adverse events (SAEs); Hematology and clinical chemistry analyte assessments; Serum lipids; Antidrug antibodies (ADAs); and ECGs | through study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The key secondary endpoint for this study is the change in mean estimated glomerular filtration rate (eGFR) from baseline to Week 24/End of Treatment (EOT) for recipients of ALE.F02 compared to placebo. |  | from baseline to Week 24/EOT | 
| Change in mean urine protein to creatinine ratio (UPCR) area under the concentration time curve (AUC) from baseline to Week 24/EOT for recipients of ALE.F02 compared to placebo; |  | from baseline to Week 24/EOT | 
| Change in mean urine protein to creatinine ratio (UPCR) area under the concentration time curve (AUC) from baseline to Week 52/End of Study (EOS) for recipients of ALE.F02 compared to placebo; |  | from baseline to Week 52/EOS | 
| Time to stable proteinuria (≤0.5 g/day for ≥14 days) during the Treatment Period for recipients of ALE.F02 compared to placebo; |  | up to 24 weeks | 
| Time to stable hematuria (≤5 RBCs/high-power field for ≥14 days) during the Treatment Period for recipients of ALE.F02 compared to placebo; |  | up to 24 weeks | 
| Incidence of renal replacement therapy (RRT) at any time during the study for recipients of ALE.F02 compared to placebo; and |  | through study completion, an average of 1 year | 
| Total glucocorticoid and immunosuppressive exposure at Week 24/EOT and Week 52/EOS for recipients of ALE.F02 compared to placebo. |  | at Week 24/EOT and Week 52/EOS |