NLRC4-MAS, XIAP Deficiency
Conditions
Brief summary
This is a Phase 3 study to assess the safety and efficacy of Tadekinig alfa in patients with monogenic, interleukin-18 (IL 18) driven autoinflammation due to Nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruiting domain (CARD domain) containing 4 (NLRC4) - Macrophage activation syndrome (MAS) mutation (NLRC4-MAS mutation) or X-linked inhibitor of apoptosis (XIAP) deficiency. Because of the likelihood for pathogenic IL-18 in certain monogenic diseases, patients known to harbor deleterious mutations in NLRC4-MAS or XIAP and who have a history of ongoing inflammation will be enrolled if they have ferritin ≥ 500 ng/mL or persistent C reactive protein (CRP) elevation ≥ 2 times the upper limit of normal (ULN) and the patients should have a Modified Autoinflammatory Disease Activity Index (mAIDAI) ≥ 4.
Detailed description
The study is designed with single-arm, open-label phase (SAOL) of Tadekinig alfa treatment duration for 18-week followed by an up to 16-week Randomized Withdrawal (RW) period for efficacy and safety evaluation, with no interruption between the two phases of treatment. The screening period will occur before the SAOL phase and before the first dose of Investigational Medicinal Product (IMP)
Interventions
DRUGTadekinig alfa
Tadekinig alfa is a soluble glycoprotein of 164 amino acids produced from Chinese Hamster Ovary cell line. Tadekinig alfa is supplied as a colorless to slightly yellow, sterile solution for injection in glass vials containing sodium chloride, and 0.02M sodium phosphate buffer as excipients. It is available in a concentration of 20mg/0.5mL.
OTHER0.9% sodium chloride
To ensure that the treatment remains blinded for the entire study period, the placebo solutions will be supplied in identical vials and similar labelling as the active drug and will be indistinguishable in terms of their texture, color, and smell.
Sponsors
AB2 Bio Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Initial phase of 18 weeks is a single arm, open-label (SAOL) period where Tadekinig alfa is administered in addition to the standard of care treatment used for the control of flares. The SAOL period will be followed by an up to 16-week randomized withdrawal phase (RW). All patients who showed response to treatment at the end of the SAOL phase will be enrolled in the RW phase. In the RW phase patients will be randomized to either Tadekinig alfa or placebo.
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Patients with genetic diagnosis of NLRC4-MAS mutation or XIAP deficiency (caused by BIRC4 gene mutation) as confirmed by analysis performed at the central genetics laboratory. If possible, flow cytometry assay will be performed in parallel to confirm diagnosis of XIAP deficiency. (Note: Previous flow cytometry assay results will be permitted for confirmation of XIAP deficiency diagnosis.) 2. Patients with XIAP deficiency and a previous bone marrow transplantation are allowed, if they show evidence of primary or secondary graft failure, or failure to achieve phenotypic correction with evidence of XIAP-related disease recurrence or clinically significant mixed chimerism. 3. Ferritin ≥ 500 ng/mL or persistent elevation of CRP ≥ 2x ULN and mAIDAI ≥4 4. Patients receiving corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) or disease modifying anti-rheumatic drugs (DMARDs), and/or IL-1 blockade with insufficient response to treatment upon enrollment are allowed into the study. Patients not receiving any of these treatments before start of therapy are also allowed. 5. Women of childbearing potential with negative urine pregnancy test (UPT) at all visits (if UPT is positive, a blood test for human chorionic gonadotropin (hCG) to be performed) and who agree to follow highly effective birth control recommendations during the study and until 1 month after the end of the treatment. Birth control methods considered highly effective are: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner or sexual abstinence. In each case of delayed menstrual period (over one month between menstruations, confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to women of childbearing potential with infrequent or irregular menstrual cycles. A post-study contraception duration of 4 weeks is recommended taking into account the median half-life of Tadekinig alfa of almost 40h and 5 half-lives representing a duration of 200 hours.
Exclusion criteria
1. Patients with life-threatening co-morbidities not associated with the underlying NLRC4-mutation or XIAP deficiency 2. Positive test for or prior history of HIV, Hepatitis B or Hepatitis C (serology) 3. Presence of active infections or a history of pulmonary TB infection with or without documented adequate therapy 4. Presence of life threatening infections 5. Oncologic causes of symptoms; current or previous history of malignancy 6. Presence of CNS manifestations (i.e. seizures, altered mental status, signs of increased intracranial pressure, chronic papilledema, loss of vision, other sensorineural deficiencies, etc.) 7. Patients suffering from biallelic mutations in any of the following genes: PRF1/Perforin, UNC13D/Munc 13-4, STX11/Syntaxin11, STXB2/Munc 18-2, RAB27A/Rab27a (Griscelli syndrome type 2), LYST (Chediak-Higashi syndrome), AP3B1, ADTB3A, HPS2 mutations (Hermansky-Pudlak syndrome 2) and X-linked lymphoproliferative syndrome (XLP)-1 with SH2D1A mutation 8. Patients who are pregnant or nursing, women of childbearing potential who are unwilling to use highly effective birth control methods (see definition in Inclusion Criteria above) through 4 weeks after the end of their participation in the study 9. Concomitant use of immunosuppression therapies excluded by the protocol. Note: NSAIDs, glucocorticoids, cyclosporine, tacrolimus, and IL-1 inhibitors (anakinra, canakinumab, or rilonacept, or others) are allowed 10. Patients and/or parents (or legal representative, if applicable) not willing to sign assent/informed consent 11. Hypersensitivity to the active substance or one of the excipients of the investigational product
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Prevention of Flares | 16 weeks | The primary outcome measure is the time to first occurrence of disease reactivation during the 16-week RW phase. Method of assessment: Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Response | 18 weeks | Best response to therapy during the SAOL phase including either complete response, partial response or disease improvement. Method of assessment: Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage. |
| Duration of Response During the SAOL Phase (Until End of Phase or Disease Reactivation) | The actual mean treatment duration in the SAOL phase was 17.6 weeks (minimum / maximum 5.9 / 22.1 weeks). | Duration of response to therapy during the SAOL phase is assessed for patients having achieved a complete or partial response to therapy during the SAOL phase. It is defined as the time from first evaluation of partial or complete response until the time of subsequent disease reactivation or end of SAOL phase, whichever occurs first. Of the 11 patients achieving partial or complete response during the SAOL phase, 8 maintained treatment response until the end of the SAOL phase. 2 of the 11 patients had a temporary disease reactivation during the protocol mandated steroid weaning in the SAOL phase; 1 of the 11 patients was withdrawn from blinded treatment following a disease reactivation. |
| Change From Baseline in mAIDAI Total Score in the SAOL Phase | 18 weeks | The mAIDAI (modified autoinflammatory disease activitiy index) is an assessment of global disease activity that measures 14 different components for disease as either absent (0 points) or present (2 points for Uveitis 3+/4+ and 1 point for all other symptoms) at each visit. The mAIDAI total score is the sum of the points assigned across all components and ranges from 0 to 15, with a higher score indicating more severe disease activity. |
| Change From Baseline in Serum Ferritin | 34 weeks | Laboratory measure |
| Change From Baseline in Serum CRP | 34 weeks | Laboratory measure |
| Resolution of Fevers, Hepato/Splenomegaly and Skin Rash | 18 weeks | Clinical assessments if present at Baseline; number displays percentage of patients with resolution of individual disease component at Week 18 or early termination visit based on the number of patients with a baseline assessment for the component of interest. |
| Improvement in Laboratory Markers - AST (SGOT) | 18 weeks | Change from Baseline mean value to Week 18 mean value |
| Improvement in Laboratory Markers - ALT (SGPT) | 18 weeks | Change from Baseline mean value to Week 18 mean value |
| Improvement in Laboratory Markers - Albumin | 18 weeks | Change from Baseline mean value to Week 18 mean value |
| Improvement in Laboratory Markers - Hemoglobin | 18 weeks | Change from Baseline mean value to Week 18 mean value |
| Improvement in Laboratory Markers - Erythrocyte Sedimentation Rate | 18 weeks | Change from Baseline mean value to Week 18 mean value |
| Improvement in Laboratory Markers - Fibrinogen | 18 weeks | Change from Baseline mean value to Week 18 mean value |
| Improvement in Laboratory Markers - D-Dimer | 18 weeks | Change from Baseline mean value to Week 18 mean value |
| Hospital Length of Stay | 34 weeks | Length of hospitalisation; emergency room attendance and unscheduled visits for treatment of disease reactivations not included |
| Change in Physician Global Assessment (PGA) | 34 weeks | The PGA is a direct surrogate of how a patient functions and assesses the severity of disease-related (auto-inflammatory) symptoms by selecting an integer score from 0 (no impact on subject; no symptoms) to 10 (no normal activities possible; highest severity of symptoms possible). The outcome lists the change from baseline of treatment phase to end of treatment phase/study in the PGA symptom severity score. |
| Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase | 16 weeks | The individual disease-related symptoms score is the sum of (x) individual symptom scores within domain each ranging from 0 (None) to 5 (Very severe) for: general wellbeing (5), gastrointestinal (7), musculoskeletal (5), skin (2), eye (2), central nervous system (3), and lymphatic (2). Highest values indicate more severe disease-related symptoms within total score range from 0-130. |
| Immunogenicity Evaluation | 34 weeks (SAOL + RW phases) | Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies |
| Local Tolerability at the Injection Site (as Defined by Number of Participants With Adverse Events of Special Interest) | 34 weeks (SAOL + RW phases) | Adverse events of special interest (AESIs) are defined for this protocol as injection site reactions (including pruritus, erythema, swelling). |
| Disease Reactivation Rate | 18 weeks | Disease reactivation rate for individual subjects (number of disease reactivations experienced per week while each subject is on the study treatment during the SAOL phase) |
| Treatment Failures | 18 weeks | Treatment failures (i.e. patients who experience at least one disease reactivation) during the SAOL phase |
| Improvement in Laboratory Markers - Platelets | 18 weeks | Change from Baseline mean value to Week 18 mean value |
Other
| Measure | Time frame | Description |
|---|---|---|
| Response to Therapy - Key Secondary Efficacy Endpoint | 18 weeks | Response to therapy (including complete response and partial response) in the SAOL phase from Week 10 onwards and observed at least at 2 consecutive visits at least 2 weeks apart during the SAOL phase |
Countries
Canada, Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Open-Label - Tadekinig Alfa The Single Arm Open-Label Full Analysis Set (SAOL-FAS) includes all patients treated with Tadekinig alfa in the first 18 weeks of treatment. | 14 |
| Randomized Double-Blind Placebo-Controlled - Placebo Arm The Randomized Double-Blind Placebo-Controlled Analysis Set (RDBPC-AS) includes 1 patient treated with Placebo in the first treatment phase. | 1 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Initial 18 Weeks Treatment Phase | Adverse Event | 1 | 0 | 0 | 0 |
| Initial 18 Weeks Treatment Phase | Disease relapse | 1 | 1 | 0 | 0 |
| Initial 18 Weeks Treatment Phase | Withdrawal by Subject | 2 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Randomized Double-Blind Placebo-Controlled - Placebo Arm | Single Arm Open-Label - Tadekinig Alfa | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 14 Participants | 15 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 1 Participants | 7 Participants | 8 Participants |
| Region of Enrollment Canada | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Germany | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 0 Participants | 11 Participants | 11 Participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 1 Participants | 10 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 1 | 0 / 5 | 0 / 5 | 0 / 15 |
| other Total, other adverse events | 14 / 14 | 1 / 1 | 4 / 5 | 4 / 5 | 7 / 15 |
| serious Total, serious adverse events | 3 / 14 | 0 / 1 | 0 / 5 | 0 / 5 | 1 / 15 |
Outcome results
Primary
Prevention of Flares
The primary outcome measure is the time to first occurrence of disease reactivation during the 16-week RW phase. Method of assessment: Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage.
Time frame: 16 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Withdrawal - Placebo Arm | Prevention of Flares | 2.71 Weeks |
| Randomized Withdrawal - Tadekinig Alfa Arm | Prevention of Flares | NA Weeks |
Secondary
Best Response
Best response to therapy during the SAOL phase including either complete response, partial response or disease improvement. Method of assessment: Biomarkers (CRP / Ferritin) and clinical manifestations of systemic inflammation and end-organ damage.
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Best Response | Complete response | 1 Participants |
| Randomized Withdrawal - Placebo Arm | Best Response | Partial response | 10 Participants |
| Randomized Withdrawal - Placebo Arm | Best Response | Disease improvement | 3 Participants |
| Randomized Withdrawal - Placebo Arm | Best Response | No response | 0 Participants |
Secondary
Change From Baseline in mAIDAI Total Score in the SAOL Phase
The mAIDAI (modified autoinflammatory disease activitiy index) is an assessment of global disease activity that measures 14 different components for disease as either absent (0 points) or present (2 points for Uveitis 3+/4+ and 1 point for all other symptoms) at each visit. The mAIDAI total score is the sum of the points assigned across all components and ranges from 0 to 15, with a higher score indicating more severe disease activity.
Time frame: 18 weeks
Population: Change from Baseline to Week 18 in mAIDAI Total Score. The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Change From Baseline in mAIDAI Total Score in the SAOL Phase | -3.9 score | Standard Deviation 0.74 |
Secondary
Change From Baseline in Serum CRP
Laboratory measure
Time frame: 34 weeks
Population: Values indicate change from Baseline to End of Phase results. The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Change From Baseline in Serum CRP | -2.28 ug/mL | Standard Deviation 4.28 |
| Randomized Withdrawal - Tadekinig Alfa Arm | Change From Baseline in Serum CRP | -0.02 ug/mL | Standard Deviation 0.19 |
| Randomized Withdrawal - Placebo Arm | Change From Baseline in Serum CRP | 0.24 ug/mL | Standard Deviation 1.35 |
Secondary
Change From Baseline in Serum Ferritin
Laboratory measure
Time frame: 34 weeks
Population: Values indicate change from Baseline to End of Phase results. The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Change From Baseline in Serum Ferritin | -8558.7 ng/mL | Standard Deviation 15700.51 |
| Randomized Withdrawal - Tadekinig Alfa Arm | Change From Baseline in Serum Ferritin | -109.5 ng/mL | Standard Deviation 167.4 |
| Randomized Withdrawal - Placebo Arm | Change From Baseline in Serum Ferritin | 211.8 ng/mL | Standard Deviation 359.1 |
Secondary
Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase
The individual disease-related symptoms score is the sum of (x) individual symptom scores within domain each ranging from 0 (None) to 5 (Very severe) for: general wellbeing (5), gastrointestinal (7), musculoskeletal (5), skin (2), eye (2), central nervous system (3), and lymphatic (2). Highest values indicate more severe disease-related symptoms within total score range from 0-130.
Time frame: 16 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase | Start of RW phase | 11.3 score | Standard Deviation 8.6 |
| Randomized Withdrawal - Placebo Arm | Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase | End of RW phase | 7.7 score | Standard Deviation 7.1 |
| Randomized Withdrawal - Placebo Arm | Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase | Change from start to end of RW phase | -3.7 score | Standard Deviation 5.7 |
| Randomized Withdrawal - Tadekinig Alfa Arm | Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase | Start of RW phase | 2.0 score | Standard Deviation 2.8 |
| Randomized Withdrawal - Tadekinig Alfa Arm | Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase | End of RW phase | 46.0 score | Standard Deviation 14.1 |
| Randomized Withdrawal - Tadekinig Alfa Arm | Change in Patient/Caregiver Qualitative Evaluation of Health Status in Randomized Withdrawal Phase | Change from start to end of RW phase | 44.0 score | Standard Deviation 17 |
Secondary
Change in Physician Global Assessment (PGA)
The PGA is a direct surrogate of how a patient functions and assesses the severity of disease-related (auto-inflammatory) symptoms by selecting an integer score from 0 (no impact on subject; no symptoms) to 10 (no normal activities possible; highest severity of symptoms possible). The outcome lists the change from baseline of treatment phase to end of treatment phase/study in the PGA symptom severity score.
Time frame: 34 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Change in Physician Global Assessment (PGA) | -5.8 score | Standard Deviation 2.1 |
| Randomized Withdrawal - Tadekinig Alfa Arm | Change in Physician Global Assessment (PGA) | 0.4 score | Standard Deviation 0.89 |
| Randomized Withdrawal - Placebo Arm | Change in Physician Global Assessment (PGA) | 2.0 score | Standard Deviation 3.39 |
Secondary
Disease Reactivation Rate
Disease reactivation rate for individual subjects (number of disease reactivations experienced per week while each subject is on the study treatment during the SAOL phase)
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Disease Reactivation Rate | 0.0 Disease reactivation rate per week | Standard Deviation 0.09 |
Secondary
Duration of Response During the SAOL Phase (Until End of Phase or Disease Reactivation)
Duration of response to therapy during the SAOL phase is assessed for patients having achieved a complete or partial response to therapy during the SAOL phase. It is defined as the time from first evaluation of partial or complete response until the time of subsequent disease reactivation or end of SAOL phase, whichever occurs first. Of the 11 patients achieving partial or complete response during the SAOL phase, 8 maintained treatment response until the end of the SAOL phase. 2 of the 11 patients had a temporary disease reactivation during the protocol mandated steroid weaning in the SAOL phase; 1 of the 11 patients was withdrawn from blinded treatment following a disease reactivation.
Time frame: The actual mean treatment duration in the SAOL phase was 17.6 weeks (minimum / maximum 5.9 / 22.1 weeks).
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Randomized Withdrawal - Placebo Arm | Duration of Response During the SAOL Phase (Until End of Phase or Disease Reactivation) | 11.9 Weeks |
Secondary
Hospital Length of Stay
Length of hospitalisation; emergency room attendance and unscheduled visits for treatment of disease reactivations not included
Time frame: 34 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Hospital Length of Stay | Baseline hospitalization | 54 days |
| Randomized Withdrawal - Placebo Arm | Hospital Length of Stay | Subsequent hospitalization | 5.5 days |
| Randomized Withdrawal - Tadekinig Alfa Arm | Hospital Length of Stay | Baseline hospitalization | NA days |
| Randomized Withdrawal - Tadekinig Alfa Arm | Hospital Length of Stay | Subsequent hospitalization | 0 days |
| Randomized Withdrawal - Placebo Arm | Hospital Length of Stay | Baseline hospitalization | NA days |
| Randomized Withdrawal - Placebo Arm | Hospital Length of Stay | Subsequent hospitalization | 0 days |
Secondary
Immunogenicity Evaluation
Generation of anti-recombinant human IL-18BP (anti-rhIL-18BP) antibodies
Time frame: 34 weeks (SAOL + RW phases)
Secondary
Improvement in Laboratory Markers - Albumin
Change from Baseline mean value to Week 18 mean value
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Improvement in Laboratory Markers - Albumin | 4.7 g/L | Standard Deviation 5.66 |
Secondary
Improvement in Laboratory Markers - ALT (SGPT)
Change from Baseline mean value to Week 18 mean value
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Improvement in Laboratory Markers - ALT (SGPT) | -581.2 U/L | Standard Deviation 1324.21 |
Secondary
Improvement in Laboratory Markers - AST (SGOT)
Change from Baseline mean value to Week 18 mean value
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Improvement in Laboratory Markers - AST (SGOT) | -286.2 U/L | Standard Deviation 727.5 |
Secondary
Improvement in Laboratory Markers - D-Dimer
Change from Baseline mean value to Week 18 mean value
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Improvement in Laboratory Markers - D-Dimer | -3.85 mg/L | Standard Deviation 5.89 |
Secondary
Improvement in Laboratory Markers - Erythrocyte Sedimentation Rate
Change from Baseline mean value to Week 18 mean value
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Improvement in Laboratory Markers - Erythrocyte Sedimentation Rate | -6.3 mm/h | Standard Deviation 10.47 |
Secondary
Improvement in Laboratory Markers - Fibrinogen
Change from Baseline mean value to Week 18 mean value
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Improvement in Laboratory Markers - Fibrinogen | 12.7 mg/dL | Standard Deviation 108.1 |
Secondary
Improvement in Laboratory Markers - Hemoglobin
Change from Baseline mean value to Week 18 mean value
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Improvement in Laboratory Markers - Hemoglobin | 17.2 g/L | Standard Deviation 18.24 |
Secondary
Improvement in Laboratory Markers - Platelets
Change from Baseline mean value to Week 18 mean value
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Improvement in Laboratory Markers - Platelets | 24.0 cells x 10^9/L | Standard Deviation 143.1 |
Secondary
Local Tolerability at the Injection Site (as Defined by Number of Participants With Adverse Events of Special Interest)
Adverse events of special interest (AESIs) are defined for this protocol as injection site reactions (including pruritus, erythema, swelling).
Time frame: 34 weeks (SAOL + RW phases)
Population: Patients reporting at least one AESI. The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Randomized Withdrawal - Placebo Arm | Local Tolerability at the Injection Site (as Defined by Number of Participants With Adverse Events of Special Interest) | 8 Participants |
| Randomized Withdrawal - Tadekinig Alfa Arm | Local Tolerability at the Injection Site (as Defined by Number of Participants With Adverse Events of Special Interest) | 3 Participants |
| Randomized Withdrawal - Placebo Arm | Local Tolerability at the Injection Site (as Defined by Number of Participants With Adverse Events of Special Interest) | 1 Participants |
Secondary
Resolution of Fevers, Hepato/Splenomegaly and Skin Rash
Clinical assessments if present at Baseline; number displays percentage of patients with resolution of individual disease component at Week 18 or early termination visit based on the number of patients with a baseline assessment for the component of interest.
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Randomized Withdrawal - Placebo Arm | Resolution of Fevers, Hepato/Splenomegaly and Skin Rash | Resolution of Organomegaly | 54 Percentage of patients with resolution |
| Randomized Withdrawal - Placebo Arm | Resolution of Fevers, Hepato/Splenomegaly and Skin Rash | Resolution of Fever | 100 Percentage of patients with resolution |
| Randomized Withdrawal - Placebo Arm | Resolution of Fevers, Hepato/Splenomegaly and Skin Rash | Resolution of Skin rash | 75 Percentage of patients with resolution |
Secondary
Treatment Failures
Treatment failures (i.e. patients who experience at least one disease reactivation) during the SAOL phase
Time frame: 18 weeks
Population: Treatment failures were defined as patients who experienced at least 1 disease reactivation. Disease reactivation includes full or partial disease reactivation after the first assessment indicating partial or complete response during the SAOL phase as defined in the statistical analysis plan.~The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Randomized Withdrawal - Placebo Arm | Treatment Failures | 3 Participants |
Other Pre-specified
Response to Therapy - Key Secondary Efficacy Endpoint
Response to therapy (including complete response and partial response) in the SAOL phase from Week 10 onwards and observed at least at 2 consecutive visits at least 2 weeks apart during the SAOL phase
Time frame: 18 weeks
Population: The safety and efficacy analyses during the SAOL phase is based on the SAOL-FAS as defined in the study protocol and statistical analysis plan. 1 patient treated with Placebo in the first treatment phase under the initial protocol design starting with a randomized treatment phase is excluded from the efficacy analysis due to the difference in treatment schedule but included in the safety analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Randomized Withdrawal - Placebo Arm | Response to Therapy - Key Secondary Efficacy Endpoint | 10 Participants |