Arthritis, Rheumatoid
Conditions
Keywords
inadequate responders, moderate to severe, Rheumatoid Arthritis
Brief summary
Phase 2 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of KPL-404 in subjects with moderate to severe Rheumatoid Arthritis.
Detailed description
This is a 28-week (up to 4-week screening period, 12-week treatment period, and 12-week safety follow-up period), multicenter, randomized, double-blind, placebo-controlled, multiple dose, proof-of-concept study with PK lead-in designed to assess the safety, PK, efficacy and PD of KPL-404 in subjects with moderate to severe, active Rheumatoid Arthritis (RA) who have an inadequate response to or are intolerant to a Janus kinase inhibitor (JAKi) AND/OR at least one biologic disease-modifying anti-rheumatic drug (bDMARD). The objectives of the study are to evaluate safety, efficacy, and PD of KPL-404 compared with placebo across the estimated therapeutic range and to characterize PK across varying dose levels of KPL-404.
Interventions
DRUGKPL-404
Humanized monoclonal antibody
DRUGPlacebo
Matching placebo
Sponsors
Kiniksa Pharmaceuticals, Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Body weight ≥ 40 to ≤ 140 kg for all cohorts. * Diagnosis of RA for ≥ 3 months fulfilling the 2010 American College of Rheumatology (ACR)/European Union League Against Rheumatism (EULAR) classification criteria for RA and that is categorized as ACR RA functional Class 1-3. * Treated with a biological disease-modifying anti-rheumatic drug (bDMARDs) AND/OR Janus kinase inhibitor (JAKi) therapy for RA for ≥ 3 months and had inadequate response or had to discontinue bDMARD AND/OR JAKi therapy due to intolerance or toxicity, regardless of treatment duration. * Currently receiving conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) therapy ≥ 3 months and on a stable dose for ≥ 4 weeks before the first dose of investigational product. 1. The following csDMARDs are allowed: oral or parenteral methotrexate (\[MTX\]; 7.5 to 25 mg/week), sulfasalazine (≤ 3000 mg/day), hydroxychloroquine (≤ 400 mg/day), chloroquine (≤ 250 mg/day), and leflunomide (≤ 20 mg/day). 2. A combination of up to 2 background csDMARDs is allowed, except the combination of MTX and leflunomide. * Meets all of the following disease activity criteria: 1. Six or more swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at screening and baseline visits; 2. Level of high-sensitivity C-reactive protein ≥ 3 mg/L (by central laboratory); 3. Documented seropositivity for serum Rheumatoid Factor (RF) and/or Anti-citrullinated protein antibody (ACPA) (\>ULN) at screening or by prior laboratory evaluation. * Has completed a locally approved authorized COVID-19 vaccine regimen according to local guidance at least 3 weeks before the first dose of the Investigational Product. * Must have discontinued all bDMARDs or JAKi prior to the first dose of investigational product. The washout period for bDMARDs or JAKi prior to the first dose of investigational product is specified below. For bDMARDs or JAKi not listed below washout should be at least 5 times the mean elimination half-life of a drug: 1. ≥ 4 weeks for etanercept; 2. ≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, tocilizumab, and sarilumab; 3. ≥ 1 year for rituximab; 4. ≥ 2 weeks for JAKi (either investigational or commercially available treatment). * Voluntarily sign and date an informed consent form approved by independent ethics committee/Institutional Review Board (IRB)
Exclusion criteria
* Prior exposure to any other anti-CD40/CD40L agent. * Inadequate response to 5 or more classes of advanced targeted therapies (bDMARD or tsDMARD; e.g., TNF inhibitors, IL-6 receptor inhibitors, T-cell costimulatory inhibitors, anti-CD-20 antibodies, JAK inhibitors). This does not include prior discontinuation due to drug intolerance. * Injectable corticosteroids (including intra-articular) or treatment with \> 10 mg/day dose oral prednisone or equivalent within 8 weeks prior to randomization. * History of any arthritis with onset prior to age 16 years or current diagnosis of inflammatory joint disease other than RA (Current diagnosis of secondary Sjogren's syndrome is permitted). * History of thromboembolic event or a significant risk of future thromboembolic events * Clinically significant active infection including signs/symptoms suggestive of infection, any significant recurrent or chronic infection, or subjects at a high risk of infection * History of cancer within the last 5 years from screening, except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured. * History of any of the following cardiovascular conditions: 1. Moderate to severe congestive heart failure (New York Heart Association class III or IV); 2. Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting; 3. Uncontrolled hypertension as defined by a confirmed systolic blood pressure \> 160 mmHg or diastolic blood pressure \> 100 mmHg. * Clinically relevant or significant electrocardiogram (ECG) abnormalities, including ECG with QT interval corrected for heart rate (QTc) \> 500 msec.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From first dose of study drug to 24 weeks | Adverse event (AE): any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. Serious AE (SAE): AE that: results in death; is immediately life-threatening; requires in-patient hospitalization/prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital abnormality/birth defect; is an important medical event. TEAEs: AEs not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug during treatment period. AE severity: mild (Grade \[Gr\] 1); moderate (Gr 2); severe (Gr 3); potentially life threatening (Gr 4); death (Gr 5). AEs of special interest: thrombosis, serious infection, serious and non-serious bacterial infections, eye disorders, and anaphylaxis/hypersensitivity reactions. |
| Cohorts 1 and 2: Maximum Serum Concentration (Cmax) | Days 1 (Dose 1) and 57 (Dose 4) | — |
| Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time of Administration to the End of the Dosing Interval, (AUCtau) | Days 1 (Dose 1) and 57 (Dose 4) | — |
| Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12 | Baseline, Week 12 | DAS28 is a measure based on assessment of 28 joints for tenderness and swelling (tender and swollen joint counts). DAS28-CRP is derived using differential weighting given to 4 components: tender joint count (range: 0-28), swollen joint count (range: 0-28), patient global assessment (recorded on a visual analog scale \[VAS\] scale of 0-100 mm), and CRP (milligram per liter). DAS28-CRP score ranges from 0 to 9.4. The lower the DAS28-CRP score is, the better the participant has response (remission = score \< 2.6, low disease activity = score \< 3.2). A negative value in change from BL indicates an improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | Baseline, Week 12 | An ACR20 response is defined as at least a 20% improvement in both tender joint count (TJC) and swollen joint count (SJC), and at least a 20% improvement in three of the following five criteria: patient global assessment (PGA), physician global assessment (PhGA), functional ability measure \[Health Assessment Questionnaire (HAQ)\], patient's assessment of pain (visual analog scale; VAS) and C-reactive protein (CRP). |
| Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12 | Baseline, Week 12 | DAS28 is a measure based on assessment of 28 joints for tenderness and swelling (tender and swollen joint counts). DAS28-CRP is derived using differential weighting given to 4 components: tender joint count (range: 0-28), swollen joint count (range: 0-28), patient global assessment (recorded on a visual analog scale \[VAS\] scale of 0-100 mm), and CRP (milligram per liter). DAS28-CRP score ranges from 0 to 9.4. The lower the DAS28-CRP score is, the better the participant has response (remission = score \< 2.6, low disease activity = score \< 3.2). A negative value in change from BL indicates an improvement. |
| Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | Baseline, Week 12 | An ACR70 response is defined as at least a 70% improvement in both tender joint count (TJC) and swollen joint count (SJC), and at least a 70% improvement in three of the following five criteria: patient global assessment (PGA), physician global assessment (PhGA), functional ability measure \[Health Assessment Questionnaire (HAQ)\], patient's assessment of pain (visual analog scale; VAS) and C-reactive protein (CRP). |
| Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | Baseline, Week 12 | An ACR50 response is defined as at least a 50% improvement in both tender joint count (TJC) and swollen joint count (SJC), and at least a 50% improvement in three of the following five criteria: patient global assessment (PGA), physician global assessment (PhGA), functional ability measure \[Health Assessment Questionnaire (HAQ)\], patient's assessment of pain (visual analog scale; VAS) and C-reactive protein (CRP). |
| Cohorts 3 and 4: Number of Participants With TEAEs | From first dose of study drug to 24 weeks | Adverse event (AE): any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. Serious AE (SAE): AE that: results in death; is immediately life-threatening; requires in-patient hospitalization/prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital abnormality/birth defect; is an important medical event. TEAEs: AEs not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug during treatment period. AE severity: mild (Grade \[Gr\] 1); moderate (Gr 2); severe (Gr 3); potentially life threatening (Gr 4); death (Gr 5). AEs of special interest: thrombosis, serious infection, serious and non-serious bacterial infections, eye disorders, and anaphylaxis/hypersensitivity reactions. |
| Cohort 3 and 4: Cmax | Days 1 (Dose 1) and 57 (Dose 4 or 8) | — |
| Cohort 3 and 4: AUCtau | Days 1 (Dose 1) and 57 (Dose 4 or 8) | — |
Countries
Bulgaria, Czechia, Georgia, Hungary, Poland, South Africa, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk KPL-404 2 mg/kg SC q2wk for 12 weeks | 6 |
| Cohort 2 KPL-404 5 mg/kg q2wk KPL-404 5 mg/kg SC q2wk for 12 weeks | 6 |
| Cohort 1/2 Placebo Placebo SC q2wk for 12 weeks | 4 |
| Cohort 3 KPL-404 5 mg/kg Qwk KPL-404 5 mg/kg SC qwk for 12 weeks | 27 |
| Cohort 3 KPL-404 5 mg/kg q2wk KPL-404 5 mg/kg SC q2wk with alternating weekly administrations of KPL-404 or placebo SC for 12 weeks | 25 |
| Cohort 3 Placebo Placebo SC qwk for 12 weeks | 26 |
| Cohort 4 KPL-404 400 mg q4wk KPL-404 SC q4wk for 12 weeks: 600 mg loading dose at baseline followed by 400 mg at Weeks 4 and 8 | 31 |
| Cohort 4 Placebo Placebo SC q4wk for 12 weeks | 20 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 2 | 0 | 2 | 1 | 3 |
Baseline characteristics
| Characteristic | Cohort 1 KPL-404 2 mg/kg q2wk | Cohort 2 KPL-404 5 mg/kg q2wk | Cohort 1/2 Placebo | Cohort 3 KPL-404 5 mg/kg Qwk | Cohort 3 KPL-404 5 mg/kg q2wk | Cohort 3 Placebo | Cohort 4 KPL-404 400 mg q4wk | Cohort 4 Placebo | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 56.8 years STANDARD_DEVIATION 15.59 | 56.3 years STANDARD_DEVIATION 13.29 | 59.8 years STANDARD_DEVIATION 13.05 | 58.5 years STANDARD_DEVIATION 9.68 | 60.0 years STANDARD_DEVIATION 10.1 | 57.6 years STANDARD_DEVIATION 9.9 | 58.8 years STANDARD_DEVIATION 9.45 | 58.3 years STANDARD_DEVIATION 11.81 | 58.5 years STANDARD_DEVIATION 10.34 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 2 Participants | 2 Participants | 3 Participants | 6 Participants | 5 Participants | 1 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 2 Participants | 2 Participants | 25 Participants | 22 Participants | 20 Participants | 26 Participants | 19 Participants | 121 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 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 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 6 Participants | 4 Participants | 25 Participants | 23 Participants | 24 Participants | 26 Participants | 17 Participants | 130 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 4 Participants | 22 Participants | 20 Participants | 24 Participants | 25 Participants | 15 Participants | 120 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 0 Participants | 5 Participants | 5 Participants | 2 Participants | 6 Participants | 5 Participants | 25 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 | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 27 | 0 / 25 | 0 / 26 | 0 / 31 | 0 / 20 |
| other Total, other adverse events | 2 / 6 | 3 / 6 | 3 / 4 | 10 / 27 | 8 / 25 | 8 / 26 | 10 / 31 | 11 / 20 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 4 | 1 / 27 | 0 / 25 | 1 / 26 | 0 / 31 | 0 / 20 |
Outcome results
Primary
Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12
DAS28 is a measure based on assessment of 28 joints for tenderness and swelling (tender and swollen joint counts). DAS28-CRP is derived using differential weighting given to 4 components: tender joint count (range: 0-28), swollen joint count (range: 0-28), patient global assessment (recorded on a visual analog scale \[VAS\] scale of 0-100 mm), and CRP (milligram per liter). DAS28-CRP score ranges from 0 to 9.4. The lower the DAS28-CRP score is, the better the participant has response (remission = score \< 2.6, low disease activity = score \< 3.2). A negative value in change from BL indicates an improvement.
Time frame: Baseline, Week 12
Population: Modified Intent-to-Treat (mITT) population: All randomized participants who received at least one dose of study drug and who had at least one post-baseline assessment for the primary efficacy endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12 | -2.17 score on a scale | Standard Error 0.216 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12 | -1.96 score on a scale | Standard Error 0.22 |
| Cohort 1/2 Placebo | Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12 | -1.61 score on a scale | Standard Error 0.218 |
| Cohort 4 KPL-404 400 mg q4wk | Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12 | -1.87 score on a scale | Standard Error 0.331 |
| Cohort 4 Placebo | Cohort 3 and 4: Change From Baseline in Disease Activity Score of 28 Joints Using C-reactive Protein (DAS28-CRP) at Week 12 | -1.30 score on a scale | Standard Error 0.338 |
p-value: 0.04795% CI: [-1.13, -0.01]ANCOVA
p-value: 0.212495% CI: [-0.92, 0.21]ANCOVA
p-value: 0.109195% CI: [-1.28, 0.13]ANCOVA
Primary
Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time of Administration to the End of the Dosing Interval, (AUCtau)
Time frame: Days 1 (Dose 1) and 57 (Dose 4)
Population: Participants treated with KPL-404, with an evaluable PK sample at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time of Administration to the End of the Dosing Interval, (AUCtau) | Day 1 | 59.0 µg·day/mL | Standard Deviation 51.1 |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time of Administration to the End of the Dosing Interval, (AUCtau) | Day 57 | 162 µg·day/mL | Standard Deviation 114 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time of Administration to the End of the Dosing Interval, (AUCtau) | Day 1 | 303 µg·day/mL | Standard Deviation 148 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Area Under the Serum Concentration-time Curve From Time of Administration to the End of the Dosing Interval, (AUCtau) | Day 57 | 810 µg·day/mL | Standard Deviation 290 |
Primary
Cohorts 1 and 2: Maximum Serum Concentration (Cmax)
Time frame: Days 1 (Dose 1) and 57 (Dose 4)
Population: Participants treated with KPL-404, with an evaluable PK sample at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Maximum Serum Concentration (Cmax) | Day 1 | 7.57 µg/mL | Standard Deviation 7.52 |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Maximum Serum Concentration (Cmax) | Day 57 | 17.8 µg/mL | Standard Deviation 13.9 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Maximum Serum Concentration (Cmax) | Day 1 | 28.0 µg/mL | Standard Deviation 13.5 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Maximum Serum Concentration (Cmax) | Day 57 | 68.3 µg/mL | Standard Deviation 25.1 |
Primary
Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Adverse event (AE): any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. Serious AE (SAE): AE that: results in death; is immediately life-threatening; requires in-patient hospitalization/prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital abnormality/birth defect; is an important medical event. TEAEs: AEs not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug during treatment period. AE severity: mild (Grade \[Gr\] 1); moderate (Gr 2); severe (Gr 3); potentially life threatening (Gr 4); death (Gr 5). AEs of special interest: thrombosis, serious infection, serious and non-serious bacterial infections, eye disorders, and anaphylaxis/hypersensitivity reactions.
Time frame: From first dose of study drug to 24 weeks
Population: Safety Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Severe | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs by maximum severity | 2 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Potentially life threatening | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Drug-related TEAEs | 1 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Drug-related SAEs | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Fatal | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to treatment discontinuation | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Mild | 1 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Injection site reactions | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs | 2 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Moderate | 1 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs of special interest | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to dose interruption | 1 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to dose interruption | 1 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs | 2 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Drug-related TEAEs | 1 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs by maximum severity | 2 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Mild | 1 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Moderate | 1 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Severe | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Potentially life threatening | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Fatal | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Drug-related SAEs | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to treatment discontinuation | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs of special interest | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Injection site reactions | 1 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Severe | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs of special interest | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to death | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Moderate | 2 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Mild | 1 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to dose interruption | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs by maximum severity | 3 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs | 3 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs leading to treatment discontinuation | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Fatal | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Drug-related TEAEs | 1 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Serious TEAEs | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Maximum Severity = Potentially life threatening | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Injection site reactions | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Drug-related SAEs | 0 Participants |
Secondary
Cohort 3 and 4: AUCtau
Time frame: Days 1 (Dose 1) and 57 (Dose 4 or 8)
Population: Participants treated with KPL-404, with an evaluable PK sample at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohort 3 and 4: AUCtau | Day 1 | 139 µg·day/mL | Standard Deviation 63.4 |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohort 3 and 4: AUCtau | Day 57 | 975 µg·day/mL | Standard Deviation 291 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohort 3 and 4: AUCtau | Day 1 | 310 µg·day/mL | Standard Deviation 105 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohort 3 and 4: AUCtau | Day 57 | 849 µg·day/mL | Standard Deviation 267 |
| Cohort 1/2 Placebo | Cohort 3 and 4: AUCtau | Day 1 | 873 µg·day/mL | Standard Deviation 363 |
| Cohort 1/2 Placebo | Cohort 3 and 4: AUCtau | Day 57 | 843 µg·day/mL | Standard Deviation 466 |
Secondary
Cohort 3 and 4: Cmax
Time frame: Days 1 (Dose 1) and 57 (Dose 4 or 8)
Population: Participants treated with KPL-404, with an evaluable PK sample at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohort 3 and 4: Cmax | Day 1 | 27.1 µg/mL | Standard Deviation 11 |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohort 3 and 4: Cmax | Day 57 | 145 µg/mL | Standard Deviation 41 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohort 3 and 4: Cmax | Day 1 | 29.4 µg/mL | Standard Deviation 10.3 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohort 3 and 4: Cmax | Day 57 | 70.9 µg/mL | Standard Deviation 21.5 |
| Cohort 1/2 Placebo | Cohort 3 and 4: Cmax | Day 1 | 48.5 µg/mL | Standard Deviation 18.2 |
| Cohort 1/2 Placebo | Cohort 3 and 4: Cmax | Day 57 | 45.6 µg/mL | Standard Deviation 21.4 |
Secondary
Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12
DAS28 is a measure based on assessment of 28 joints for tenderness and swelling (tender and swollen joint counts). DAS28-CRP is derived using differential weighting given to 4 components: tender joint count (range: 0-28), swollen joint count (range: 0-28), patient global assessment (recorded on a visual analog scale \[VAS\] scale of 0-100 mm), and CRP (milligram per liter). DAS28-CRP score ranges from 0 to 9.4. The lower the DAS28-CRP score is, the better the participant has response (remission = score \< 2.6, low disease activity = score \< 3.2). A negative value in change from BL indicates an improvement.
Time frame: Baseline, Week 12
Population: mITT Population: All randomized participants who received at least one dose of study drug and who had at least one post-baseline assessment for the primary efficacy endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12 | -3.16 score on a scale | Standard Deviation 1.13 |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12 | -3.44 score on a scale | Standard Deviation 1.45 |
| Cohort 1/2 Placebo | Cohorts 1 and 2: Change From Baseline in DAS28-CRP at Week 12 | -1.09 score on a scale | Standard Deviation 1.373 |
p-value: 0.0312t-test
p-value: 0.0338t-test
Secondary
Cohorts 3 and 4: Number of Participants With TEAEs
Adverse event (AE): any untoward medical occurrence, which does not necessarily have a causal relationship with this treatment. Serious AE (SAE): AE that: results in death; is immediately life-threatening; requires in-patient hospitalization/prolongation of existing hospitalization; results in persistent or significant disability/incapacity; results in a congenital abnormality/birth defect; is an important medical event. TEAEs: AEs not present before exposure to study drug or any event already present that worsens in either intensity or frequency after exposure to study drug during treatment period. AE severity: mild (Grade \[Gr\] 1); moderate (Gr 2); severe (Gr 3); potentially life threatening (Gr 4); death (Gr 5). AEs of special interest: thrombosis, serious infection, serious and non-serious bacterial infections, eye disorders, and anaphylaxis/hypersensitivity reactions.
Time frame: From first dose of study drug to 24 weeks
Population: Safety Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related SAEs | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Serious TEAEs | 1 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Fatal | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs | 12 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs of special interest | 1 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs by maximum severity | 12 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to treatment discontinuation | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Mild | 8 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Injection site reactions | 1 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to dose interruption | 1 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Moderate | 4 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related TEAEs | 2 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to death | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Severe | 0 Participants |
| Cohort 1 KPL-404 2 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Potentially life threatening | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Severe | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Potentially life threatening | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs | 6 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Serious TEAEs | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Mild | 3 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to death | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Fatal | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to dose interruption | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs of special interest | 1 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related TEAEs | 2 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related SAEs | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs by maximum severity | 6 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Injection site reactions | 1 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to treatment discontinuation | 0 Participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Moderate | 3 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Fatal | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs | 8 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related TEAEs | 2 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs by maximum severity | 8 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Mild | 4 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Moderate | 4 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Severe | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Potentially life threatening | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Serious TEAEs | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related SAEs | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to death | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to dose interruption | 1 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to treatment discontinuation | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs of special interest | 0 Participants |
| Cohort 1/2 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Injection site reactions | 0 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to death | 0 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs by maximum severity | 9 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related SAEs | 0 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to treatment discontinuation | 1 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Moderate | 5 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Mild | 4 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related TEAEs | 3 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | Injection site reactions | 2 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Fatal | 0 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs | 9 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to dose interruption | 0 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Potentially life threatening | 0 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs of special interest | 1 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | Serious TEAEs | 0 Participants |
| Cohort 4 KPL-404 400 mg q4wk | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Severe | 0 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Serious TEAEs | 0 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs of special interest | 2 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related SAEs | 0 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Moderate | 3 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs | 8 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to death | 0 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Mild | 5 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to dose interruption | 0 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs by maximum severity | 8 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Injection site reactions | 0 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | TEAEs leading to treatment discontinuation | 1 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Drug-related TEAEs | 1 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Fatal | 0 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Potentially life threatening | 0 Participants |
| Cohort 4 Placebo | Cohorts 3 and 4: Number of Participants With TEAEs | Maximum Severity = Severe | 0 Participants |
Secondary
Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12
An ACR20 response is defined as at least a 20% improvement in both tender joint count (TJC) and swollen joint count (SJC), and at least a 20% improvement in three of the following five criteria: patient global assessment (PGA), physician global assessment (PhGA), functional ability measure \[Health Assessment Questionnaire (HAQ)\], patient's assessment of pain (visual analog scale; VAS) and C-reactive protein (CRP).
Time frame: Baseline, Week 12
Population: mITT population: All randomized participants who received at least one dose of study drug and who had at least one post-baseline assessment for the primary efficacy endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 100 percentage of participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 83.3 percentage of participants |
| Cohort 1/2 Placebo | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 25.0 percentage of participants |
| Cohort 4 KPL-404 400 mg q4wk | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 74.1 percentage of participants |
| Cohort 4 Placebo | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 60.0 percentage of participants |
| Cohort 3 Placebo | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 50.0 percentage of participants |
| Cohort 4 KPL-404 400 mg q4wk | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 80.6 percentage of participants |
| Cohort 4 Placebo | Percentage of Participants Achieving American College of Rheumatology 20% (ACR20) Response at Week 12 | 40.0 percentage of participants |
p-value: 0.0333Fisher exact test
p-value: 0.1905Fisher exact test
p-value: 0.071695% CI: [0.9, 9.65]Cochran-Mantel-Haenszel
p-value: 0.47195% CI: [0.5, 4.67]Cochran-Mantel-Haenszel
p-value: 0.005795% CI: [1.62, 22.88]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12
An ACR50 response is defined as at least a 50% improvement in both tender joint count (TJC) and swollen joint count (SJC), and at least a 50% improvement in three of the following five criteria: patient global assessment (PGA), physician global assessment (PhGA), functional ability measure \[Health Assessment Questionnaire (HAQ)\], patient's assessment of pain (visual analog scale; VAS) and C-reactive protein (CRP).
Time frame: Baseline, Week 12
Population: mITT population: All randomized participants who received at least one dose of study drug and who had at least one post-baseline assessment for the primary efficacy endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 66.7 percentage of participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 16.7 percentage of participants |
| Cohort 1/2 Placebo | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 0 percentage of participants |
| Cohort 4 KPL-404 400 mg q4wk | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 33.3 percentage of participants |
| Cohort 4 Placebo | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 36.0 percentage of participants |
| Cohort 3 Placebo | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 23.1 percentage of participants |
| Cohort 4 KPL-404 400 mg q4wk | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 32.3 percentage of participants |
| Cohort 4 Placebo | Percentage of Participants Achieving American College of Rheumatology 50% (ACR50) Response at Week 12 | 30.0 percentage of participants |
p-value: 0.0762Fisher exact test
p-value: 1Fisher exact test
p-value: 0.417295% CI: [0.49, 5.62]Cochran-Mantel-Haenszel
p-value: 0.314495% CI: [0.55, 6.45]Cochran-Mantel-Haenszel
p-value: 0.95695% CI: [0.28, 3.39]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12
An ACR70 response is defined as at least a 70% improvement in both tender joint count (TJC) and swollen joint count (SJC), and at least a 70% improvement in three of the following five criteria: patient global assessment (PGA), physician global assessment (PhGA), functional ability measure \[Health Assessment Questionnaire (HAQ)\], patient's assessment of pain (visual analog scale; VAS) and C-reactive protein (CRP).
Time frame: Baseline, Week 12
Population: mITT population: All randomized participants who received at least one dose of study drug and who had at least one post-baseline assessment for the primary efficacy endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 KPL-404 2 mg/kg q2wk | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 33.3 percentage of participants |
| Cohort 2 KPL-404 5 mg/kg q2wk | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 16.7 percentage of participants |
| Cohort 1/2 Placebo | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 0 percentage of participants |
| Cohort 4 KPL-404 400 mg q4wk | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 7.4 percentage of participants |
| Cohort 4 Placebo | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 20.0 percentage of participants |
| Cohort 3 Placebo | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 3.8 percentage of participants |
| Cohort 4 KPL-404 400 mg q4wk | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 9.7 percentage of participants |
| Cohort 4 Placebo | Percentage of Participants Achieving American College of Rheumatology 70% (ACR70) Response at Week 12 | 25.0 percentage of participants |
p-value: 0.4667Fisher exact test
p-value: 1Fisher exact test
p-value: 0.578995% CI: [0.17, 22.3]Cochran-Mantel-Haenszel
p-value: 0.079995% CI: [0.62, 60.1]Cochran-Mantel-Haenszel
p-value: 0.103495% CI: [0.06, 1.35]Cochran-Mantel-Haenszel