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
- Trial ID
- 2022-502184-38-00
- Protocol
- ALE.F02.03
- Sponsor
- Alentis Therapeutics AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of ALE.F02 when administered as a continuous intravenous infusion in patients with rapidly progressive glomerulonephritis (RPGN) attributed to antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This is clinically relevant as ensuring the safety and tolerability of new treatments is crucial for patient care and the development of effective therapeutic strategies.
Secondary objectives include:
- Assessing the ability of ALE.F02 to preserve renal function and estimated glomerular filtration rate (eGFR) over time in patients diagnosed with RPGN attributed to AAV when added to standard of care (SOC).
- Evaluating the use of glucocorticoids and immunosuppressant concomitant medications in these patients when ALE.F02 is added to SOC.
- Determining the pharmacokinetic (PK) properties of ALE.F02 in patients diagnosed with RPGN attributed to AAV.
Participants
The clinical trial involves a total of **17 participants** diagnosed with **rapidly progressive glomerulonephritis** (RPGN) attributed to ANCA-associated vasculitis (AAV). The study population includes both male and female subjects aged **18 years and older**, without any specific upper age limit mentioned. Participants are required to have a score of less than 7 on the Clinical Frailty Scale, indicating a relatively stable general health status. The selection criteria ensure that individuals are newly diagnosed with RPGN within 45 days prior to the initiation of the study drug treatment. Participants must have evidence of renal function loss, as demonstrated by an estimated glomerular filtration rate (eGFR) between 10 and 50 mL/min/1.73 m², and a history of proteinuria or hematuria. Lifestyle considerations such as diet and physical activity are not specified, but participants must comply with study requirements, including renal biopsy procedures and contraceptive measures. The trial includes a vulnerable population, emphasizing the need for careful monitoring and ethical considerations throughout the study.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety, tolerability, pharmacokinetics, and renal sparing effects of the investigational product ALE.F02 in patients with **rapidly progressive glomerulonephritis** (RPGN) attributed to antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The trial is categorized as a Phase 2 study and is expected to conclude by April 2026, with recruitment having commenced in September 2023. The study involves the administration of ALE.F02 as a continuous intravenous infusion, with a primary focus on assessing safety and tolerability through various endpoints, including adverse events, serious adverse events, hematology, clinical chemistry, serum lipids, antidrug antibodies, and electrocardiograms.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, renal function, and diagnostic tests for AAV. Following the screening, participants will be randomized to receive either ALE.F02 or a placebo. The trial includes multiple follow-up visits, with key assessments at Week 6, Week 24 (end of treatment), and Week 52 (end of study). These visits are designed to monitor the primary and secondary endpoints, including changes in estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio, and incidence of renal replacement therapy.
The expected duration of participant involvement is approximately 52 weeks, with conditions for early termination including non-compliance with study requirements, withdrawal of consent, or adverse events that compromise participant safety. The study aims to provide comprehensive data on the efficacy and safety of ALE.F02, contributing to the understanding of its potential benefits in managing RPGN associated with AAV.
Treatment
The clinical trial involves the administration of **Rituximab**, a monoclonal antibody, as part of the treatment regimen. Rituximab is provided in the pharmaceutical form of PHF00230MIG and is administered via **intravenous infusion**. The maximum daily dose is 1000 mg, with a total maximum dose of 2500 mg over a treatment period of up to 24 weeks. This medication is not a pediatric formulation and is used as an auxiliary treatment in the trial.
**Lixudebart**, another monoclonal antibody, is the primary investigational product in this study. It is supplied as a concentrate for solution for infusion and is administered through **intravenous use**. The dosing regimen allows for a maximum daily dose of 15 mg/kg, with a total maximum dose of 195 mg/kg over a 24-week period. Lixudebart is not formulated for pediatric use and is the main test product in the trial.
The study also includes the use of **Cyclophosphamide**, a chemical agent, provided in the pharmaceutical form PHF00231MIG. Cyclophosphamide is administered via **intravenous administration**. The dosing schedule permits a maximum daily dose of 15 mg/kg, with a total maximum dose of 90 mg/kg over a 13-week period. This agent is used as an auxiliary treatment in the trial.
Additionally, the trial involves the administration of a chemical agent categorized under **immunosuppressive agents**. This product is provided in the pharmaceutical form PHF2355 and is administered orally. The maximum daily dose is 200 mg, with a total maximum dose of 50400 mg over a 36-week period. This agent is also used as an auxiliary treatment in the study.
Another chemical agent used in the trial is categorized under **glucocorticoids**. It is provided in the pharmaceutical form PHF00231MIG and administered orally. The dosing regimen allows for a maximum daily dose of 75 mg, with a total maximum dose of 2730 mg over a 22-week period. This agent serves as an auxiliary treatment in the trial.
Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the treatment regimen. The trial is designed to evaluate the safety, tolerability, pharmacokinetics, and renal sparing effects of the investigational product Lixudebart in patients with antineutrophil cytoplasmic antibody-associated vasculitis with rapidly progressive glomerulonephritis.
Efficacy
Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the safety and tolerability of ALE.F02, administered as a continuous intravenous infusion in patients with **Rapidly Progressive Glomerulonephritis** (RPGN) attributed to Antineutrophil Cytoplasmic Antibody-Associated Vasculitis (AAV). Safety endpoints include the monitoring of all adverse events (AEs), serious adverse events (SAEs), hematology and clinical chemistry analyte assessments, serum lipids, antidrug antibodies (ADAs), and electrocardiograms (ECGs).
The secondary endpoints are designed to evaluate the efficacy of ALE.F02 in comparison to placebo. These include the change in mean estimated glomerular filtration rate (eGFR) from baseline to Week 24 or end-of-treatment (EOT), and the change in mean urine protein to creatinine ratio (UPCR) area under the curve (AUC) from baseline to Week 24/EOT and Week 52/end-of-study (EOS). Additionally, the time to stable proteinuria (≤0.5 g/day for ≥14 days) and stable hematuria (≤5 red blood cells/high-power field for ≥14 days) during the treatment period will be assessed. The incidence of renal replacement therapy (RRT) at any time during the study and the total glucocorticoid and immunosuppressive exposure at Week 24/EOT and Week 52/EOS will also be evaluated.
Inclusion and Exclusion Criteria
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.
- Have a weight of ≤130 kg;
- 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; alternatively, a historical biopsy performed up to 45 days prior to the initiation of study drug administration is considered acceptable;
- Have been newly diagnosed with RPGN within 45 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 ≥10 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.
- 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 MPO or anti-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 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 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.
- Applicable ONLY to Part B: Have been treated with avacopan up to 14 days prior to Screening and initiated avacopan treatment no later than Study Day 1; and
- Applicable ONLY to Part B: Are being treated with avacopan as per the SmPC and according to local institutional guidelines.
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 received a course of SOC therapy which exceeds a high-dose prolonged regimen of treatment of ANCA RPGN, such as >3000 mg of IV methylprednisoloneequipotent glucocorticoids, or >1 mg/kg/day of oral glucocorticoids (prednisone equivalent) for >14 days (doses are provided as a guidance for assessment of intensity; patients who received highdose glucocorticoids should be discussed with and approved by the Medical Monitor and the Sponsor);
- 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 poor venous access;
- 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 7 days prior to Screening;
- Have undergone therapeutic plasma exchange within 7 days prior to Screening; or
- Have a diagnosis of systemic lupus erythematosus-AAV overlap syndrome;
- Have a diagnosis of eosinophilic granulomatosis with polyangiitis;
- 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 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 known hypersensitivity to the study drug or any of the excipients used in the formulation of the study drug.
- 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 a positive serology test for anti-glomerular basement membrane antibodies;
- Have been diagnosed within the preceding 5 years with a malignant neoplastic disease, other than locally invasive cutaneous squamous or basal cell carcinoma;
- Have evidence of active or latent TB determined by a positive (not indeterminate) QuantiFERON®-TB Gold test (or equivalent). In countries where QuantiFERON®-TB Gold test (or equivalent) is not available, radiological criteria, including chest X-ray or computed tomography scan, may alternatively be used;
- Have a chronic infection that could be exacerbated by RPGN or SOC therapy for RPGN;
- Have active hepatitis B, hepatitis C, or HIV infection. Active hepatitis B infection will be determined by hepatitis B surface antigen and antibody to hepatitis B core antigen testing;
- Have taken any prohibited medications;
- Applicable ONLY to Part A: Have been treated with or are expected to be treated with avacopan;
- Applicable ONLY to Part B: Have been treated with avacopan >14 days prior to Screening;
- Applicable ONLY to Part B: Have known hypersensitivity to avacopan or any of the excipients used in the formulation of avacopan;
- Applicable ONLY to Part B: Have evidence of hepatic disease (cirrhosis, other liver diseases AND a Child-Pugh Class C) or aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, or bilirubin >3 × the upper limit of normal before Study Day 1;
- Applicable ONLY to Part B: Have had a white blood cell count <3500/μL, neutrophil count <1500/μL, or lymphocyte count <500/μL before Study Day 1; or
- Applicable ONLY to Part B: Have an intake of strong cytochrome P450 (CYP) (CYP3A4) inducers and/or inhibitors, if not in line with the latest SmPC of avacopan.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 01 Sept 2023 | 4 |
 Denmark | Recruiting | 01 Sept 2023 | 10 |
 France | Recruiting | 01 Sept 2023 | 8 |
 Germany | Recruiting | 01 Sept 2023 | 15 |
 Italy | Recruiting | 01 Sept 2023 | 4 |
 Spain | Recruiting | 01 Sept 2023 | 4 |
 Sweden | Recruiting | 01 Sept 2023 | 6 |
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 |
|---|---|---|---|---|---|---|
- | Other | PHF2355 | ORAL USE | 200 | 36 | L04A |
RITUXIMAB | Other | PHF00230MIG | INTRAVENIOUS INFUSION | 1000 | 24 | SCP24437829 |
Test IMP (ALE.F02) without active substance | Placebo | N/A | — | — | — | N/A |
LIXUDEBART | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 15 | 24 | PRD10047976 |
CYCLOPHOSPHAMIDE | Other | PHF00231MIG | INTRAVENOUS ADMINISTRATION | 15 | 13 | SCP1728208 |
- | Other | PHF00231MIG | ORAL USE | 75 | 22 | H02AB |