Study to Evaluate the Safety, PK, PD and Efficacy of AMG 827 in Adults With Rheumatoid Arthritis

Phase 1

Completed

Conditions: Rheumatoid Arthritis

Interventions: Biological: Brodalumab
Other: Placebo

Registration Number: NCT00771030

Lead Sponsor: Amgen

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 40

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 Exclusion Criteria Apply

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Brodalumab 140 mg SC (Cohort 2)	Brodalumab	Participants received 140 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses.
Brodalumab 50 mg SC (Cohort 1)	Brodalumab	Participants received 50 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses.
Placebo SC (Cohorts 1-3)	Placebo	Participants received placebo to brodalumab by subcutaneous (SC) injection once every 2 weeks for a total of six doses.
Brodalumab 420 mg IV (Cohort 5)	Brodalumab	Participants received 420 mg brodalumab by IV infusion once every 4 weeks for a total of two doses.
Brodalumab 700 mg IV (Cohort 6)	Brodalumab	Participants received 700 mg brodalumab by IV infusion once every 4 weeks for a total of two doses.
Placebo IV (Cohorts 5-6)	Placebo	Participants received placebo to brodalumab by intravenous (IV) infusion every 4 weeks for a total of two doses.
Brodalumab 210 mg SC (Cohort 3)	Brodalumab	Participants received 210 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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).
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.
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.
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).