Back to resultsStudy to Evaluate the Safety, PK, PD and Efficacy of AMG 827 in Adults With Rheumatoid Arthritis
Primary Purpose
Rheumatoid Arthritis
Status
Completed
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Brodalumab
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Rheumatoid Arthritis
Eligibility Criteria
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm Type
Placebo Comparator
Placebo Comparator
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
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)
Arm Description
Participants received placebo to brodalumab by subcutaneous (SC) injection once every 2 weeks for a total of six doses.
Participants received placebo to brodalumab by intravenous (IV) infusion every 4 weeks for a total of two doses.
Participants received 50 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses.
Participants received 140 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses.
Participants received 210 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses.
Participants received 420 mg brodalumab by IV infusion once every 4 weeks for a total of two doses.
Participants received 700 mg brodalumab by IV infusion once every 4 weeks for a total of two doses.
Outcomes
Primary Outcome Measures
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.
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.
Number of Participants With Clinically Significant Changes in Physical Examination Findings, Vital Signs, or Electrocardiogram Findings
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.
Secondary Outcome Measures
Time to Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses
Maximum Concentration of Brodalumab After Single and Multiple Subcutaneous Doses
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
Accumulation Ratio for Brodalumab After Subcutaneous Dosing
Accumulation was measured by AUC0-t, last dose / AUC0-t, first dose).
Time to Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses
Maximum Concentration of Brodalumab After Single and Multiple Intravenous Doses
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
Accumulation Ratio for Brodalumab After Intravenous Dosing
Accumulation was measured by AUC0-t, last dose / AUC0-t, first dose).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00771030
Brief Title
Study to Evaluate the Safety, PK, PD and Efficacy of AMG 827 in Adults With Rheumatoid Arthritis
Official Title
A Randomized, Double-blind, Placebo-controlled, Ascending Multiple-dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of AMG 827 in Subjects With Rheumatoid Arthritis
Study Type
Interventional
2. Study Status
Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
October 27, 2008 (Actual)
Primary Completion Date
May 25, 2010 (Actual)
Study Completion Date
May 25, 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amgen
4. Oversight
5. Study Description
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).
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rheumatoid Arthritis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
40 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Placebo SC (Cohorts 1-3)
Arm Type
Placebo Comparator
Arm Description
Participants received placebo to brodalumab by subcutaneous (SC) injection once every 2 weeks for a total of six doses.
Arm Title
Placebo IV (Cohorts 5-6)
Arm Type
Placebo Comparator
Arm Description
Participants received placebo to brodalumab by intravenous (IV) infusion every 4 weeks for a total of two doses.
Arm Title
Brodalumab 50 mg SC (Cohort 1)
Arm Type
Experimental
Arm Description
Participants received 50 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses.
Arm Title
Brodalumab 140 mg SC (Cohort 2)
Arm Type
Experimental
Arm Description
Participants received 140 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses.
Arm Title
Brodalumab 210 mg SC (Cohort 3)
Arm Type
Experimental
Arm Description
Participants received 210 mg brodalumab by subcutaneous injection once every 2 weeks for a total of six doses.
Arm Title
Brodalumab 420 mg IV (Cohort 5)
Arm Type
Experimental
Arm Description
Participants received 420 mg brodalumab by IV infusion once every 4 weeks for a total of two doses.
Arm Title
Brodalumab 700 mg IV (Cohort 6)
Arm Type
Experimental
Arm Description
Participants received 700 mg brodalumab by IV infusion once every 4 weeks for a total of two doses.
Intervention Type
Biological
Intervention Name(s)
Brodalumab
Other Intervention Name(s)
AMG 827
Intervention Description
Solution for subcutaneous or intravenous administration
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Solution for subcutaneous or intravenous administration
Primary Outcome Measure Information:
Title
Number of Participants With Treatment-emergent Adverse Events
Description
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).
Title
Number of Participants With Clinically Significant Changes in Safety Laboratory Tests
Description
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.
Title
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.
Title
Number of Participants With Anti-brodalumab Antibodies
Description
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
Secondary Outcome Measure Information:
Title
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.
Title
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.
Title
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.
Title
Accumulation Ratio for Brodalumab After Subcutaneous Dosing
Description
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.
Title
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.
Title
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.
Title
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.
Title
Accumulation Ratio for Brodalumab After Intravenous Dosing
Description
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.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
MD
Organizational Affiliation
Amgen
Official's Role
Study Director
12. IPD Sharing Statement
Citations:
PubMed Identifier
24286136
Citation
Martin DA, Churchill M, Flores-Suarez L, Cardiel MH, Wallace D, Martin R, Phillips K, Kaine JL, Dong H, Salinger D, Stevens E, Russell CB, Chung JB. A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis. Arthritis Res Ther. 2013 Oct 25;15(5):R164. doi: 10.1186/ar4347.
Results Reference
derived
Links:
URL
http://www.amgentrials.com
Description
AmgenTrials clinical trials website
Learn more about this trial
Study to Evaluate the Safety, PK, PD and Efficacy of AMG 827 in Adults With Rheumatoid Arthritis
We'll reach out to this number within 24 hrs