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

NCT03410056 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 201701492017-001944-36
• Study Type: interventional
• Target: 36
• Locations: 5 countries
• Sites: 15

Brief 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.

Conditions

Rheumatoid Arthritis RA

Outcome Measures

Primary Outcomes (5)

• 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

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

• 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.

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

• 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.

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

• 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.

  Baseline up to end of treatment maximum of 12 weeks

• 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)

  Baseline and Week 12

Secondary Outcomes (17)

• Phase 1b: Efavaleukin Alfa Serum Concentrations

  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

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

  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

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

  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

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

  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

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

  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

Study Arms (7)

Phase 1b: Placebo

PLACEBO COMPARATOR

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

Phase 1b: Efavaleukin alfa Cohort 1

EXPERIMENTAL

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

Phase 1b: Efavaleukin alfa Cohort 2

EXPERIMENTAL

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

Phase 1b: Efavaleukin alfa Cohort 3

EXPERIMENTAL

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

Phase 1b: Efavaleukin alfa Cohort 4

EXPERIMENTAL

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

Phase 2a: Placebo

PLACEBO COMPARATOR

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

Phase 2a: Efavaleukin alfa

EXPERIMENTAL

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

Efavaleukin alfa DRUG

Efavaleukin alfa administered as a subcutaneous injection.

Also known as: AMG 592

Phase 1b: Efavaleukin alfa Cohort 1; Phase 1b: Efavaleukin alfa Cohort 2; Phase 1b: Efavaleukin alfa Cohort 3; Phase 1b: Efavaleukin alfa Cohort 4; Phase 2a: Efavaleukin alfa

Placebo DRUG

Placebo administered as a subcutaneous injection.

Phase 1b: Placebo; Phase 2a: Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Amgen: lead

Study Sites (15)

Research Site

Anniston, Alabama, 36207, United States

Location

Research Site

Torrance, California, 90502, United States

Location

Research Site

Lansing, Michigan, 48910, United States

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Research Site

Duncansville, Pennsylvania, 16635, United States

Location

Research Site

Dallas, Texas, 75231, United States

Location

Research Site

Sofia, 1612, Bulgaria

Location

Research Site

Berlin, 10117, Germany

Location

Research Site

Frankfurt am Main, 60590, Germany

Location

Research Site

Józefów, 05-410, Poland

Location

Research Site

Krakow, 30-348, Poland

Location

Research Site

Poznan, 60-848, Poland

Location

Research Site

Stalowa Wola, 37-450, Poland

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Research Site

Świdnik, 21-040, Poland

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Research Site

Wroclaw, 51-128, Poland

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Research Site

A Coruña, Galicia, 15006, Spain

Location

Related Links

• AmgenTrials clinical trials website

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.

Results Point of Contact

• Title: Study Director
• Organization: Amgen Inc.

medinfo@amgen.com

866-572-6436

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 3, 2018
• First Posted: January 25, 2018
• Study Start: May 22, 2018
• Primary Completion: December 10, 2019
• Study Completion: May 13, 2020
• Last Updated: June 22, 2021
• Results First Posted: June 4, 2021

Record last verified: 2021-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.

Locations

ES (1); DE (2); BU (1); US (5); PL (6)