Granulomatosis With Polyangiitis (GPA), Microscopic Polyangiitis (MPA)
Conditions
Keywords
Granulomatosis with Polyangiitis (GPA), Microscopic Polyangiitis (MPA), IFX-1, ANCA, AAV
Brief summary
The purpose of this study is to investigate the safety and tolerability of two dose regimens of IFX-1 as add-on to standard of care (SOC) in subjects with GPA and MPA compared with placebo.
Detailed description
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are related systemic v anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a potentially life-threatening disease. GPA is a necrotizing vasculitis predominantly involving small- to medium-sized vessels (e.g., capillaries, venules, arterioles, arteries, and veins). MPA is a necrotizing vasculitis that primarily affects capillaries, venules, or arterioles, most commonly manifesting as necrotizing glomerulonephritis and/or pulmonary capillaritis. MPA. Primed neutrophils are activated by ANCA and generate C5a that engages C5a receptors on neutrophils. Therefore, patients with ANCA-related disease have elevated plasma and urine levels of C5a in active disease and not in remission. IFX-1 is a monoclonal antibody specifically binding to the soluble human complement split product C5a and the resulting nearly complete blockade of C5a-induced biological effects may be effective in the treatment of subjects with AAV.
Interventions
DRUGIFX-1 low dose
Single IV infusions of IFX-1
DRUGIFX-1 high dose
Single IV infusions of IFX-1
DRUGPlacebo
Placebo
Sponsors
Iqvia Pty Ltd
InflaRx GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, ≥18 years of age. 2. Diagnosis of GPA or MPA according to the definitions of the Chapel Hill Consensus Conference. 3. Have at least one major item, or at least three other items, or at least two renal items on the Birmingham Vasculitis Activity Score (BVAS) Version 3.0. 4. New or relapsed GPA or MPA that require treatment with CYC or RTX plus GCs.
Exclusion criteria
1. Any other multisystem autoimmune disease 2. Requires mechanical ventilation because of alveolar hemorrhage at Screening. 3. Human immunodeficiency virus, hepatitis B, or hepatitis C viral screening test showing evidence of active or chronic viral infection at Screening or a documented history of the human immunodeficiency virus, hepatitis B, or hepatitis C. 4. Received CYC or RTX 12 weeks before Screening; if on azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), or mycophenolate sodium (MPS) at the time of Screening, these drugs must be withdrawn prior to receiving CYC or RTX. 5. Received more than 3 g cumulative high dose intravenous GCs within 4 weeks before Screening. 6. On an oral dose of a GC of more than 10 mg prednisone equivalent at Screening or for more than 6 weeks before Screening. 7. Received a CD20 inhibitor, anti-tumor necrosis factor treatment, abatacept, alemtuzumab, any other experimental or biological therapy, intravenous immunoglobulin or plasma exchange, antithymocyte globulin, or required dialysis within 12 weeks before Screening. 8. Received a live vaccination within 4 weeks before Screening or planned between Screening and Week 24. 9. Female subjects of childbearing potential unwilling or unable to use a highly effective method of contraception (pearl index \<1%) such as complete sexual abstinence, combined oral contraceptive, vaginal hormone ring, transdermal contraceptive patch, contraceptive implant, or depot contraceptive injection in combination with a second method of contraception such as condom, cervical cap, or diaphragm with spermicide during the study and for at least 4 weeks after last administration of IFX-1 (timeframes for SOC have to be considered as described in the respective Prescribing Information).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Participants With at Least One TEAE Per Treatment Group. | Week 24 | Number and percentage of participants who experience at least one treatment-emergent adverse event (TEAE) per treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinical Remission (BVAS = 0) | Week 16 | Efficacy Endpoint that evaluates participants with complete remission |
| IFX-1 Concentration Pre-dose | Week 16 | Assess the pharmacokinetic of the investigational medicinal product. |
| IFX 1 Concentration at Predose (0 Hours), After the End of the Infusion (+10minutes), and at 2, 6, 24, and 48 Hours After the Start of the Infusion for Participants in the PK Substudy | Weeks 1, 4 and 16 | Analyze the IMP plasma concentration using a PK model: IFX 1 concentration at predose (0 hours), after the end of the infusion (+10minutes), and at 2, 6, 24, and 48 hours after the start of the infusion for participants in the PK substudy |
| Percentage of Participants Achieving Clinical Response | Week 16 | Efficacy Endpoint based on clinical response evaluated through BVAS. Clinical response is defined as a reduction in BVAS of ≥50% and no worsening in any body system and no administration of rescue medication prior to the response assessment. |
| IFX-1 Blocking Activity 2.5 nM | Week 16 | Pharmacodynamic Parameter of IFX-1 blocking activity 2.5 nM |
| IFX-1 Blocking Activity 10 nM | Week 16 | Pharmacodynamic Parameter of IFX-1 blocking activity 10 nM |
| C5a Plasma Concentration | Week 16 | Pharmacodynamic parameter concentration |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IFX-1 Low Dose Will receive IFX-1 low dose regimen diluted in sodium chloride solution
IFX-1: Single IV infusions of IFX-1 | 7 |
| IFX-1 High Dose Will receive IFX-1 high dose regimen diluted in sodium chloride solution
IFX-1: Single IV infusions of IFX-1 | 6 |
| Placebo Will receive placebo
Placebo: Placebo | 6 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Failure to meet randomization criteria | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | IFX-1 Low Dose | IFX-1 High Dose | Total | Placebo |
|---|---|---|---|---|
| AAV disease type GPA | 5 Participants | 4 Participants | 13 Participants | 4 Participants |
| AAV disease type MPA | 2 Participants | 2 Participants | 6 Participants | 2 Participants |
| Age, Continuous | 65.0 years STANDARD_DEVIATION 15.1 | 54.8 years STANDARD_DEVIATION 12 | 59.1 years STANDARD_DEVIATION 14.5 | 56.5 years STANDARD_DEVIATION 16.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 4 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 4 Participants | 15 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 5 Participants | 14 Participants | 5 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 13 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 7 | 0 / 6 |
| other Total, other adverse events | 6 / 6 | 7 / 7 | 5 / 6 |
| serious Total, serious adverse events | 2 / 6 | 1 / 7 | 0 / 6 |
Outcome results
Primary
Number and Percentage of Participants With at Least One TEAE Per Treatment Group.
Number and percentage of participants who experience at least one treatment-emergent adverse event (TEAE) per treatment group.
Time frame: Week 24
Population: Safety Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IFX-1 High Dose | Number and Percentage of Participants With at Least One TEAE Per Treatment Group. | 6 Participants |
| IFX-1 Low Dose | Number and Percentage of Participants With at Least One TEAE Per Treatment Group. | 7 Participants |
| Placebo | Number and Percentage of Participants With at Least One TEAE Per Treatment Group. | 5 Participants |
Secondary
C5a Plasma Concentration
Pharmacodynamic parameter concentration
Time frame: Week 16
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 High Dose | C5a Plasma Concentration | 9.4475 ng/mL | Standard Deviation 7.9414 |
| IFX-1 Low Dose | C5a Plasma Concentration | 37.1361 ng/mL | Standard Deviation 9.7106 |
| Placebo | C5a Plasma Concentration | 31.6571 ng/mL | Standard Deviation 6.9818 |
Secondary
IFX-1 Blocking Activity 10 nM
Pharmacodynamic Parameter of IFX-1 blocking activity 10 nM
Time frame: Week 16
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 High Dose | IFX-1 Blocking Activity 10 nM | 101.693 percentage of IFX-1 blocking activity | Standard Deviation 0.771 |
| IFX-1 Low Dose | IFX-1 Blocking Activity 10 nM | 60.473 percentage of IFX-1 blocking activity | Standard Deviation 29.531 |
Secondary
IFX-1 Blocking Activity 2.5 nM
Pharmacodynamic Parameter of IFX-1 blocking activity 2.5 nM
Time frame: Week 16
Population: Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 High Dose | IFX-1 Blocking Activity 2.5 nM | 103.873 percentage of IFX-1 blocking activity | Standard Deviation 4.667 |
| IFX-1 Low Dose | IFX-1 Blocking Activity 2.5 nM | 82.383 percentage of IFX-1 blocking activity | Standard Deviation 21.957 |
Secondary
IFX 1 Concentration at Predose (0 Hours), After the End of the Infusion (+10minutes), and at 2, 6, 24, and 48 Hours After the Start of the Infusion for Participants in the PK Substudy
Analyze the IMP plasma concentration using a PK model: IFX 1 concentration at predose (0 hours), after the end of the infusion (+10minutes), and at 2, 6, 24, and 48 hours after the start of the infusion for participants in the PK substudy
Time frame: Weeks 1, 4 and 16
Population: Safety Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| IFX-1 High Dose | IFX 1 Concentration at Predose (0 Hours), After the End of the Infusion (+10minutes), and at 2, 6, 24, and 48 Hours After the Start of the Infusion for Participants in the PK Substudy | NA ng/mL |
| IFX-1 Low Dose | IFX 1 Concentration at Predose (0 Hours), After the End of the Infusion (+10minutes), and at 2, 6, 24, and 48 Hours After the Start of the Infusion for Participants in the PK Substudy | NA ng/mL |
| Placebo | IFX 1 Concentration at Predose (0 Hours), After the End of the Infusion (+10minutes), and at 2, 6, 24, and 48 Hours After the Start of the Infusion for Participants in the PK Substudy | NA ng/mL |
Secondary
IFX-1 Concentration Pre-dose
Assess the pharmacokinetic of the investigational medicinal product.
Time frame: Week 16
Population: Safety Analysis Set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IFX-1 High Dose | IFX-1 Concentration Pre-dose | 115598.80 ng/mL | Geometric Coefficient of Variation 82.84 |
| IFX-1 Low Dose | IFX-1 Concentration Pre-dose | 7258.96 ng/mL | Geometric Coefficient of Variation 45.57 |
| Placebo | IFX-1 Concentration Pre-dose | 38.09 ng/mL | Geometric Coefficient of Variation 137.68 |
Secondary
Percentage of Participants Achieving Clinical Response
Efficacy Endpoint based on clinical response evaluated through BVAS. Clinical response is defined as a reduction in BVAS of ≥50% and no worsening in any body system and no administration of rescue medication prior to the response assessment.
Time frame: Week 16
Population: Full Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IFX-1 High Dose | Percentage of Participants Achieving Clinical Response | 5 Participants |
| IFX-1 Low Dose | Percentage of Participants Achieving Clinical Response | 6 Participants |
| Placebo | Percentage of Participants Achieving Clinical Response | 6 Participants |
Secondary
Percentage of Participants With Clinical Remission (BVAS = 0)
Efficacy Endpoint that evaluates participants with complete remission
Time frame: Week 16
Population: Full Analysis Set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IFX-1 High Dose | Percentage of Participants With Clinical Remission (BVAS = 0) | 3 Participants |
| IFX-1 Low Dose | Percentage of Participants With Clinical Remission (BVAS = 0) | 6 Participants |
| Placebo | Percentage of Participants With Clinical Remission (BVAS = 0) | 4 Participants |