Study of IFX-1 to Replace Steroids in Patients With Granulomatosis With Polyangiitis and Microscopic Polyangiitis.

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy of IFX-1 treatment as replacement for glucocorticoid (GC) therapy in subjects with polyangiitis (GPA) or microscopic polyangiitis (MPA).

Detailed Description
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Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a group of potentially life-threatening autoimmune diseases. Preclinical data demonstrate that primed neutrophils are activated by anti-neutrophil cytoplasmic antibody (ANCA) and generate C5a that engages C5a receptors on neutrophils. Patients with ANCA-related disease have elevated plasma and urine levels of C5a in active disease but not in remission. IFX-1 is as a monoclonal antibody specifically binding to the soluble human complement split product C5a, which results in nearly complete blockade of C5a induced biological effects. Therefore, IFX-1 may be effective in the treatment of subjects with AAV. In this Phase II study of 20 to 55 subjects with granulomatosis with GPA and MPA, IFX-1 will be administered in combination with reduced dose glucocorticoids or a placebo glucocorticoid compared with standard dose glucocorticoids.

Official Title
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A Randomized, Double-blind, Double-dummy, Active-controlled, Multicenter, 2-part Phase II Study on Replacement of Steroids by IFX-1 in Active Granulomatosis With Polyangiitis (GPA) and Microscopic Polyangiitis (MPA)

Conditions
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Granulomatosis With Polyangiitis (GPA), Microscopic Polyangiitis (MPA)

Intervention / Treatment
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* Drug: IFX-1
* Drug: Placebo-IFX-1
* Drug: Glucocorticoid (GC)
* Drug: Placebo-Glucocorticoid (Placebo-GC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) Have ≥ 1 major item, or ≥ 3 other items, or ≥ 2 renal items on the Birmingham Vasculitis Activity Score Version 3 (BVASv3). Newly diagnosed or relapsed GPA or MPA that requires treatment with Cyclophosphamide (CYC) or Rituximab (RTX) plus GCs. Glomerular filtration rate ≥ 20 mL/min/1.73 m². Exclusion Criteria: Any other multi-system autoimmune disease. Require mechanical ventilation at screening. Known hypersensitivity to any investigational medicinal product and/or any excipient. Rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. Have required management of infections, as follows (a) Chronic infection requiring anti-infective therapy within 3 months before screening. (b) Use of intravenous antibacterials, antivirals, anti-fungals, or anti-parasitic agents within 30 days of screening Current and/or history (within the previous 5 years) of drug and/or alcohol abuse and/or dependence. Evidence of Hep B, C and/ or HIV infection. Only subjects with documented negative historical results (within 4 weeks before screening) for Hep B,C Virus and HIV or a negative test by Screening can be included into the study. Abnormal laboratory findings at screening Current or history of malignancy, lymphoproliferative, or myeloproliferative disorder Received CYC or RTX within 12 weeks before screening or within 12 weeks before CYC or RTX is started for remission induction within 2 weeks before screening. Received > 3 g cumulative intravenous GCs within 4 weeks before screening. Received an oral daily dose of a GC of > 10 mg prednisone-equivalent for more than 6 weeks continuously prior to screening. Received an oral daily dose of a GC of > 80 mg prednisone equivalent within 2 weeks before screening. Received a CD20 inhibitor, anti-tumor necrosis factor treatment, abatacept, alemtuzumab, any other experimental or biological therapy, intravenous immunoglobulin (Ig) or plasma exchange, antithymocyte globulin, or required renal dialysis within 12 weeks before screening. Received a live vaccination within 4 weeks before screening Either active or latent tuberculosis treatment is ongoing. Pregnant or lactating. Abnormal electrocardiogram. Female subjects of childbearing potential unwilling or unable to use a highly effective method of contraception Participation in an investigational clinical study during the 12 weeks before screening. Male subjects with female partners of childbearing potential unwilling to use contraception

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A Experimental + active comparator<br>IFX-1 + reduced dose GC | Drug: IFX-1<br>* intravenously administered<br>* Other names: CaCP29;Drug: Glucocorticoid (GC)<br>* orally administered<br>* Other names: Prednisone;|
| Active Comparator: Group B Placebo + active comparator<br>Placebo-IFX-1 + standard dose GC | Drug: Placebo-IFX-1<br>* intravenously administered<br>* Other names: Placebo;Drug: Glucocorticoid (GC)<br>* orally administered<br>* Other names: Prednisone;|
| Placebo Comparator: Group C Experimental + placebo comparator<br>IFX-1 + Placebo-GC | Drug: IFX-1<br>* intravenously administered<br>* Other names: CaCP29;Drug: Placebo-Glucocorticoid (Placebo-GC)<br>* orally administered<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects Achieving Clinical Response | Efficacy Endpoint: Percentage of subjects achieving clinical response (reduction in Birmingham Vasculitis Activity Score version 3 [BVASv3] of ≥50% compared to baseline and no worsening in any body system). Subjects who received rescue therapy after Day 1 or discontinued due to related adverse event, lack of efficacy or progressive disease are considered as non-responders at all subsequent visits. The BVASv3 score ranges from 0 to 63 with higher values representing higher disease activity. | Baseline, Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Subjects With Clinical Remission | Efficacy endpoint: Percentage of subjects with clinical remission, defined as having a BVASv3 = 0. Subjects who received rescue therapy after Day 1 or discontinued due to related adverse event, lack of efficacy or progressive disease are considered as non-responders at all subsequent visits. The BVASv3 score ranges from 0 to 63 with higher values representing higher disease activity. | Week 16 | 
| Change From Baseline in BVASv3 Total Score | Efficacy endpoint: Absolute Change from baseline (= screening assessment) in Birmingham Vasculitis Activity Score version 3 (BVASv3) total score; The BVASv3 score ranges from 0 to 63 with higher values representing higher disease activity. The total score is derived by summing up item scores according to the scoring manual for the BVASv3. | Baseline, Week 16 | 
| Vasculitis Damage Index (VDI) | Efficacy endpoint: Absolute values of VDI; The VDI total score ranges from 0 to 64 with higher scores indicating more organ damage since the onset of vasculitis. The total score is the number of present damage items. | Week 16 | 
| Physician Global Assessment (PGA) | Efficacy endpoint: Absolute values in PGA; Physician global assessment scale: 0 = Remission to 10 = Maximum activity; | Week 16 | 
| Estimated Glomerular Filtration Rate | Efficacy endpoint: Absolute values of estimated glomerular filtration rate (eGFR) in mL/min/1.73 m²; The eGFR was calculated by the central laboratory according to the Modified Diet in Renal Disease equation: eGFR = 175 x (serum creatinine, mg/dL)-1.154 x (age, years)-0.203 x (0.742 if female) x (1.212 if black) | Week 16 | 
| Number and Percentage of Subjects Who Had a Treatment-emergent Adverse Event (TEAE) | Safety endpoint: Number and percentage of subjects who had a treatment-emergent adverse event (TEAE) | Week 24 | 
| Glucocorticoid Toxicity Index (GTI) | Safety endpoint: The GTI total score ranges from -35 to 410 (because the bone domain is excluded in this study) with higher score indicating greater Glucocorticoid toxicity. Scoring was performed in the electronic case report form according to the corresponding scoring manual in Development of a Glucocorticoid Toxicity Index (GTI) using multicriteria decision analysis. by Miloslavsky EM, Naden RP, Bijlsma JW, Brogan PA, Brown ES, Brunetta P, et al. | Week 16 | 
| IFX-1 Plasma Concentrations (Pre-dose) | Pharmacokinetics endpoint: IFX-1 plasma concentrations assessed prior to study drug administration at corresponding visit. | Week 16 (pre-dose) | 
| Plasma Concentrations of C5a | Pharmacodynamics endpoint: Plasma concentrations of C5a | Week 16 | 
| IFX-1 Blocking Activity 10 nM | Pharmacodynamics endpoint: IFX-1 blocking activity 10 nM | Week 16 | 
| IFX-1 Blocking Activity 2.5 nM | Pharmacodynamics endpoint: IFX-1 blocking activity 2.5 nM | Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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granulomatosis, polyangiitis, corticosteroid, replacement, glucocorticoid