Granulomatosis With Polyangiitis (GPA), Microscopic Polyangiitis (MPA)
Conditions
Keywords
granulomatosis, polyangiitis, corticosteroid, replacement, glucocorticoid
Brief summary
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
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.
Interventions
DRUGIFX-1
intravenously administered
DRUGPlacebo-IFX-1
intravenously administered
orally administered
DRUGPlacebo-Glucocorticoid (Placebo-GC)
orally administered
Sponsors
InflaRx GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Achieving Clinical Response | Baseline, Week 16 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in BVASv3 Total Score | Baseline, Week 16 | 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. |
| Vasculitis Damage Index (VDI) | Week 16 | 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. |
| Physician Global Assessment (PGA) | Week 16 | Efficacy endpoint: Absolute values in PGA; Physician global assessment scale: 0 = Remission to 10 = Maximum activity; |
| Estimated Glomerular Filtration Rate | Week 16 | 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) |
| Number and Percentage of Subjects Who Had a Treatment-emergent Adverse Event (TEAE) | Week 24 | Safety endpoint: Number and percentage of subjects who had a treatment-emergent adverse event (TEAE) |
| Percentage of Subjects With Clinical Remission | Week 16 | 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. |
| IFX-1 Plasma Concentrations (Pre-dose) | Week 16 (pre-dose) | Pharmacokinetics endpoint: IFX-1 plasma concentrations assessed prior to study drug administration at corresponding visit. |
| Plasma Concentrations of C5a | Week 16 | Pharmacodynamics endpoint: Plasma concentrations of C5a |
| IFX-1 Blocking Activity 10 nM | Week 16 | Pharmacodynamics endpoint: IFX-1 blocking activity 10 nM |
| IFX-1 Blocking Activity 2.5 nM | Week 16 | Pharmacodynamics endpoint: IFX-1 blocking activity 2.5 nM |
| Glucocorticoid Toxicity Index (GTI) | Week 16 | 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. |
Countries
Belgium, Czechia, France, Germany, Italy, Netherlands, Russia, Spain, Sweden, Switzerland, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IFX-1 + Placebo-GC IFX-1: intravenously administered; Placebo-Glucocorticoid (Placebo-GC): orally administered | 18 |
| Placebo-IFX-1 + Standard Dose GC Placebo-IFX-1: intravenously administered; Glucocorticoid (GC): orally administered | 24 |
| IFX-1 + Reduced Dose GC IFX-1: intravenously administered; Glucocorticoid (GC): orally administered | 15 |
| Total | 57 |
Baseline characteristics
| Characteristic | IFX-1 + Placebo-GC | Placebo-IFX-1 + Standard Dose GC | Total | IFX-1 + Reduced Dose GC |
|---|---|---|---|---|
| AAV disease type Granulomatosis with polyangiitis (GPA) | 10 Participants | 16 Participants | 37 Participants | 11 Participants |
| AAV disease type Microscopic polyangiitis (MPA) | 8 Participants | 8 Participants | 20 Participants | 4 Participants |
| Age, Continuous | 60.8 years STANDARD_DEVIATION 11.4 | 55.0 years STANDARD_DEVIATION 12.3 | 57.8 years STANDARD_DEVIATION 12.6 | 58.5 years STANDARD_DEVIATION 14 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 24 Participants | 56 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 18 Participants | 24 Participants | 57 Participants | 15 Participants |
| Sex: Female, Male Female | 6 Participants | 6 Participants | 17 Participants | 5 Participants |
| Sex: Female, Male Male | 12 Participants | 18 Participants | 40 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 18 | 0 / 24 | 0 / 15 |
| other Total, other adverse events | 15 / 18 | 23 / 24 | 15 / 15 |
| serious Total, serious adverse events | 5 / 18 | 4 / 24 | 3 / 15 |
Outcome results
Primary
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.
Time frame: Baseline, Week 16
Population: Full Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IFX-1 + Placebo-GC | Percentage of Subjects Achieving Clinical Response | 16 Participants |
| Placebo-IFX-1 + Standard Dose GC | Percentage of Subjects Achieving Clinical Response | 22 Participants |
| IFX-1 + Reduced Dose GC | Percentage of Subjects Achieving Clinical Response | 10 Participants |
Secondary
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.
Time frame: Baseline, Week 16
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 + Placebo-GC | Change From Baseline in BVASv3 Total Score | -13.8 score on a scale | Standard Deviation 4.1 |
| Placebo-IFX-1 + Standard Dose GC | Change From Baseline in BVASv3 Total Score | -14.7 score on a scale | Standard Deviation 5.9 |
| IFX-1 + Reduced Dose GC | Change From Baseline in BVASv3 Total Score | -16.6 score on a scale | Standard Deviation 5.8 |
Secondary
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)
Time frame: Week 16
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 + Placebo-GC | Estimated Glomerular Filtration Rate | 50.2 mL/min/1.73 m² | Standard Deviation 17.7 |
| Placebo-IFX-1 + Standard Dose GC | Estimated Glomerular Filtration Rate | 57.0 mL/min/1.73 m² | Standard Deviation 22.8 |
| IFX-1 + Reduced Dose GC | Estimated Glomerular Filtration Rate | 51.2 mL/min/1.73 m² | Standard Deviation 26.2 |
Secondary
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.
Time frame: Week 16
Population: Safety Analysis Set (Data missing from 2 patients in IFX-1 + Placebo-GC group, from 2 patients in Placebo-IFX-1 + standard dose GC group, and from 3 patients in IFX-1 + reduced dose GC group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 + Placebo-GC | Glucocorticoid Toxicity Index (GTI) | 0.8 score on a scale | Standard Deviation 9 |
| Placebo-IFX-1 + Standard Dose GC | Glucocorticoid Toxicity Index (GTI) | 44.9 score on a scale | Standard Deviation 41.5 |
| IFX-1 + Reduced Dose GC | Glucocorticoid Toxicity Index (GTI) | 26.1 score on a scale | Standard Deviation 39.2 |
Secondary
IFX-1 Blocking Activity 10 nM
Pharmacodynamics endpoint: IFX-1 blocking activity 10 nM
Time frame: Week 16
Population: Full Analysis Set (Data missing from 4 patients in IFX-1 + Placebo-GC group, and from 7 patients in IFX-1 + reduced dose GC group, IFX-1 blocking activity was not assessed for patients in Placebo-IFX-1 + standard dose GC group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 + Placebo-GC | IFX-1 Blocking Activity 10 nM | 100.571 percentage of IFX-1 blocking activity | Standard Deviation 2.651 |
| IFX-1 + Reduced Dose GC | IFX-1 Blocking Activity 10 nM | 100.508 percentage of IFX-1 blocking activity | Standard Deviation 10.051 |
Secondary
IFX-1 Blocking Activity 2.5 nM
Pharmacodynamics endpoint: IFX-1 blocking activity 2.5 nM
Time frame: Week 16
Population: Full Analysis Set (Data missing from 4 patients in IFX-1 + Placebo-GC group, and from 7 patients in IFX-1 + reduced dose GC group, IFX-1 blocking activity was not assessed for patients in Placebo-IFX-1 + standard dose GC group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 + Placebo-GC | IFX-1 Blocking Activity 2.5 nM | 98.260 percentage of IFX-1 blocking activity | Standard Deviation 16.731 |
| IFX-1 + Reduced Dose GC | IFX-1 Blocking Activity 2.5 nM | 121.881 percentage of IFX-1 blocking activity | Standard Deviation 59.979 |
Secondary
IFX-1 Plasma Concentrations (Pre-dose)
Pharmacokinetics endpoint: IFX-1 plasma concentrations assessed prior to study drug administration at corresponding visit.
Time frame: Week 16 (pre-dose)
Population: Safety Analysis Set (Data missing from 5 patients in IFX-1 + Placebo-GC group, from 7 patients in Placebo-IFX-1 + standard dose GC group, and from 7 patients in IFX-1 + reduced dose GC group)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 + Placebo-GC | IFX-1 Plasma Concentrations (Pre-dose) | 67077.19 ng/mL | Geometric Coefficient of Variation 77.33 |
| Placebo-IFX-1 + Standard Dose GC | IFX-1 Plasma Concentrations (Pre-dose) | 47.80 ng/mL | Geometric Coefficient of Variation 152.42 |
| IFX-1 + Reduced Dose GC | IFX-1 Plasma Concentrations (Pre-dose) | 52597.85 ng/mL | Geometric Coefficient of Variation 118.15 |
Secondary
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)
Time frame: Week 24
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IFX-1 + Placebo-GC | Number and Percentage of Subjects Who Had a Treatment-emergent Adverse Event (TEAE) | 16 Participants |
| Placebo-IFX-1 + Standard Dose GC | Number and Percentage of Subjects Who Had a Treatment-emergent Adverse Event (TEAE) | 24 Participants |
| IFX-1 + Reduced Dose GC | Number and Percentage of Subjects Who Had a Treatment-emergent Adverse Event (TEAE) | 15 Participants |
Secondary
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.
Time frame: Week 16
Population: Full Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IFX-1 + Placebo-GC | Percentage of Subjects With Clinical Remission | 14 Participants |
| Placebo-IFX-1 + Standard Dose GC | Percentage of Subjects With Clinical Remission | 20 Participants |
| IFX-1 + Reduced Dose GC | Percentage of Subjects With Clinical Remission | 10 Participants |
Secondary
Physician Global Assessment (PGA)
Efficacy endpoint: Absolute values in PGA; Physician global assessment scale: 0 = Remission to 10 = Maximum activity;
Time frame: Week 16
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 + Placebo-GC | Physician Global Assessment (PGA) | 0.4 score on a scale | Standard Deviation 1 |
| Placebo-IFX-1 + Standard Dose GC | Physician Global Assessment (PGA) | 0.1 score on a scale | Standard Deviation 0.5 |
| IFX-1 + Reduced Dose GC | Physician Global Assessment (PGA) | 0.7 score on a scale | Standard Deviation 1.8 |
Secondary
Plasma Concentrations of C5a
Pharmacodynamics endpoint: Plasma concentrations of C5a
Time frame: Week 16
Population: Full Analysis Set (Data missing from 4 patients in IFX-1 + Placebo-GC group, from 10 patients in Placebo-IFX-1 + standard dose GC group, and from 8 patients in IFX-1 + reduced dose GC group)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 + Placebo-GC | Plasma Concentrations of C5a | 10.6816 ng/mL | Standard Deviation 5.8505 |
| Placebo-IFX-1 + Standard Dose GC | Plasma Concentrations of C5a | 39.2822 ng/mL | Standard Deviation 25.6249 |
| IFX-1 + Reduced Dose GC | Plasma Concentrations of C5a | 13.6320 ng/mL | Standard Deviation 12.304 |
Secondary
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.
Time frame: Week 16
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 + Placebo-GC | Vasculitis Damage Index (VDI) | 1.0 score on a scale | Standard Deviation 1 |
| Placebo-IFX-1 + Standard Dose GC | Vasculitis Damage Index (VDI) | 1.5 score on a scale | Standard Deviation 1.1 |
| IFX-1 + Reduced Dose GC | Vasculitis Damage Index (VDI) | 1.9 score on a scale | Standard Deviation 1.8 |