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Study 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
Amgen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

    First Posted
    October 9, 2008
    Last Updated
    October 29, 2021
    Sponsor
    Amgen
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    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

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