IgG4 Related Disease
Conditions
Brief summary
This study aims to evaluate the efficacy and safety of inebilizumab for the prevention of flare of Immunoglobulin G4-related disease (IgG4-RD).
Detailed description
After a screening period of up to 28 days, subjects with IgG4-RD at high risk of flare due to multi-organ disease and recent active disease will be randomized in a 1:1 ratio to receive intravenous (IV) inebilizumab or placebo after premedication during the 52-week randomized control period (RCP). All subjects will receive an initial tapering dose of glucocorticoids (GCs) to complete treatment of their active disease. Flares occurring during study will be treated. The primary endpoint is time to a first adjudication committee-determined, investigator-treated disease flare during the RCP. The primary analysis will be conducted when the last subject completes the RCP visit or discontinues the RCP. This study includes an optional 3-year open-label treatment period. The study also includes a Safety Follow-up Period (SFUP) of up to 730 days for all participants. The expected duration of each subject's participation in this study is up to 400 days (screening and RCP), plus up to 1095 days for eligible subjects who enroll in the optional open label period (OLP), and up to 730 days for the SFUP, for a total maximum duration of up to 2273 days (screening, RCP, interval between RCP and OLP, OLP, and FSUP). Study acquired from Horizon in 2024.
Interventions
DRUGInebilizumab
Inebilizumab is a monoclonal antibody that depletes B cells.
OTHERPlacebo
Placebo
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Male or female adults, ≥ 18 years of age at time of informed consent. 2. Clinical diagnosis of IgG4-RD. 3. Fulfillment of the 2019 ACR/EULAR classification criteria. 4. Experiencing (or recently experienced) an IgG4-RD flare that requires initiation or continuation of glucocorticoid (GC) treatment at the time of informed consent. 5. IgG4-RD affecting at least 2 organs/sites at any time in the course of IgG4-RD 6. Non-sterilized male subjects who are sexually active with a female partner of childbearing potential must use a condom with spermicide from Day 1 through to the end of the study and must agree to continue using such precautions for at least 6 months after the final dose of IP. Females of childbearing potential who are sexually active with a non-sterilized male partner must use a highly effective method of contraception Key
Exclusion criteria
1. History of solid organ or cell-based transplantation or known immunodeficiency disorder. 2. Active malignancy or history of malignancy that was active within the last 10 years (some specific situations for cervical, skin or prostate cancer are acceptable). 3. Receipt of any biologic B cell-depleting therapy or non-depleting B-cell-directed therapy in the 6 months prior to screening. 4. Receipt of non-biologic DMARD or immunosuppressive agent other than GCs within 4 weeks prior to screening. 5. Active tuberculosis or high risk for tuberculosis; hepatitis C infection in absence of curative treatment; evidence of hepatitis B infection. 6. Receipt of live vaccine or live therapeutic infectious agent within 2 weeks prior to screening. 7. Estimated glomerular filtration rate \< 30 mL/min/1.73 m\^2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| RCP: Time to Disease Flare | Up to Week 52 | Time to disease flare was defined as the number of days from Day 1 (dosing) to the date of the first treated and Adjudication Committee (AC)-determined IgG4-RD flare within the 52-week RCP. The date of disease flare was determined by the initiation of any flare treatment, including new or increased glucocorticoid (GC) treatment, other immunotherapy, or an interventional procedure, as deemed necessary by the Investigator to address the flare. Kaplan-Meier (KM) method was used to estimate the median time to flare, and 95% confidence interval (CI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| RCP: Percentage of Participants Achieving Flare-free, Treatment-free Complete Remission at Week 52 | Week 52 | Flare-free, treatment-free complete remission at Week 52 was defined as the absence of evident disease activity at Week 52, no AC-determined flare during the RCP, and no treatment for flare or disease control, except for the required 8-week glucocorticoid taper. Lack of evident disease activity was determined by either a score of 0 on the IgG4-RD Responder Index (score range: 0-4, with lower scores indicating better disease control) or an investigator's assessment that no disease activity was present based on physical, laboratory, pathology, or other evidence. |
| RCP: Percentage of Participants Achieving Flare-free, Corticosteroid-free Complete Remission at Week 52 | Week 52 | Flare-free, corticosteroid-free complete remission at Week 52 was defined as the absence of evident disease activity at Week 52, no AC-determined flare during the RCP, and no corticosteroid treatment for flare or disease control, except for the required 8-week glucocorticoid taper. Lack of evident disease activity was determined by either a score of 0 on the IgG4-RD Responder Index (score range: 0-4, with lower scores indicating better disease control) or an investigator's assessment that no disease activity was present based on physical, laboratory, pathology, or other evidence. |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP | Up to Week 52 | An adverse event (AE) referred to any untoward medical occurrence in a clinical study participant, regardless of a causal relationship with the study treatment. TEAEs included any event occurring after the participant received the study treatment. Clinically significant changes in vital signs, electrocardiograms, and laboratory tests recorded after treatment administration were documented as TEAEs. Serious AEs (SAEs) were untoward medical occurrences after the first dose, irrespective of a causal link to the study treatment, that led to death, were life-threatening, required hospitalization or its prolongation, caused significant disability, resulted in congenital anomalies, or were considered other medically important events. AEs were graded (Grade 3: severe; Grade 4: life-threatening; Grade 5: death) using the Common Terminology Criteria for Adverse Events \[CTCAE\]). |
| Number of Participants Who Experienced TEAEs During the OLP | From the first dose of investigational product in OLP to the end of OLP or cutoff date; median (min, max) duration was 51.6 (0.1, 108.3) weeks. | An AE referred to any untoward medical occurrence in a clinical study participant, regardless of a causal relationship with the study treatment. TEAEs included any event occurring after the participant received the study treatment. Clinically significant changes in vital signs, electrocardiograms, and laboratory tests recorded after treatment administration were documented as TEAEs. SAEs were untoward medical occurrences after the first dose, irrespective of a causal link to the study treatment, that led to death, were life-threatening, required hospitalization or its prolongation, caused significant disability, resulted in congenital anomalies, or were considered other medically important events. AEs were graded (Grade 3: severe; Grade 4: life-threatening; Grade 5: death) using the CTCAE). |
| RCP: Annualized Rate of Treated and AC-Determined Flares During the RCP | Week 52 | The annualized rate of treated and AC-determined flares during the 52-week RCP was calculated by dividing the total number of treated and AC-determined flares by the total time at risk (in years) for all participants. This measure reflected the frequency of disease flares per person per year during the RCP. |
| RCP: Time to Initiation of First Treatment for New or Worsening Disease Activity Within the RCP | Week 52 | Time to initiation of the first treatment (medication or procedure) for new or worsening disease activity, as determined by the investigator, within the RCP, was measured from day 1 (dosing) to the date the first treatment was administered. It Included any treatment initiated by the investigator for disease activity, regardless of the AC determination of flare. KM method was used to estimate the median time to the initiation of first treatment or worsening of disease activity, and 95% CI. |
| RCP: Annualized Flare Rate for AC-Determined IgG4-RD Flares at Week 52 | Week 52 | The annualized flare rate for AC-determined IgG4-RD flares, whether or not treated, during the RCP was calculated by dividing the total number of AC-determined flares by the total time at risk (in years) for all participants. This measure reflected the frequency of IgG4-RD flares, irrespective of treatment, per participant per year during the study period. |
| RCP: Cumulative Glucocorticoid (GC) Use for IgG4-RD Disease Control by Week 52 | Week 52 | GC use was calculated as the cumulative glucocorticoid dose (in milligrams) taken for the purpose of IgG4-RD disease control during the RCP. This measure accounted for all GC treatments administered to participants to manage disease activity throughout the study period. |
| RCP: Number of Participants With Anti-drug Antibodies (ADA) to Inebilizumab by Week 52 | Baseline to Week 52 | Incidence was the proportion of the participants with ADA positive post-baseline only or boosted their preexisting ADA (at least 4-fold over the baseline titer) during the study period. Baseline was defined as the last valid value on or before the first dose of RCP. |
Countries
Argentina, Australia, Canada, China, France, Germany, Hong Kong, Hungary, India, Ireland, Israel, Italy, Japan, Mexico, Netherlands, Poland, Spain, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants affected by immunoglobulin G4-related disease (IgG4-RD) were recruited across 46 sites in Argentina, Australia, Canada, China, France, Germany, Israel, Italy, Japan, Mexico, Netherlands, Poland, Spain, Turkey, the United Kingdom and the United States, between December 2020 and February 2024 which was the safety data cutoff date.
Pre-assignment details
After a 28-day screening period, participants entered a 52-week randomized controlled period (RCP), followed by an optional 3-year open-label period (OLP). The study also included a 2-year safety follow-up (SFUP). The study is ongoing; efficacy data covers the 52-week RCP, while safety data, including 90 participants, were collected up to the cut-off date in February 2024.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants with IgG4-RD were randomized to receive placebo IV infusion on Day 1, Day 15, and Week 26 during the 52-week RCP. Treatment assignment was stratified based on whether the participant was newly diagnosed or had a recurrent IgG4-RD manifestation. After completing the RCP, participants had the option to enter the optional 3-year OLP, where they received inebilizumab on OLP Days 1 and 15. Participants then received inebilizumab every 6 months (Q6M) for the duration of the OLP. | 67 |
| Inebilizumab 300 mg Participants with IgG4-RD were randomized to receive inebilizumab 300 mg IV infusion on Day 1, Day 15, and Week 26 during the 52-week RCP. Treatment assignment was stratified based on whether the participant was newly diagnosed or had a recurrent IgG4-RD manifestation. | 68 |
| Total | 135 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Miscellaneous | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo | Inebilizumab 300 mg |
|---|---|---|---|
| Age, Continuous | 58.2 Years STANDARD_DEVIATION 11.8 | 58.2 Years STANDARD_DEVIATION 12.2 | 58.2 Years STANDARD_DEVIATION 11.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 8 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 109 Participants | 53 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 63 Participants | 25 Participants | 38 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Reported | 10 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 53 Participants | 32 Participants | 21 Participants |
| Sex: Female, Male Female | 47 Participants | 18 Participants | 29 Participants |
| Sex: Female, Male Male | 88 Participants | 49 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 67 | 0 / 68 | 0 / 90 |
| other Total, other adverse events | 49 / 67 | 54 / 68 | 51 / 90 |
| serious Total, serious adverse events | 6 / 67 | 12 / 68 | 14 / 90 |
Outcome results
Primary
RCP: Time to Disease Flare
Time to disease flare was defined as the number of days from Day 1 (dosing) to the date of the first treated and Adjudication Committee (AC)-determined IgG4-RD flare within the 52-week RCP. The date of disease flare was determined by the initiation of any flare treatment, including new or increased glucocorticoid (GC) treatment, other immunotherapy, or an interventional procedure, as deemed necessary by the Investigator to address the flare. Kaplan-Meier (KM) method was used to estimate the median time to flare, and 95% confidence interval (CI).
Time frame: Up to Week 52
Population: Full Analysis Set: all participants who received any dose of investigational product during the RCP.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | RCP: Time to Disease Flare | 246.0 Days |
| Inebilizumab 300 mg | RCP: Time to Disease Flare | NA Days |
95% CI: [0.06, 0.28]
Secondary
Number of Participants Who Experienced TEAEs During the OLP
An AE referred to any untoward medical occurrence in a clinical study participant, regardless of a causal relationship with the study treatment. TEAEs included any event occurring after the participant received the study treatment. Clinically significant changes in vital signs, electrocardiograms, and laboratory tests recorded after treatment administration were documented as TEAEs. SAEs were untoward medical occurrences after the first dose, irrespective of a causal link to the study treatment, that led to death, were life-threatening, required hospitalization or its prolongation, caused significant disability, resulted in congenital anomalies, or were considered other medically important events. AEs were graded (Grade 3: severe; Grade 4: life-threatening; Grade 5: death) using the CTCAE).
Time frame: From the first dose of investigational product in OLP to the end of OLP or cutoff date; median (min, max) duration was 51.6 (0.1, 108.3) weeks.
Secondary
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP
An adverse event (AE) referred to any untoward medical occurrence in a clinical study participant, regardless of a causal relationship with the study treatment. TEAEs included any event occurring after the participant received the study treatment. Clinically significant changes in vital signs, electrocardiograms, and laboratory tests recorded after treatment administration were documented as TEAEs. Serious AEs (SAEs) were untoward medical occurrences after the first dose, irrespective of a causal link to the study treatment, that led to death, were life-threatening, required hospitalization or its prolongation, caused significant disability, resulted in congenital anomalies, or were considered other medically important events. AEs were graded (Grade 3: severe; Grade 4: life-threatening; Grade 5: death) using the Common Terminology Criteria for Adverse Events \[CTCAE\]).
Time frame: Up to Week 52
Population: Safety Analysis Set RCP: All participants who received any dose of investigational product during the RCP. Participants were analyzed according to the treatment they actually received. Specifically, participants randomized to the inebilizumab group who received all placebo dose were included in the placebo group.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP | TEAEs | 66 Participants |
| Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP | SAEs | 6 Participants |
| Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP | Fatal TEAEs | 0 Participants |
| Placebo | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP | Grade ≥ 3 TEAEs | 8 Participants |
| Inebilizumab 300 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP | Grade ≥ 3 TEAEs | 12 Participants |
| Inebilizumab 300 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP | TEAEs | 66 Participants |
| Inebilizumab 300 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP | Fatal TEAEs | 0 Participants |
| Inebilizumab 300 mg | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) During the RCP | SAEs | 12 Participants |
Secondary
RCP: Annualized Flare Rate for AC-Determined IgG4-RD Flares at Week 52
The annualized flare rate for AC-determined IgG4-RD flares, whether or not treated, during the RCP was calculated by dividing the total number of AC-determined flares by the total time at risk (in years) for all participants. This measure reflected the frequency of IgG4-RD flares, irrespective of treatment, per participant per year during the study period.
Time frame: Week 52
Population: Full Analysis Set: all participants who received any dose of investigational product during the RCP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | RCP: Annualized Flare Rate for AC-Determined IgG4-RD Flares at Week 52 | 0.75 Flares per participant per year |
| Inebilizumab 300 mg | RCP: Annualized Flare Rate for AC-Determined IgG4-RD Flares at Week 52 | 0.16 Flares per participant per year |
Secondary
RCP: Annualized Rate of Treated and AC-Determined Flares During the RCP
The annualized rate of treated and AC-determined flares during the 52-week RCP was calculated by dividing the total number of treated and AC-determined flares by the total time at risk (in years) for all participants. This measure reflected the frequency of disease flares per person per year during the RCP.
Time frame: Week 52
Population: Full Analysis Set: all participants who received any dose of investigational product during the RCP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | RCP: Annualized Rate of Treated and AC-Determined Flares During the RCP | 0.71 Flares per person per year |
| Inebilizumab 300 mg | RCP: Annualized Rate of Treated and AC-Determined Flares During the RCP | 0.10 Flares per person per year |
Secondary
RCP: Cumulative Glucocorticoid (GC) Use for IgG4-RD Disease Control by Week 52
GC use was calculated as the cumulative glucocorticoid dose (in milligrams) taken for the purpose of IgG4-RD disease control during the RCP. This measure accounted for all GC treatments administered to participants to manage disease activity throughout the study period.
Time frame: Week 52
Population: Full Analysis Set: all participants who received any dose of investigational product during the RCP.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | RCP: Cumulative Glucocorticoid (GC) Use for IgG4-RD Disease Control by Week 52 | 1384.53 mg | Standard Deviation 1723.26 |
| Inebilizumab 300 mg | RCP: Cumulative Glucocorticoid (GC) Use for IgG4-RD Disease Control by Week 52 | 118.25 mg | Standard Deviation 438.97 |
Secondary
RCP: Number of Participants With Anti-drug Antibodies (ADA) to Inebilizumab by Week 52
Incidence was the proportion of the participants with ADA positive post-baseline only or boosted their preexisting ADA (at least 4-fold over the baseline titer) during the study period. Baseline was defined as the last valid value on or before the first dose of RCP.
Time frame: Baseline to Week 52
Population: Full Analysis Set: all participants who received any dose of investigational product during the RCP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | RCP: Number of Participants With Anti-drug Antibodies (ADA) to Inebilizumab by Week 52 | 5 Participants |
| Inebilizumab 300 mg | RCP: Number of Participants With Anti-drug Antibodies (ADA) to Inebilizumab by Week 52 | 6 Participants |
Secondary
RCP: Percentage of Participants Achieving Flare-free, Corticosteroid-free Complete Remission at Week 52
Flare-free, corticosteroid-free complete remission at Week 52 was defined as the absence of evident disease activity at Week 52, no AC-determined flare during the RCP, and no corticosteroid treatment for flare or disease control, except for the required 8-week glucocorticoid taper. Lack of evident disease activity was determined by either a score of 0 on the IgG4-RD Responder Index (score range: 0-4, with lower scores indicating better disease control) or an investigator's assessment that no disease activity was present based on physical, laboratory, pathology, or other evidence.
Time frame: Week 52
Population: Full Analysis Set: all participants who received any dose of investigational product during the RCP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | RCP: Percentage of Participants Achieving Flare-free, Corticosteroid-free Complete Remission at Week 52 | 15 Participants |
| Inebilizumab 300 mg | RCP: Percentage of Participants Achieving Flare-free, Corticosteroid-free Complete Remission at Week 52 | 40 Participants |
Secondary
RCP: Percentage of Participants Achieving Flare-free, Treatment-free Complete Remission at Week 52
Flare-free, treatment-free complete remission at Week 52 was defined as the absence of evident disease activity at Week 52, no AC-determined flare during the RCP, and no treatment for flare or disease control, except for the required 8-week glucocorticoid taper. Lack of evident disease activity was determined by either a score of 0 on the IgG4-RD Responder Index (score range: 0-4, with lower scores indicating better disease control) or an investigator's assessment that no disease activity was present based on physical, laboratory, pathology, or other evidence.
Time frame: Week 52
Population: Full Analysis Set: all participants who received any dose of investigational product during the RCP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | RCP: Percentage of Participants Achieving Flare-free, Treatment-free Complete Remission at Week 52 | 15 Participants |
| Inebilizumab 300 mg | RCP: Percentage of Participants Achieving Flare-free, Treatment-free Complete Remission at Week 52 | 39 Participants |
Secondary
RCP: Time to Initiation of First Treatment for New or Worsening Disease Activity Within the RCP
Time to initiation of the first treatment (medication or procedure) for new or worsening disease activity, as determined by the investigator, within the RCP, was measured from day 1 (dosing) to the date the first treatment was administered. It Included any treatment initiated by the investigator for disease activity, regardless of the AC determination of flare. KM method was used to estimate the median time to the initiation of first treatment or worsening of disease activity, and 95% CI.
Time frame: Week 52
Population: Full Analysis Set: all participants who received any dose of investigational product during the RCP, and experienced IgG4-RD flares, regardless of the AC determination of flare.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | RCP: Time to Initiation of First Treatment for New or Worsening Disease Activity Within the RCP | 237.0 Days |
| Inebilizumab 300 mg | RCP: Time to Initiation of First Treatment for New or Worsening Disease Activity Within the RCP | NA Days |
95% CI: [0.05, 0.26]