Efficacy of Imlifidase Combined with Standard of Care in Severe ANCA-Associated Vasculitis with Pulmonary Hemorrhage
- Trial ID
- 2024-516727-13-00
- Protocol
- ImlifidARDSe.01
Trial statistics
Objectives
The primary objective of this study is to define the **efficacy** of imlifidase in combination with standard of care (SoC) for patients with severe anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, specifically those experiencing pulmonary hemorrhage. This is clinically relevant as ANCA-associated vasculitis with severe diffuse alveolar hemorrhage is a life-threatening condition, and effective treatment options are crucial for improving patient outcomes.
Secondary objectives include:
- Defining the impact of imlifidase plus SoC on clinical and laboratory parameters.
- Assessing the safety of imlifidase plus SoC in patients with severe ANCA-associated vasculitis with pulmonary hemorrhage.
Participants
The clinical trial focuses on individuals diagnosed with **anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis** with severe diffuse alveolar hemorrhage. The study population includes both male and female participants, with an age range that encompasses adults and older adults. Participants are required to have a new or previous clinical diagnosis of ANCA-associated vasculitis, specifically granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), consistent with revised Chapel Hill definitions. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants' general health status is characterized by the presence of pulmonary hemorrhage due to active vasculitis, as evidenced by specific clinical criteria. Lifestyle considerations such as diet, physical activity, or habits are not specified. The selection process for the trial population is based on specific inclusion criteria, including a confirmed ANCA titer and evidence of pulmonary hemorrhage, among others. The trial aims to define the efficacy of imlifidase plus standard of care in this patient population.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** of **imlifidase** in combination with standard of care for patients with severe **ANCA-associated vasculitis** and pulmonary hemorrhage. This is a Phase 4, randomized, double-blind, controlled trial. The trial is expected to commence recruitment on May 17, 2024, and conclude by June 30, 2026. Participants will be randomly assigned to receive either the investigational product or a placebo, with both groups receiving standard care. The trial will involve intravenous infusion of the investigational product, Idefirix, which is a powder for concentrate for solution for infusion.
Study visits will follow a structured sequence, beginning with a screening visit to confirm eligibility based on inclusion criteria such as a clinical diagnosis of ANCA-associated vasculitis and evidence of pulmonary hemorrhage. Participants must provide written informed consent and demonstrate willingness and ability to comply with the protocol. The primary endpoint is ANCA seroconversion within 24 hours of imlifidase administration, with secondary endpoints including time to seroconversion, mortality, and amelioration of lung and kidney function.
Follow-up visits will be scheduled to monitor the participants' response to treatment and assess safety endpoints, including adverse events and infectious complications. The end-of-study visit will evaluate the overall outcomes and collect final data. The expected length of participant involvement is approximately one year, with conditions for early termination including withdrawal of consent or non-compliance with the study protocol. The trial will ensure rigorous monitoring to maintain participant safety and data integrity throughout its duration.
Treatment
The clinical trial involves the administration of **Imlifidase**, marketed under the name Idefirix, which is a **powder for concentrate for solution for infusion**. This investigational medicinal product is designed for intravenous infusion and is utilized in the treatment of severe ANCA-associated vasculitis with pulmonary hemorrhage. Imlifidase is a protein of biotechnological origin, specifically produced using recombinant DNA technology from *E. coli*. The active substance, Imlifidase, is also known by synonyms such as Immunoglobulin G degrading enzyme of *Streptococcus pyogenes*, HMED-IDES, and IDES. The maximum daily and total dose of Imlifidase is 0.50 mg/kg, with a treatment period not exceeding one day.
In addition to the experimental treatment, participants will receive standard-of-care (SoC) therapy as part of the study protocol. The SoC therapy is not specified in the provided data but typically includes treatments that are widely accepted and used by healthcare professionals for managing ANCA-associated vasculitis. The combination of Imlifidase and SoC aims to evaluate the efficacy of the investigational product in the specified patient population. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.
Efficacy
Efficacy in the clinical trial of Imlifidase for the treatment of severe ANCA-associated vasculitis with pulmonary hemorrhage will be assessed using both primary and secondary endpoints. The primary endpoint is the **ANCA seroconversion**, indicated by a titer below the reference range within 24 hours of Imlifidase administration. Secondary endpoints include the time to ANCA seroconversion, rebound of ANCA serology greater than 50% of the initial fall in titer, 30-day mortality, duration of ICU stay, and amelioration of lung and kidney function. Lung function improvement will be measured by the duration of invasive ventilation or ECMO and the time to resolution of ARDS, assessed by the Horowitz Index. Kidney function improvement will be evaluated by upstaging of KDIGO AKI stages and kidney replacement therapy dependency at 3 and 6 months post-inclusion.
Safety endpoints will also be monitored, including the frequency and distribution of adverse events, severe adverse events, clinical laboratory tests, vital signs, and the frequency and quality of infectious complications. The trial is set to begin recruitment on May 17, 2024, with an estimated end date of June 30, 2026. The trial is categorized as a Phase 4 therapeutic exploratory study, focusing on the efficacy and safety of Imlifidase in combination with standard care for this condition.
Inclusion and Exclusion Criteria
Inclusion Criteria
- New or previous clinical diagnosis of ANCA-associated vasculitis, (granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) consistent with revised Chapel Hill definitions
- ANCA titer >= 50 (AU/ml) (i.e. anti-myeloperoxidase / antiproteinase 3) no more than 14 days prior to inclusion measured by certified clinical laboratory
- Pulmonary hemorrhage due to active vasculitis defined by the following: o A compatible chest x-ray or CT scan (diffuse pulmonary infiltrates) o The absence of an alternative explanation for all pulmonary infiltrates (i.e. volume overload or pulmonary infection) o At least one of the following: § Evidence of alveolar hemorrhage on bronchoscopic examination or increasingly bloody returns with bronchoalveolar lavage § Observed hemoptysis § Unexplained anemia (<10 g/dL) or documented drop in hemoglobin (>1 g/dL) from less than 10g/dl § Acute respiratory distress syndrome (ARDS, according to Berlin definition)
- Provision of written informed consent by patients before any study related procedure
- Willingness and ability to comply with the protocol
- For female subjects: Confirmed post-menopausal state (defined as amenorrhea for at least 12 months)
Exclusion Criteria
- Subjects aged < 18 or > 80 years
- Subjects physically or mentally unable to give written informed consent
- Subjects deprived of freedom i.e., detainment or commitment to psychiatric ward, prison or state institution by law court or legal authority
- Female subjects: pregnant or breastfeeding or of childbearing potential
- Male subjects: unwilling to use double-barrier contraception for the duration of this study.
- Concomitant autoimmunological disease (e.g. Goodpasture, vasculitis other than AAV)
- Diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) consistent with revised Chapel Hill definitions
- Concomitant pulmonary disease (e.g. chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD))
- Known allergy/sensitivity to imlifidase, IVIg and/or the respective excipients
- Previous treatment with imlifidase
- Previous or ongoing high dose IVIg treatment (2 g/kg) within 28 days prior to inclusion
- More than two plasma exchanges prior to administration of imlifidase within 28 days prior to inclusion
- Participation in an other interventional clinical trial or intake of other investigational medicinal product within 5 half-lives (or similar) of the product prior to inclusion
- Symptomatic congestive heart failure (NYHA class 2-4) requiring prescription medication or clinically evident peripheral edema of cardiac origin or documented evidence/history of NYHA class 2-4 heart failure
- A comorbidity or indication of such based on medical history, physical examination, and clinical laboratory assessments which precludes the use of cyclophosphamide, glucocorticoids, or imlifidase.
- Evidence of moderate or severe hepatic impairment indicated by elevated aminotransferases (ALT or AST) or bilirubin greater than double (2.0 x) the upper limit of normal (ULN)
- Ongoing bacterial or fungal infection requiring antibiotic /-fungal therapy (or completed within 7 days prior to inclusion). Viral infection with Hepatitis B, C and HIV (up to 14 days old negative test results are accepted); or active tuberculosis as indicated by chest X-ray. Every patient will be screened for SARS-CoV2, positive cases will be excluded.
- Active malignant disease or a history of malignancy within two years prior to diagnosis/infusion other than non-melanoma resected or cured skin cancer
- Any condition that in the opinion of the investigator could increase the subject's risk by participating in the study other than those specified.
- Present or history of thrombotic thrombocytopenic purpura (TTP), or known familial history of TTP
- Subject who might be dependent on the sponsor, the investigator or the trial site.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 17 May 2024 | 10 |
Sites & Investigators
Research 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 |
|---|---|---|---|---|---|---|
Idefirix 11 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 0.50 | 1 | PRD8297747 |