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TerminatedNCT03410056Updated Jun 22, 2021Results posted

Safety and Efficacy of Efavaleukin Alfa in Subjects With Active Rheumatoid Arthritis

A Phase 1/2 interventional study of Efavaleukin alfa and Placebo in Rheumatoid Arthritis RA, sponsored by Amgen. Terminated at 15 sites in 5 countries. Open to participants aged 18 Years to 70 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-06-22.

Sponsored by Amgen · Phase 1/2, Interventional, and Treatment

Why this study was terminated
Amgen made a business decision not to proceed with Phase 2.
Phase
Phase 1/2
Study type
Interventional
Enrollment
36
Allocation
Randomized
Ages
18 Years to 70 Years
Sex
All
01

Study summary

Phase 1b. To evaluate the safety and tolerability of subcutaneous (SC) dose administrations of Efavaleukin alfa in subjects with active rheumatoid arthritis (RA).

Phase 2a. To evaluate the efficacy of Efavaleukin alfa at week 12 as measured by the American College of Rheumatology 20 percent improvement criteria (ACR 20) in adult subjects with moderate to severe RA.

02

Conditions studied

  • Rheumatoid Arthritis RA
03

Who can participate

Ages eligible
18 Years to 70 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

Inclusion criteria

  • Subject has provided informed consent prior to initiation of any study specific activities/procedures.
  • Age ≥ 18 to ≤ 70 years of age at screening.
  • A diagnosis of RA consistent with the 1987 or 2010 American College of Rheumatology (ACR)/European League Against Rheumatism classification criteria.
  • Active RA defined as: Phase 1b: DAS-28-CRP > 2.6 at screening. The 28-joint count consists of the finger joints excluding the distal interphalangeal joints, the wrists, elbows, shoulders, and knees. Phase 2a: ≥ 6 swollen joints (based on 66-joint count) and ≥ 6 tender joints (based on 68-joint count) at screening and baseline. The distal interphalangeal joint should be evaluated but not included in the total count to determine eligibility. Additionally, C-reactive protein (CRP) must be greater than the upper limit of normal (ULN) per the central laboratory at screening.
  • Receiving treatment with methotrexate for ≥ 12 weeks and on a stable dose ≥ 15 mg weekly for ≥ 8 weeks prior to day 1. A lower methotrexate dose is acceptable (but no lower than 10 mg weekly) if it is the highest tolerated dose and gastrointestinal or hematologic toxicity at doses ≥ 15 mg weekly is documented by the investigator.
  • Receiving treatment with folic or folinic acid per investigator judgment or according to local standard of care.
  • Phase 1b only: Subject may be receiving a stable dose of leflunomide, sulfasalazine, hydroxychloroquine, minocycline in combination with methotrexate and the dose must be stable for ≥ 8 weeks prior to day 1.
  • Subject may be receiving a stable dose of prednisone ≤ 10mg daily or other equivalent corticosteroid dose and the dose must be stable for ≥ 2 weeks prior today 1.
  • Phase 1b only. Normal or clinically acceptable electrocardiogram (ECG) values (12-lead reporting ventricular rate and PR, QRS, QT and QTc interval) at screening and baseline based on opinion of the investigator.
  • Immunizations (tetanus, diphtheria, pertussis, seasonal influenza [during flu season], and pneumococcal [polysaccharide] vaccinations) up to date per local standards as determined by the investigator.

Exclusion criteria

Exclusion Criteria:

  • Class IV RA according to ACR revised response criteria
  • Diagnosis of Felty's Syndrome (RA, splenomegaly and granulocytopenia).
  • Prosthetic joint infection within 3 years of screening or native joint infection within 1 year prior to screening.
  • Active infection (including chronic or localized infections) for which anti-infectives were indicated within 4 weeks prior to day 1 OR presence of serious infection, defined as requiring hospitalization or intravenous anti-infectives within 8 weeks prior to day 1.
  • Known history of active tuberculosis.
  • Positive test for tuberculosis during screening defined as either: positive purified protein derivative (PPD) (≥ 5 mm of induration at 48 to 72 hours after test is placed) OR positive Quantiferon test: a positive PPD and a history of Bacillus Calmette-Guérin vaccination are allowed with a negative Quantiferon test and negative chest x ray; a positive PPD test (without a history of Bacillus Calmette-Guérin vaccination) or a positive or indeterminate Quantiferon test are allowed if they have ALL of the following at screening: no symptoms per tuberculosis or sheet provided by Amgen; document history of a completed course of adequate prophylaxis(completed treatment for latent tuberculosis per local standard of care prior to the start of investigational product); no known exposure to a case of active tuberculosis after most recent prophylaxis; negative chest X-ray.
  • Positive for hepatitis B surface antigen, hepatitis B core antibody (confirmed by hepatitis B deoxyribonucleic acid (DNA) polymerase chain reaction [PCR] test) or detectable hepatitis C virus ribonucleic acid (RNA) by PCR (screening is generally done by hepatitis C antibody [HepCAb], followed by hepatitis C virus RNA by PCR if HepCAb is positive). A history of hepatitis B vaccination without history of hepatitis B is allowed.
  • Phase 1b only: Positive for Human Immunodeficiency Virus (HIV) at screening or known to be HIV positive. Phase 2a only: Known history of HIV
  • Phase 1b only: Positive drug or alcohol urine test for illicit drugs at screening. Prescription medications detected by the drug test are allowed if they are being taken under the direction of a physician.
  • Presence of one or more significant concurrent medical conditions per investigator judgment, including but not limited to the following: poorly controlled diabetes or hypertension; chronic kidney disease stage IIIb, IV, or V; symptomatic heart failure (New York Heart Association class II, III, or IV); myocardial infarction or unstable angina pectoris within the past 12 months prior to randomization; severe chronic pulmonary disease (eg, requiring oxygen therapy); multiple sclerosis or any other demyelinating disease; major chronic inflammatory disease or connective tissue disease other than RA (eg, systemic lupus erythematosus with the exception of secondary Sjögren's syndrome).
  • Malignancy except non-melanoma skin cancers, cervical or breast ductal carcinoma in situ within the last 5 years.
  • History of alcohol or substance abuse within 6 months of screening
  • Phase 1b only: Current smoker, and/or use of any nicotine or tobacco containing products within the last 6 months prior to day 1. These types of products include but are not limited to: snuff, chewing tobacco, cigars, electronic cigarettes, cigarettes, pipes, or nicotine patches.
  • Phase 1b only: Subject unwilling to limit alcohol consumption to ≤ 1 drink of alcohol per day and ≤ 3 drinks per week for the duration of the study, where a drink is equivalent to 12 ounces of regular beer, 8 to 9 ounces of malt liquor, 5 ounces of wine, or 1.5 ounces of 80 proof distilled spirits. Phase 1b only: Unwilling or unable to abstain from alcohol consumption within 48 hours prior to each visit (including screening).
  • Subjects who have received intra-articular or systemic corticosteroid injections for treatment of acute RA flare (not being part of a regular therapeutic regimen) within 4 weeks prior to screening.
  • Currently receiving or had treatment with cyclophosphamide, chlorambucil, nitrogen mustard, or any other alkylating agent ≤ 6 months prior to day 1.

  • Prior treatment with more than a total of 3 therapies that include biologic disease modifying anti-rheumatic drug (DMARDs) or oral synthetic DMARDs (such as tofacinitib, baricitinib). Prior treatment consists of at least 4 doses of a given therapy where the doses were given solely for treatment of RA disease. Prior therapies must not have been used within the following time periods:

    • ≤ 4 weeks prior to day 1 for etanercept and anakinra
    • ≤ 6 months for rituximab
    • ≤ 2 weeks for oral janus kinase inhibitors
    • ≤ 9 weeks prior to day 1 for all therapies not listed above

  • Currently receiving or had treatment with any of the following ≤ 12 weeks prior to day 1:

    • azathioprine
    • cyclosporine
    • gold
    • mycophenolate mofetil
    • Prosorba column
    • Tacrolimus
  • Phase 2a only: Currently receiving or had treatment with leflunomide ≤ 12 weeks prior to day 1 unless an active washout with cholestyramine has been performed.

  • Phase 2a only: Currently receiving or had treatment with any of the following ≤ 4 weeks prior to day 1:

    • hydroxychloroquine
    • sulfasalazine
    • minocycline
    • oral janus kinase inhibitor (eg, tofacitinib, baricitinib)
    • intra-articular, intramuscular or intravenous corticosteroids, including adrenocorticotropic hormone
    • intra-articular hyaluronic acid injections
    • live vaccines -- For Phase 2 only:
  • Unstable dose of non-steroidal anti-inflammatory drugs (NSAID), acetaminophen, and/or analgesics which is taken on an unscheduled basis (ie, not daily or scheduled every certain number of hours) and/or initiated \<4 weeks prior to day 1.
  • Received the following within 12 hours prior to screening or day 1:

acetaminophen, NSAIDs, tramadol, and/or any narcotic analgesics such as but not limited to hydrocodone, codeine, tramadol, propoxyphene and/or oxycodone (unless in the form of oxycontin). Subject has taken oxycontin within 24 hours prior to screening or day 1.

  • Phase 1b only: Received any herbal medicines (eg St John's wort),or non-vitamin dietary supplements (eg, magnesium) with the exception of calcium within 4 weeks prior to day 1.
  • Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded.

  • Presence of laboratory abnormalities at screening including the following:

    • Aspartate aminotransferase (AST) or alanine amino transferase (ALT) at screening > 1.5X upper limit of normal (ULN)
    • Serum total bilirubin (TBL) ≥ 1.5 mg/dL (≥ 26 μmol/L)
    • Hemoglobin ≤ 10.5 g/dL(≤105 g/L)
    • Platelet count \< 100,000/mm\^3 (\<100 x 10\^9/L)
    • White blood cell count \< 2,500 cells/mm\^3 (2.5 x 10\^9/L)
    • Absolute neutrophil count (ANC) \< 1,000/mm\^3 (1.0 x 10\^9/L)
    • Calculated glomerular filtration rate of ≤ 50 mL/min/1.73 m\^2 using the Modification of Diet in Renal Disease (MDRD) formula
  • Any other laboratory abnormality, which, in the opinion of the investigator, poses a safety risk, will prevent the subject from completing the study, will interfere with the interpretation of the study results, or might cause the study to be detrimental to the subject.
  • Female subject is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 weeks after the last dose of investigational product.
  • Females of child-bearing potential with a positive pregnancy test (assessed by a serum pregnancy test at screening and a urine pregnancy test at baseline).
  • Female subjects of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 6 weeks after the last dose of investigational product.
  • Subject has known sensitivity to any of the products or components to be administered during dosing.
  • Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures (eg, Clinical Outcome Assessments [COAs]) to the best of the subject and investigator's knowledge.
  • History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion
04

Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Sequential assignment
Masking
Double (Participant, Investigator)
Enrollment
36 participants (actual)

Study arms

  • Placebo comparator
    Phase 1b: Placebo

    Matching placebo administered via subcutaneous injection for a total of up to 12 weeks. Participants received placebo in 1 of 2 dosing schedules (i.e. dosing schedule A \[less frequent\] or schedule B \[more frequent\]).

    Drug: Placebo

  • Experimental
    Phase 1b: Efavaleukin alfa Cohort 1

    A low dose of Efavaleukin alfa administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks.

    Drug: Efavaleukin alfa

  • Experimental
    Phase 1b: Efavaleukin alfa Cohort 2

    A high dose of Efavaleukin alfa administered via subcutaneous injection using dosing schedule A (less frequent than schedule B) for a total of up to 12 weeks.

    Drug: Efavaleukin alfa

  • Experimental
    Phase 1b: Efavaleukin alfa Cohort 3

    A medium dose of Efavaleukin alfa administered via subcutaneous injection using dosing schedule B (more frequent than schedule A) for a total of up to 12 weeks.

    Drug: Efavaleukin alfa

  • Experimental
    Phase 1b: Efavaleukin alfa Cohort 4

    A medium/high dose of Efavaleukin alfa administered via subcutaneous injection using dosing schedule B (more frequent than schedule A) for a total of up to 12 weeks.

    Drug: Efavaleukin alfa

  • Placebo comparator
    Phase 2a: Placebo

    Matching placebo administered via subcutaneous injection, depending on the recommended phase 2 dose (RP2D) and dosing schedule as determined in phase 1b, for a total of up to 12 weeks.

    Drug: Placebo

  • Experimental
    Phase 2a: Efavaleukin alfa

    Efavaleukin alfa administered via subcutaneous injection depending on the RP2D and dosing schedule determined in phase 1b, for up to a total of up to 12 weeks.

    Drug: Efavaleukin alfa

Interventions

  • DrugEfavaleukin alfa

    Efavaleukin alfa administered as a subcutaneous injection.

    Also known as: AMG 592

  • DrugPlacebo

    Placebo administered as a subcutaneous injection.

05

What researchers measure

Primary outcomes

  1. Phase 1b: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

    TEAEs were events with an onset after the administration of the first dose of study treatment. TEAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE). Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limited age appropriate instrumental activities of daily life (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated. Serious adverse events (SAEs) were defined as meeting at least 1 of the following criteria: * Results in death (fatal) * Immediately life-threatening * Requires in-patient hospitalization or prolongation of existing hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Other medically important serious event

    Time frame: Day 1 up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)

  2. Phase 1b: Number of Participants Who Experienced a Clinically Significant Change in Vital Signs

    Any changes in systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature that were deemed as clinically significant by the Investigator were reported.

    Time frame: Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)

  3. Phase 1b: Number of Participants Who Experienced a Clinically Significant Change in Laboratory Safety Tests

    Laboratory safety tests included chemistry and hematology parameters. Clinically significant laboratory safety tests were any events assessed as CTCAE Grade ≥3 at any post-baseline visit. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated.

    Time frame: Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)

  4. Phase 1b: Number of Participants Who Experienced a Clinically Significant Change in Electrocardiograms (ECGs)

    Any changes in ECG parameters that were deemed clinically significant by the investigator were reported.

    Time frame: Baseline up to end of treatment maximum of 12 weeks

  5. Phase 2a: Number of Participants Who Achieved an American College of Rheumatology 20 Percent Improvement Criteria (ACR 20) at Week 12

    ACR 20 response defined as at least 20 percent improvement from baseline in both tender and swollen joint counts, and a 20 percent improvement or more in at least 3 of the following 5 criteria: * physician global assessment of disease activity (PGA) * subject global assessment of disease activity (SGA) * patient global assessment of joint pain * subject self-assessment of disability (HAQ-DI) * C-Reactive Protein (CRP)

    Time frame: Baseline and Week 12

Secondary outcomes

  1. Phase 1b: Efavaleukin Alfa Serum Concentrations

    A summary of mean serum concentrations of Efavaleukin alfa over time is presented. Any results below the lower limit of quantification were set to 0.00.

    Time frame: Day 1 (pre-dose), 6 and 12 hours post-dose, and days 2, 3, 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and Day 85 (pre-dose), 6 and 12 hours post-dose and days 86, 87, 88, 92, 99, 113 and 127

  2. Phase 1b: Maximum Observed Serum Concentration (Cmax) of Efavaleukin Alfa

    Time frame: Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, Day 85 (pre-dose) and 6 to 72 hours post-dose, and days 92, 99, 113 and 127

  3. Phase 1b: Time to Maximum Observed Serum Concentration (Tmax) of Efavaleukin Alfa

    Time frame: Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, Day 85 (pre-dose) and 6 to 72 hours post-dose, and days 92, 99, 113 and 127

  4. Phase 1b: Area Under the Concentration-time Curve From Time 0 to 14 Days (AUC0-14) Post Dose

    AUC0-14 was only assessed for the participants who received Efavaleukin alfa using dosing schedule A.

    Time frame: Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4, 8, 11 and 15, Day 85 (pre-dose) and 6 to 72 hours post-dose, and days 92 and 99

  5. Phase 1b: Area Under the Concentration-time Curve From Time 0 to 7 Days (AUC0-7) Post Dose

    AUC0-7 was only assessed for the participants who received Efavaleukin alfa using dosing schedule B.

    Time frame: Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4 and 8, Day 85 (pre-dose) and 6 to 72 hours post-dose, and Day 92

  6. Phase 1b: Number of Participants With Anti-Efavaleukin Alfa Binding Antibodies and Anti-Interleukin (IL-2) Binding Antibodies

    Number of participants who tested positive for anti-Efavaleukin alfa binding antibodies and number of those participants who cross-reacted with native human IL-2 (i.e. with anti-IL-2 binding antibodies) are reported.

    Time frame: Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)

  7. Phase 1b: Number of Participants With Anti-Efavaleukin Alfa Neutralizing Antibodies and Anti-IL-2 Neutralizing Antibodies

    The number of participants who tested positive for anti-Efavaleukin alfa neutralizing antibodies and number of participants with anti-IL2 neutralizing antibodies who tested negative or no result at baseline are reported.

    Time frame: Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)

  8. Phase 2a: Number of Participants Who Achieved an American College of Rheumatology 50 Percent Improvement Criteria (ACR 50) or 70 Percent Improvement Criteria (ACR 70) at Week 12

    ACR 50 and ACR 70 response defined as at least 50 percent or 70 percent improvement from baseline in both tender and swollen joint counts, and a 50 percent or 70 percent improvement or more in at least 3 of the following 5 criteria: * physician global assessment of disease activity (PGA) * subject global assessment of disease activity (SGA) * patient global assessment of joint pain * subject self-assessment of disability (HAQ-DI) * C-Reactive Protein (CRP)

    Time frame: Baseline and Week 12

  9. Phase 2a: Change From Baseline in Disease Activity Score (28 Joint) Calculated Using The Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at Week 12

    Change from baseline in DAS28-ER at Week 12. DAS28-ESR was to assess disease activity in patients with rheumatoid arthritis. DAS28-ESR is a composite score that includes 4 variables: tender joint count (TJC) (based on 28 joints); swollen joint count (SJC) (based on 28 joints); participant's global assessment of health activity using 100 mm VAS: range 0 (no pain) to 100 (maximum pain imaginable); marker of inflammation assessed by ESR in mm/h. DAS28-ESR total score range from 0-10, higher score indicates more disease activity.

    Time frame: Baseline and Week 12

  10. Phase 2a: Change From Baseline in Disease Activity Score (28 Joint) Calculated Using the C-reactive Protein Formula (DAS-28-CRP) at Week 12

    Change from baseline in DAS28-CRP at Week 12. 2. DAS28-CRP was to assess disease activity in patients with rheumatoid arthritis. DAS28-CRP is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); participant's global assessment of health activity using 100 mm VAS: range 0 (no pain) to 100 (maximum pain imaginable); marker of inflammation assessed by CRP in mg/L. DAS28-CRP total score range from 0-10, higher score indicates more disease activity.

    Time frame: Baseline and Week 12

  11. Phase 2a: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

    TEAEs were events with an onset after the administration of the first dose of study treatment. TEAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE).

    Time frame: Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)

  12. Phase 2a: Number of Participants Who Experienced a Clinically Significant Change in Vital Signs

    Any changes in systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature that were deemed as clinically significant by the Investigator were reported.

    Time frame: Baseline up to Week 12

  13. Phase 2a: Number of Participants Who Experienced a Clinically Significant Change in Laboratory Safety Tests

    Laboratory safety tests included chemistry and hematology parameters. Clinically significant laboratory safety tests were any events assessed as CTCAE Grade ≥3 at any post-baseline visit. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated.

    Time frame: Day 1 up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)

  14. Phase 2a: Efavaleukin Alfa Serum Concentration

    A summary of mean serum concentrations of Efavaleukin alfa over time.

    Time frame: Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12

  15. Phase 2a: Maximum Observed Serum Concentration (Cmax) of Efavaleukin Alfa

    Time frame: Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12

  16. Phase 2a: Time to Maximum Observed Serum Concentration (Tmax) of Efavaleukin Alfa

    Time frame: Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12

  17. Phase 2a: Area Under the Concentration-time Curve (AUC) of Efavaleukin Alfa

    Time frame: Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12

06

Results

Posted Jun 4, 2021
Limitations and caveats
Enrollment of the phase 1b part of this study was stopped as of 30 September 2019 due to data that suggested that there is not sufficient benefit-risk for the use of Efavaleukin alfa plus standard of care therapy in this study population. The study was terminated prior to the enrollment of any participants into phase 1b Cohort 4 and phase 2a cohorts.

Participant flow

Participants in phase 1b were to be enrolled into 1 of 4 planned dosing cohorts and randomized in a 3:1 ratio to receive Efavaleukin alfa or placebo according to 1 of 2 dosing schedules; A (less frequent) and B (more frequent).

Participant flow — Overall Study
MilestonePhase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3Phase 1b: Efavaleukin Alfa Cohort 4Phase 2a: PlaceboPhase 2a: Efavaleukin Alfa
Started861111000
Received treatment861111000
Completed8436000
Not completed0285000
Withdrew: Decision by sponsor0030000
Withdrew: Withdrawal by subject0255000

Outcome measures

PrimaryPhase 1b: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

TEAEs were events with an onset after the administration of the first dose of study treatment. TEAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE). Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limited age appropriate instrumental activities of daily life (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated. Serious adverse events (SAEs) were defined as meeting at least 1 of the following criteria: * Results in death (fatal) * Immediately life-threatening * Requires in-patient hospitalization or prolongation of existing hospitalization * Results in persistent or significant disability/incapacity * Is a congenital anomaly/birth defect * Other medically important serious event

Time frame:
Day 1 up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
Reported as:
Count of participants · Participants
Phase 1b: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
ParticipantsPhase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
TEAEs351111
Grade ≥ 2 TEAEs2388
Grade ≥ 3 TEAEs0010
Grade ≥ 4 TEAEs0000
SAEs0010
TEAEs leading to discontinuation of study treatment0173
Life-threatening TEAEs0000
Fatal TEAEs0000
PrimaryPhase 1b: Number of Participants Who Experienced a Clinically Significant Change in Vital Signs

Any changes in systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature that were deemed as clinically significant by the Investigator were reported.

Time frame:
Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
Reported as:
Count of participants · Participants
Phase 1b: Number of Participants Who Experienced a Clinically Significant Change in Vital Signs
ParticipantsPhase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
Phase 1b: Number of Participants Who Experienced a Clinically Significant Change in Vital Signs0000
PrimaryPhase 1b: Number of Participants Who Experienced a Clinically Significant Change in Laboratory Safety Tests

Laboratory safety tests included chemistry and hematology parameters. Clinically significant laboratory safety tests were any events assessed as CTCAE Grade ≥3 at any post-baseline visit. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated.

Time frame:
Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
Reported as:
Count of participants · Participants
Phase 1b: Number of Participants Who Experienced a Clinically Significant Change in Laboratory Safety Tests
ParticipantsPhase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
Phase 1b: Number of Participants Who Experienced a Clinically Significant Change in Laboratory Safety Tests0010
PrimaryPhase 1b: Number of Participants Who Experienced a Clinically Significant Change in Electrocardiograms (ECGs)

Any changes in ECG parameters that were deemed clinically significant by the investigator were reported.

Time frame:
Baseline up to end of treatment maximum of 12 weeks
Reported as:
Count of participants · Participants
Phase 1b: Number of Participants Who Experienced a Clinically Significant Change in Electrocardiograms (ECGs)
ParticipantsPhase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
Phase 1b: Number of Participants Who Experienced a Clinically Significant Change in Electrocardiograms (ECGs)0000
PrimaryPhase 2a: Number of Participants Who Achieved an American College of Rheumatology 20 Percent Improvement Criteria (ACR 20) at Week 12

ACR 20 response defined as at least 20 percent improvement from baseline in both tender and swollen joint counts, and a 20 percent improvement or more in at least 3 of the following 5 criteria: * physician global assessment of disease activity (PGA) * subject global assessment of disease activity (SGA) * patient global assessment of joint pain * subject self-assessment of disability (HAQ-DI) * C-Reactive Protein (CRP)

Time frame:
Baseline and Week 12

No measurements were reported for this outcome.

SecondaryPhase 1b: Efavaleukin Alfa Serum Concentrations

A summary of mean serum concentrations of Efavaleukin alfa over time is presented. Any results below the lower limit of quantification were set to 0.00.

Time frame:
Day 1 (pre-dose), 6 and 12 hours post-dose, and days 2, 3, 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, and Day 85 (pre-dose), 6 and 12 hours post-dose and days 86, 87, 88, 92, 99, 113 and 127
Reported as:
Mean · ng/mL
Phase 1b: Efavaleukin Alfa Serum Concentrations
ng/mLPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
Day 1 (pre-dose)0.00 ± 0.000.0 ± 0.000.00 ± 0.00
Day 1 (6 hours post-dose)1.35 ± 0.7957.67 ± 8.012.13 ± 2.98
Day 1 (12 hours post-dose)2.43 ± 0.86714.6 ± 12.14.09 ± 4.70
Day 22.59 ± 0.87522.0 ± 11.55.44 ± 5.09
Day 31.70 ± 0.85018.6 ± 9.163.65 ± 3.13
Day 40.727 ± 0.2777.65 ± 5.852.36 ± 2.84
Day 80.0555 ± 0.09240.108 ± 0.1460.0284 ± 0.0624
Day 110.0230 ± 0.05140.0115 ± 0.03640.930 ± 0.780
Day 150.00 ± 0.000.00 ± 0.000.107 ± 0.150
Day 220.0830 ± 0.1440.0703 ± 0.1120.235 ± 0.373
Day 290.00 ± 0.000.00 ± 0.000.217 ± 0.344
Day 360.0644 ± 0.1440.102 ± 0.2030.239 ± 0.425
Day 430.00 ± 0.000.00 ± 0.000.104 ± 0.275
Day 500.205 ± 0.3040.105 ± 0.2100.122 ± 0.322
Day 570.0368 ± 0.07350.00 ± 0.000.0886 ± 0.234
Day 640.336 ± NA0.212 ± 0.4240.0294 ± 0.0657
Day 710.0635 ± NA0.00 ± 0.000.00 ± 0.00
Day 780.154 ± 0.2670.355 ± 0.6140.0508 ± 0.0819
Day 85 (pre-dose)0.00 ± 0.000.00 ± 0.000.0578 ± 0.0958
Day 85 (6 hours post-dose)2.41 ± 1.565.91 ± NA1.92 ± 2.64
Day 85 (12 hours post-dose)4.00 ± 2.0512.9 ± NA2.92 ± 4.03
Day 863.60 ± 2.0712.3 ± NA2.97 ± 4.48
Day 872.10 ± 1.154.39 ± NA1.87 ± 2.43
Day 881.48 ± 0.6231.01 ± NA0.903 ± 1.17
Day 920.113 ± NA0.00 ± NA0.0953 ± 0.115
Day 990.00 ± 0.000.00 ± NA0.110 ± 0.268
Day 1130.00 ± 0.000.00 ± NA0.00 ± 0.00
Day 1270.00 ± 0.000.00 ± NA0.00 ± 0.00
SecondaryPhase 1b: Maximum Observed Serum Concentration (Cmax) of Efavaleukin Alfa
Time frame:
Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, Day 85 (pre-dose) and 6 to 72 hours post-dose, and days 92, 99, 113 and 127
Reported as:
Mean · ng/mL
Phase 1b: Maximum Observed Serum Concentration (Cmax) of Efavaleukin Alfa
ng/mLPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
First dose (Day 1)2.66 ± 0.85223.0 ± 11.25.71 ± 5.10
Last dose (Day 85)4.00 ± 2.05NA ± NA3.22 ± 4.35
SecondaryPhase 1b: Time to Maximum Observed Serum Concentration (Tmax) of Efavaleukin Alfa
Time frame:
Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4, 8, 11, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, Day 85 (pre-dose) and 6 to 72 hours post-dose, and days 92, 99, 113 and 127
Reported as:
Median · hours
Phase 1b: Time to Maximum Observed Serum Concentration (Tmax) of Efavaleukin Alfa
hoursPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
First dose (Day 1)18 (12 to 24)24 (24 to 48)24 (12 to 72)
Last dose (Day 85)12 (12 to 12)30 (12 to 48)12 (6.0 to 24)
SecondaryPhase 1b: Area Under the Concentration-time Curve From Time 0 to 14 Days (AUC0-14) Post Dose

AUC0-14 was only assessed for the participants who received Efavaleukin alfa using dosing schedule A.

Time frame:
Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4, 8, 11 and 15, Day 85 (pre-dose) and 6 to 72 hours post-dose, and days 92 and 99
Reported as:
Mean · hr*ng/mL
Phase 1b: Area Under the Concentration-time Curve From Time 0 to 14 Days (AUC0-14) Post Dose
hr*ng/mLPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2
First dose (Day 1)167 ± 60.91570 ± 859
Last dose (Day 85)282 ± 207NA ± NA
SecondaryPhase 1b: Area Under the Concentration-time Curve From Time 0 to 7 Days (AUC0-7) Post Dose

AUC0-7 was only assessed for the participants who received Efavaleukin alfa using dosing schedule B.

Time frame:
Day 1 (pre-dose) and 6 to 48 hours post-dose, and days 4 and 8, Day 85 (pre-dose) and 6 to 72 hours post-dose, and Day 92
Reported as:
Mean · hr*ng/mL
Phase 1b: Area Under the Concentration-time Curve From Time 0 to 7 Days (AUC0-7) Post Dose
hr*ng/mLPhase 1b: Efavaleukin Alfa Cohort 3
First dose (Day 1)315 ± 239
Last dose (Day 85)195 ± 264
SecondaryPhase 1b: Number of Participants With Anti-Efavaleukin Alfa Binding Antibodies and Anti-Interleukin (IL-2) Binding Antibodies

Number of participants who tested positive for anti-Efavaleukin alfa binding antibodies and number of those participants who cross-reacted with native human IL-2 (i.e. with anti-IL-2 binding antibodies) are reported.

Time frame:
Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
Reported as:
Count of participants · Participants
Phase 1b: Number of Participants With Anti-Efavaleukin Alfa Binding Antibodies and Anti-Interleukin (IL-2) Binding Antibodies
ParticipantsPhase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
Binding anti-AMG 592 antibody positive post-baseline with a negative or no result at baseline2365
Binding anti-IL2 antibody positive post-baseline with a negative or no result at baseline0011
SecondaryPhase 1b: Number of Participants With Anti-Efavaleukin Alfa Neutralizing Antibodies and Anti-IL-2 Neutralizing Antibodies

The number of participants who tested positive for anti-Efavaleukin alfa neutralizing antibodies and number of participants with anti-IL2 neutralizing antibodies who tested negative or no result at baseline are reported.

Time frame:
Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)
Reported as:
Count of participants · Participants
Phase 1b: Number of Participants With Anti-Efavaleukin Alfa Neutralizing Antibodies and Anti-IL-2 Neutralizing Antibodies
ParticipantsPhase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
Neutralizing anti-AMG 592 antibodies positive post-baseline with a negative or no result at baseline2175
Neutralizing anti-IL2 antibody positive post-baseline with a negative or no result at baseline0011
SecondaryPhase 2a: Number of Participants Who Achieved an American College of Rheumatology 50 Percent Improvement Criteria (ACR 50) or 70 Percent Improvement Criteria (ACR 70) at Week 12

ACR 50 and ACR 70 response defined as at least 50 percent or 70 percent improvement from baseline in both tender and swollen joint counts, and a 50 percent or 70 percent improvement or more in at least 3 of the following 5 criteria: * physician global assessment of disease activity (PGA) * subject global assessment of disease activity (SGA) * patient global assessment of joint pain * subject self-assessment of disability (HAQ-DI) * C-Reactive Protein (CRP)

Time frame:
Baseline and Week 12

No measurements were reported for this outcome.

SecondaryPhase 2a: Change From Baseline in Disease Activity Score (28 Joint) Calculated Using The Erythrocyte Sedimentation Rate Formula (DAS28-ESR) at Week 12

Change from baseline in DAS28-ER at Week 12. DAS28-ESR was to assess disease activity in patients with rheumatoid arthritis. DAS28-ESR is a composite score that includes 4 variables: tender joint count (TJC) (based on 28 joints); swollen joint count (SJC) (based on 28 joints); participant's global assessment of health activity using 100 mm VAS: range 0 (no pain) to 100 (maximum pain imaginable); marker of inflammation assessed by ESR in mm/h. DAS28-ESR total score range from 0-10, higher score indicates more disease activity.

Time frame:
Baseline and Week 12

No measurements were reported for this outcome.

SecondaryPhase 2a: Change From Baseline in Disease Activity Score (28 Joint) Calculated Using the C-reactive Protein Formula (DAS-28-CRP) at Week 12

Change from baseline in DAS28-CRP at Week 12. 2. DAS28-CRP was to assess disease activity in patients with rheumatoid arthritis. DAS28-CRP is a composite score that includes 4 variables: TJC (based on 28 joints); SJC (based on 28 joints); participant's global assessment of health activity using 100 mm VAS: range 0 (no pain) to 100 (maximum pain imaginable); marker of inflammation assessed by CRP in mg/L. DAS28-CRP total score range from 0-10, higher score indicates more disease activity.

Time frame:
Baseline and Week 12

No measurements were reported for this outcome.

SecondaryPhase 2a: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)

TEAEs were events with an onset after the administration of the first dose of study treatment. TEAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE).

Time frame:
Baseline up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)

No measurements were reported for this outcome.

SecondaryPhase 2a: Number of Participants Who Experienced a Clinically Significant Change in Vital Signs

Any changes in systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature that were deemed as clinically significant by the Investigator were reported.

Time frame:
Baseline up to Week 12

No measurements were reported for this outcome.

SecondaryPhase 2a: Number of Participants Who Experienced a Clinically Significant Change in Laboratory Safety Tests

Laboratory safety tests included chemistry and hematology parameters. Clinically significant laboratory safety tests were any events assessed as CTCAE Grade ≥3 at any post-baseline visit. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated.

Time frame:
Day 1 up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up)

No measurements were reported for this outcome.

SecondaryPhase 2a: Efavaleukin Alfa Serum Concentration

A summary of mean serum concentrations of Efavaleukin alfa over time.

Time frame:
Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12

No measurements were reported for this outcome.

SecondaryPhase 2a: Maximum Observed Serum Concentration (Cmax) of Efavaleukin Alfa
Time frame:
Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12

No measurements were reported for this outcome.

SecondaryPhase 2a: Time to Maximum Observed Serum Concentration (Tmax) of Efavaleukin Alfa
Time frame:
Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12

No measurements were reported for this outcome.

SecondaryPhase 2a: Area Under the Concentration-time Curve (AUC) of Efavaleukin Alfa
Time frame:
Day 1 (pre-dose) and weeks 2, 4, 6, 8, 10 and 12

No measurements were reported for this outcome.

Adverse events

Collected over Day 1 up to end of study, maximum of 18 weeks (12-weeks double-blind treatment, 6-weeks safety follow-up). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Phase 1b: Placebo0/8 (0%)0/8 (0%)3/8 (37.5%)
Phase 1b: Efavaleukin Alfa Cohort 10/6 (0%)0/6 (0%)5/6 (83.3%)
Phase 1b: Efavaleukin Alfa Cohort 20/11 (0%)1/11 (9.1%)11/11 (100%)
Phase 1b: Efavaleukin Alfa Cohort 30/11 (0%)0/11 (0%)11/11 (100%)
Most frequent serious events
Most frequent serious events
EventPhase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
HypersensitivityImmune system disorders0/80/61/110/11
Most frequent other events
Showing 10 of 72
Most frequent other events
EventPhase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3
Injection site reactionGeneral disorders0/80/66/118/11
Injection site erythemaGeneral disorders0/84/62/113/11
Rheumatoid arthritisMusculoskeletal and connective tissue disorders1/80/64/112/11
Oropharyngeal painRespiratory, thoracic and mediastinal disorders0/82/60/110/11
EosinophiliaBlood and lymphatic system disorders0/80/63/111/11
ArthralgiaMusculoskeletal and connective tissue disorders0/81/63/110/11
Abdominal painGastrointestinal disorders0/80/62/110/11
Peripheral swellingGeneral disorders0/80/62/111/11
Back painMusculoskeletal and connective tissue disorders0/80/60/112/11
HeadacheNervous system disorders1/80/61/112/11

Baseline characteristics

The safety analysis set: All participants who received at least 1 dose of investigational product. Only cohorts with enrolled participants are included in the baseline population.

Age, Continuous
Age, Continuous(years)Phase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3Total
Mean46.4 ± 12.157.8 ± 8.453.1 ± 10.751.4 ± 15.351.9 ± 12.4
Sex: Female, Male
Sex: Female, Male(Participants)Phase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3Total
Female469827
Male40239
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Phase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3Total
Hispanic or Latino10214
Not Hispanic or Latino7691032
Unknown or Not Reported00000
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Phase 1b: PlaceboPhase 1b: Efavaleukin Alfa Cohort 1Phase 1b: Efavaleukin Alfa Cohort 2Phase 1b: Efavaleukin Alfa Cohort 3Total
Black or African American21003
White65111133
07

Study locations

15 sites
  • Research Site
    Anniston, Alabama 36207, United States
  • Research Site
    Torrance, California 90502, United States
  • Research Site
    Lansing, Michigan 48910, United States
  • Research Site
    Duncansville, Pennsylvania 16635, United States
  • Research Site
    Dallas, Texas 75231, United States
  • Research Site
    Sofia, 1612, Bulgaria
  • Research Site
    Berlin, 10117, Germany
  • Research Site
    Frankfurt am Main, 60590, Germany
  • Research Site
    Jozefow, 05-410, Poland
  • Research Site
    Krakow, 30-348, Poland
  • Research Site
    Poznan, 60-848, Poland
  • Research Site
    Stalowa Wola, 37-450, Poland
  • Research Site
    Swidnik, 21-040, Poland
  • Research Site
    Wroclaw, 51-128, Poland
  • Research Site
    A Coruña, Galicia 15006, Spain
08

References and documents

Study documents

  • Study protocol · Jun 6, 2019
  • Statistical analysis plan · Feb 7, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.

Supporting information: Study protocol, Sap, Icf, Csr

09

Registry details

Key details

Study ID
NCT03410056
Lead sponsor
Amgen
Responsible party
Sponsor
First posted
Jan 25, 2018
Start date
May 22, 2018
Primary completion
Dec 10, 2019
Completion
May 13, 2020
Results posted
Jun 4, 2021
Last update
Jun 22, 2021

Study contacts

MD
study director · Amgen

Oversight

Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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