Rheumatoid Arthritis
Conditions
Brief summary
This Phase 1b/2a study will evaluate safety, tolerability pharmacokinetics (PK) and pharmacodynamics (PD) of brodalumab when administered in multiple subcutaneous (SC) and intravenous (IV) doses in patients with active rheumatoid arthritis (RA) in combination with a stable dose of disease modulating anti-rheumatic drugs (DMARDs). Part A is dose escalation (to assess safety & tolerability), and Part B is dose expansion (to assess clinical efficacy) at the highest tolerated dose level of brodalumab from Part A.
Detailed description
The dose-escalation phase consisted of 5 sequentially enrolled dose cohorts. Within each cohort participants were randomly assigned in a 3:1 ratio to receive brodalumab or placebo subcutaneously (cohorts 1 to 3) or intravenously (cohorts 5 and 6). Dose escalations required acceptable safety data based on blinded review following completion of the day 15/week 3 visit by the final participant in each cohort and when six or more participants in a cohort had been administered at least three doses of brodalumab (cohorts 1, 2, 3 and 5). In cohort 6, dose escalation followed completion of the day 15/week 3 visit by the final patient in cohort 5 and six or more participants in cohort 5 had been administered two or more IV infusions of brodalumab. Cohort 4 was designed to be used in the dose expansion phase to provide evidence of biological impact in 70 patients with RA receiving brodalumab at the dose determined during the dose escalation phase of the study. This cohort was not enrolled because a decision was made not to conduct Part B of the study; instead a separate phase 2 multiple-dose study was conducted to evaluate efficacy of brodalumab in patients with RA (Study 20090061; NCT00950989).
Interventions
BIOLOGICALBrodalumab
Solution for subcutaneous or intravenous administration
OTHERPlacebo
Solution for subcutaneous or intravenous administration
Sponsors
Amgen
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 70 Years
Healthy volunteers
No
Inclusion criteria
* Male or female between 18 to 70 years of age, inclusive at the time of screening * Diagnosed with RA as determined by meeting 1987 American College of Rheumatology (ACR) classification criteria * Active RA defined as ≥ 6 swollen joints (out of 66 joints examined) and ≥ 8 tender/painful joints (out of 68 joints examined) and at least 1 of the following: * Erythrocyte sedimentation rate (ESR) ≥ 28 mm, or * C-reactive protein (CRP) \> 15 mg/L, or * Morning stiffness \> 45 minutes (applicable to subjects in Part A ONLY) * Duration of RA for at least 6 months * Currently taking methotrexate (MTX) consecutively for ≥ 12 weeks and on a stable dose of oral or SC MTX at 15-25 mg weekly for ≥ 4 weeks at day -1. A lower MTX dose is acceptable if it is the highest tolerated dose, however, toxicity documentation by the Investigator is required. All subjects will take folic acid to minimize toxicity, according to local guidelines. * Additional Inclusion Criteria Apply
Exclusion criteria
* History or evidence of a clinically significant disorder other than RA (including but not limited to cardiopulmonary, oncologic, renal, metabolic, hematologic or psychiatric), condition or disease that, in the opinion of the Investigator and Amgen physician would pose a risk to subject safety or interfere with the study evaluation, procedures or completion * Uncontrolled, clinically significant systemic disease other than RA such as diabetes mellitus, liver disease, asthma, cardiovascular disease or hypertension * Malignancy within 5 years (except successfully treated in situ cervical cancer or squamous or basal cell carcinoma of the skin) * Presence of a serious or chronic infections * Subject (male or female) is not willing to use highly effective contraception, defined as a double barrier method (ie, spermicidal jelly and condom, or condom and diaphragm) during treatment and up to end of study * Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events | From first dose of study drug up to end of study (week 19). | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment, including any such occurrence (eg, sign, symptom, or diagnosis) or worsening of a pre-existing medical condition. A serious adverse event was defined as an adverse event that was fatal; was life threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or other significant medical hazard. |
| Number of Participants With Clinically Significant Changes in Safety Laboratory Tests | Blood samples were taken on days 2, 8, 15, 29, 43, 57, 71, 85, 106, and 127. | The investigator reviewed laboratory test results and determined whether an abnormal value in an individual study participant represented a change from prestudy values and determined if changes were clinically significant. The number of participants with clinically significant changes in lab values at any time during the study is reported. |
| Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings | From first dose of study drug up to 4 weeks after last dose; 14 weeks for Cohorts 1, 2, and 3 and 8 weeks for Cohorts 5 and 6. | — |
| Number of Participants With Anti-brodalumab Antibodies | Days 1 (pre-dose), 29 (pre-dose), 85, and 127 | Samples were tested in a validated immunoassay for the presence of anti-brodalumab binding antibodies. Samples found to be positive for binding antibodies were further tested using a validated cell-based bioassay to determine if the antibodies were able to neutralize the activity of brodalumab. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | After first dose on days 1 (pre-dose and 0.5 and 4 hours post-dose), 2, 3, 5, 8, 11, and 15, and after last dose on days 29 (pre-dose and 0.5 and 4 hours post-dose), 30, 31, 33, 36, 39, 43, 57, 85, 106 and 127. | — |
| Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | After first dose on days 1 (pre-dose and 0.5 and 4 hours post-dose), 2, 3, 5, 8, 11, and 15, and after last dose on days 29 (pre-dose and 0.5 and 4 hours post-dose), 30, 31, 33, 36, 39, 43, 57, 85, 106 and 127. | — |
| Time to Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | After first dose on days 1 (pre-dose and 4 hours post-dose), 2, 3, 5, 8, 11, and 15 (pre-dose), and after last dose on days 71 (pre-dose and 4 hours post-dose), 72, 73, 75, 78, 81, 85, 106 and 127. | — |
| Accumulation Ratio for Brodalumab After Intravenous Dosing | After first dose on days 1 (pre-dose and 0.5 and 4 hours post-dose), 2, 3, 5, 8, 11, and 15, and after last dose on days 29 (pre-dose and 0.5 and 4 hours post-dose), 30, 31, 33, 36, 39, 43, 57, 85, 106 and 127. | Accumulation was measured by AUC0-t, last dose / AUC0-t, first dose). |
| Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Intravenous Doses | After first dose on days 1 (pre-dose and 0.5 and 4 hours post-dose), 2, 3, 5, 8, 11, and 15, and after last dose on days 29 (pre-dose and 0.5 and 4 hours post-dose), 30, 31, 33, 36, 39, 43, 57, 85, 106 and 127. | — |
| Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | After first dose on days 1 (pre-dose and 4 hours post-dose), 2, 3, 5, 8, 11, and 15 (pre-dose), and after last dose on days 71 (pre-dose and 4 hours post-dose), 72, 73, 75, 78, 81, 85, 106 and 127. | — |
| Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Subcutaneous Doses | After first dose on days 1 (pre-dose and 4 hours post-dose), 2, 3, 5, 8, 11, and 15 (pre-dose), and after last dose on days 71 (pre-dose and 4 hours post-dose), 72, 73, 75, 78, 81, 85, 106 and 127. | — |
| Accumulation Ratio for Brodalumab After Subcutaneous Dosing | After first dose on days 1 (pre-dose and 4 hours post-dose), 2, 3, 5, 8, 11, and 15 (pre-dose), and after last dose on days 71 (pre-dose and 4 hours post-dose), 72, 73, 75, 78, 81, 85, 106 and 127. | Accumulation was measured by AUC0-t, last dose / AUC0-t, first dose). |
Participant flow
Recruitment details
This study was conducted at 11 sites: 7 in the United States, 2 in Canada and 2 in Mexico.
Pre-assignment details
Within each cohort participants were randomized 3:1 to receive ascending doses of brodalumab or placebo subcutaneously (cohorts 1 to 3) or intravenously (cohorts 5 and 6). Cohort 4 was designed to be used in the dose expansion part of the study, however, this cohort was not enrolled because experimental endpoints would be achieved during a separate phase II study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo SC (Cohorts 1-3) Participants received placebo to brodalumab by subcutaneous (SC) injection once every 2 weeks for a total of six doses. | 6 |
| Placebo IV (Cohorts 5-6) Participants received placebo to brodalumab by intravenous (IV) infusion every 4 weeks for a total of two doses. | 4 |
| Brodalumab 50 mg SC (Cohort 1) Participants received 50 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses. | 6 |
| Brodalumab 140 mg SC (Cohort 2) Participants received 140 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses. | 6 |
| Brodalumab 210 mg SC (Cohort 3) Participants received 210 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses. | 6 |
| Brodalumab 420 mg IV (Cohort 5) Participants received 420 mg brodalumab by IV infusion once every 4 weeks for a total of two doses. | 6 |
| Brodalumab 700 mg IV (Cohort 6) Participants received 700 mg brodalumab by IV infusion once every 4 weeks for a total of two doses. | 6 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo SC (Cohorts 1-3) | Placebo IV (Cohorts 5-6) | Brodalumab 50 mg SC (Cohort 1) | Brodalumab 140 mg SC (Cohort 2) | Brodalumab 210 mg SC (Cohort 3) | Brodalumab 420 mg IV (Cohort 5) | Brodalumab 700 mg IV (Cohort 6) | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 51.7 years STANDARD_DEVIATION 10.3 | 55.5 years STANDARD_DEVIATION 11.7 | 46.2 years STANDARD_DEVIATION 11.7 | 56.8 years STANDARD_DEVIATION 8.7 | 45.7 years STANDARD_DEVIATION 10.1 | 55.5 years STANDARD_DEVIATION 7.3 | 50.0 years STANDARD_DEVIATION 5.9 | 51.4 years STANDARD_DEVIATION 9.7 |
| Race/Ethnicity, Customized Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 1 Participants | 3 Participants | 4 Participants | 4 Participants | 1 Participants | 5 Participants | 19 Participants |
| Race/Ethnicity, Customized White | 4 Participants | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 5 Participants | 1 Participants | 18 Participants |
| Sex: Female, Male Female | 5 Participants | 4 Participants | 6 Participants | 6 Participants | 5 Participants | 5 Participants | 3 Participants | 34 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 3 Participants | 6 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 6 | 4 / 4 | 5 / 6 | 5 / 6 | 4 / 6 | 5 / 6 | 4 / 6 |
| serious Total, serious adverse events | 1 / 6 | 0 / 4 | 0 / 6 | 0 / 6 | 0 / 6 | 1 / 6 | 0 / 6 |
Outcome results
Primary
Number of Participants With Anti-brodalumab Antibodies
Samples were tested in a validated immunoassay for the presence of anti-brodalumab binding antibodies. Samples found to be positive for binding antibodies were further tested using a validated cell-based bioassay to determine if the antibodies were able to neutralize the activity of brodalumab.
Time frame: Days 1 (pre-dose), 29 (pre-dose), 85, and 127
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Number of Participants With Anti-brodalumab Antibodies | Binding antibodies | 0 Participants |
| Placebo SC (Cohorts 1-3) | Number of Participants With Anti-brodalumab Antibodies | Neutralizing antibodies | 0 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Anti-brodalumab Antibodies | Binding antibodies | 0 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Anti-brodalumab Antibodies | Neutralizing antibodies | 0 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Anti-brodalumab Antibodies | Binding antibodies | 1 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Anti-brodalumab Antibodies | Neutralizing antibodies | 0 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Anti-brodalumab Antibodies | Binding antibodies | 0 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Anti-brodalumab Antibodies | Neutralizing antibodies | 0 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Anti-brodalumab Antibodies | Binding antibodies | 1 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Anti-brodalumab Antibodies | Neutralizing antibodies | 0 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Anti-brodalumab Antibodies | Binding antibodies | 0 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Anti-brodalumab Antibodies | Neutralizing antibodies | 0 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Anti-brodalumab Antibodies | Binding antibodies | 0 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Anti-brodalumab Antibodies | Neutralizing antibodies | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings
Time frame: From first dose of study drug up to 4 weeks after last dose; 14 weeks for Cohorts 1, 2, and 3 and 8 weeks for Cohorts 5 and 6.
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo SC (Cohorts 1-3) | Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings | 0 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings | 0 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings | 0 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings | 0 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings | 0 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings | 0 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings | 0 Participants |
Primary
Number of Participants With Clinically Significant Changes in Safety Laboratory Tests
The investigator reviewed laboratory test results and determined whether an abnormal value in an individual study participant represented a change from prestudy values and determined if changes were clinically significant. The number of participants with clinically significant changes in lab values at any time during the study is reported.
Time frame: Blood samples were taken on days 2, 8, 15, 29, 43, 57, 71, 85, 106, and 127.
Population: All participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo SC (Cohorts 1-3) | Number of Participants With Clinically Significant Changes in Safety Laboratory Tests | 0 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Clinically Significant Changes in Safety Laboratory Tests | 0 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Clinically Significant Changes in Safety Laboratory Tests | 0 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Clinically Significant Changes in Safety Laboratory Tests | 0 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Clinically Significant Changes in Safety Laboratory Tests | 0 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Clinically Significant Changes in Safety Laboratory Tests | 0 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Clinically Significant Changes in Safety Laboratory Tests | 0 Participants |
Primary
Number of Participants With Treatment-emergent Adverse Events
An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment, including any such occurrence (eg, sign, symptom, or diagnosis) or worsening of a pre-existing medical condition. A serious adverse event was defined as an adverse event that was fatal; was life threatening; required in-patient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or other significant medical hazard.
Time frame: From first dose of study drug up to end of study (week 19).
Population: All randomized participants who received at least 1 dose of study drug (placebo or brodalumab).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 3 Participants |
| Placebo SC (Cohorts 1-3) | Number of Participants With Treatment-emergent Adverse Events | Serious TEAEs | 1 Participants |
| Placebo SC (Cohorts 1-3) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related TEAEs | 1 Participants |
| Placebo SC (Cohorts 1-3) | Number of Participants With Treatment-emergent Adverse Events | Deaths on study | 0 Participants |
| Placebo SC (Cohorts 1-3) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious TEAEs | 0 Participants |
| Placebo SC (Cohorts 1-3) | Number of Participants With Treatment-emergent Adverse Events | Discontinuation of study drug due to TEAE | 0 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related TEAEs | 2 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Treatment-emergent Adverse Events | Discontinuation of study drug due to TEAE | 0 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Treatment-emergent Adverse Events | Serious TEAEs | 0 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Treatment-emergent Adverse Events | Deaths on study | 0 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 4 Participants |
| Placebo IV (Cohorts 5-6) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious TEAEs | 0 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Treatment-emergent Adverse Events | Serious TEAEs | 0 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Treatment-emergent Adverse Events | Deaths on study | 0 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious TEAEs | 0 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related TEAEs | 0 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Treatment-emergent Adverse Events | Discontinuation of study drug due to TEAE | 0 Participants |
| Brodalumab 50 mg SC (Cohort 1) | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 5 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious TEAEs | 0 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Treatment-emergent Adverse Events | Discontinuation of study drug due to TEAE | 0 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Treatment-emergent Adverse Events | Deaths on study | 0 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 5 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Treatment-emergent Adverse Events | Serious TEAEs | 0 Participants |
| Brodalumab 140 mg SC (Cohort 2) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related TEAEs | 3 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Treatment-emergent Adverse Events | Deaths on study | 0 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Treatment-emergent Adverse Events | Serious TEAEs | 0 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related TEAEs | 2 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious TEAEs | 0 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 4 Participants |
| Brodalumab 210 mg SC (Cohort 3) | Number of Participants With Treatment-emergent Adverse Events | Discontinuation of study drug due to TEAE | 0 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 5 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Treatment-emergent Adverse Events | Deaths on study | 0 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious TEAEs | 0 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Treatment-emergent Adverse Events | Serious TEAEs | 1 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Treatment-emergent Adverse Events | Discontinuation of study drug due to TEAE | 0 Participants |
| Brodalumab 420 mg IV (Cohort 5) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related TEAEs | 2 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Treatment-emergent Adverse Events | Serious TEAEs | 0 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Treatment-emergent Adverse Events | Deaths on study | 0 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Treatment-emergent Adverse Events | Discontinuation of study drug due to TEAE | 1 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Treatment-emergent Adverse Events | Any treatment-emergent adverse event (TEAE) | 4 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related TEAEs | 0 Participants |
| Brodalumab 700 mg IV (Cohort 6) | Number of Participants With Treatment-emergent Adverse Events | Treatment-related serious TEAEs | 0 Participants |
Secondary
Accumulation Ratio for Brodalumab After Intravenous Dosing
Accumulation was measured by AUC0-t, last dose / AUC0-t, first dose).
Time frame: After first dose on days 1 (pre-dose and 0.5 and 4 hours post-dose), 2, 3, 5, 8, 11, and 15, and after last dose on days 29 (pre-dose and 0.5 and 4 hours post-dose), 30, 31, 33, 36, 39, 43, 57, 85, 106 and 127.
Population: Participants who received brodalumab by intravenous infusion with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Accumulation Ratio for Brodalumab After Intravenous Dosing | 1.1 ratio | Standard Deviation 0.2 |
| Placebo IV (Cohorts 5-6) | Accumulation Ratio for Brodalumab After Intravenous Dosing | 1.2 ratio | Standard Deviation 0.1 |
Secondary
Accumulation Ratio for Brodalumab After Subcutaneous Dosing
Accumulation was measured by AUC0-t, last dose / AUC0-t, first dose).
Time frame: After first dose on days 1 (pre-dose and 4 hours post-dose), 2, 3, 5, 8, 11, and 15 (pre-dose), and after last dose on days 71 (pre-dose and 4 hours post-dose), 72, 73, 75, 78, 81, 85, 106 and 127.
Population: Participants who received subcutaneously administered brodalumab with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Accumulation Ratio for Brodalumab After Subcutaneous Dosing | 24.4 ratio | Standard Deviation 51.4 |
| Placebo IV (Cohorts 5-6) | Accumulation Ratio for Brodalumab After Subcutaneous Dosing | 1.3 ratio | Standard Deviation 0.8 |
| Brodalumab 50 mg SC (Cohort 1) | Accumulation Ratio for Brodalumab After Subcutaneous Dosing | 1.5 ratio | Standard Deviation 0.6 |
Secondary
Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Intravenous Doses
Time frame: After first dose on days 1 (pre-dose and 0.5 and 4 hours post-dose), 2, 3, 5, 8, 11, and 15, and after last dose on days 29 (pre-dose and 0.5 and 4 hours post-dose), 30, 31, 33, 36, 39, 43, 57, 85, 106 and 127.
Population: Participants who received brodalumab by intravenous infusion with available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Intravenous Doses | Day 1 (first dose) | 831 days*μg/mL | Standard Deviation 197 |
| Placebo SC (Cohorts 1-3) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Intravenous Doses | Day 29 (last dose) | 951 days*μg/mL | Standard Deviation 307 |
| Placebo IV (Cohorts 5-6) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Intravenous Doses | Day 1 (first dose) | 1840 days*μg/mL | Standard Deviation 602 |
| Placebo IV (Cohorts 5-6) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Intravenous Doses | Day 29 (last dose) | 2230 days*μg/mL | Standard Deviation 998 |
Secondary
Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Subcutaneous Doses
Time frame: After first dose on days 1 (pre-dose and 4 hours post-dose), 2, 3, 5, 8, 11, and 15 (pre-dose), and after last dose on days 71 (pre-dose and 4 hours post-dose), 72, 73, 75, 78, 81, 85, 106 and 127.
Population: Participants who received subcutaneously administered brodalumab with available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Subcutaneous Doses | Day 1 (first dose) | 1.77 days*μg/mL | Standard Deviation 1.61 |
| Placebo SC (Cohorts 1-3) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Subcutaneous Doses | Day 71 (last dose) | 4.13 days*μg/mL | Standard Deviation 3.2 |
| Placebo IV (Cohorts 5-6) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Subcutaneous Doses | Day 1 (first dose) | 37.6 days*μg/mL | Standard Deviation 27.8 |
| Placebo IV (Cohorts 5-6) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Subcutaneous Doses | Day 71 (last dose) | 50.8 days*μg/mL | Standard Deviation 51.5 |
| Brodalumab 50 mg SC (Cohort 1) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Subcutaneous Doses | Day 1 (first dose) | 142 days*μg/mL | Standard Deviation 67.3 |
| Brodalumab 50 mg SC (Cohort 1) | Area Under the Concentration-time Curve From Time Zero to the Time of the Final Quantifiable Sample (AUC0-t) for Brodalumab After Single and Multiple Subcutaneous Doses | Day 71 (last dose) | 191 days*μg/mL | Standard Deviation 82.7 |
Secondary
Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses
Time frame: After first dose on days 1 (pre-dose and 0.5 and 4 hours post-dose), 2, 3, 5, 8, 11, and 15, and after last dose on days 29 (pre-dose and 0.5 and 4 hours post-dose), 30, 31, 33, 36, 39, 43, 57, 85, 106 and 127.
Population: Participants who received brodalumab by intravenous infusion with available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | Day 1 (first dose) | 111 μg/mL | Standard Deviation 19.2 |
| Placebo SC (Cohorts 1-3) | Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | Day 29 (last dose) | 127 μg/mL | Standard Deviation 12.1 |
| Placebo IV (Cohorts 5-6) | Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | Day 1 (first dose) | 240 μg/mL | Standard Deviation 44.8 |
| Placebo IV (Cohorts 5-6) | Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | Day 29 (last dose) | 655 μg/mL | Standard Deviation 949 |
Secondary
Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses
Time frame: After first dose on days 1 (pre-dose and 4 hours post-dose), 2, 3, 5, 8, 11, and 15 (pre-dose), and after last dose on days 71 (pre-dose and 4 hours post-dose), 72, 73, 75, 78, 81, 85, 106 and 127.
Population: Participants who received subcutaneously administered brodalumab with available data
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 1 (first dose) | 0.742 μg/mL | Standard Deviation 0.522 |
| Placebo SC (Cohorts 1-3) | Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 71 (last dose) | 1.35 μg/mL | Standard Deviation 1.07 |
| Placebo IV (Cohorts 5-6) | Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 1 (first dose) | 5.67 μg/mL | Standard Deviation 2.98 |
| Placebo IV (Cohorts 5-6) | Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 71 (last dose) | 5.93 μg/mL | Standard Deviation 5.15 |
| Brodalumab 50 mg SC (Cohort 1) | Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 1 (first dose) | 16.6 μg/mL | Standard Deviation 8.97 |
| Brodalumab 50 mg SC (Cohort 1) | Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 71 (last dose) | 18.4 μg/mL | Standard Deviation 7.21 |
Secondary
Time to Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses
Time frame: After first dose on days 1 (pre-dose and 0.5 and 4 hours post-dose), 2, 3, 5, 8, 11, and 15, and after last dose on days 29 (pre-dose and 0.5 and 4 hours post-dose), 30, 31, 33, 36, 39, 43, 57, 85, 106 and 127.
Population: Participants who received brodalumab by intravenous infusion with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Time to Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | Day 1 (first dose) | 4.07 hours |
| Placebo SC (Cohorts 1-3) | Time to Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | Day 29 (last dose) | 0.98 hours |
| Placebo IV (Cohorts 5-6) | Time to Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | Day 1 (first dose) | 0.92 hours |
| Placebo IV (Cohorts 5-6) | Time to Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses | Day 29 (last dose) | 0.83 hours |
Secondary
Time to Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses
Time frame: After first dose on days 1 (pre-dose and 4 hours post-dose), 2, 3, 5, 8, 11, and 15 (pre-dose), and after last dose on days 71 (pre-dose and 4 hours post-dose), 72, 73, 75, 78, 81, 85, 106 and 127.
Population: Participants who received subcutaneously administered brodalumab with available data
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo SC (Cohorts 1-3) | Time to Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 1 (first dose) | 1.46 days |
| Placebo SC (Cohorts 1-3) | Time to Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 71 (last dose) | 2.00 days |
| Placebo IV (Cohorts 5-6) | Time to Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 1 (first dose) | 3.96 days |
| Placebo IV (Cohorts 5-6) | Time to Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 71 (last dose) | 3.95 days |
| Brodalumab 50 mg SC (Cohort 1) | Time to Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 1 (first dose) | 2.99 days |
| Brodalumab 50 mg SC (Cohort 1) | Time to Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses | Day 71 (last dose) | 4.00 days |