E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10039075 |
E.1.2 | Term | Rheumatoid arthritis and associated conditions |
E.1.2 | System Organ Class | 100000004870 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase 1b • To evaluate the safety and tolerability of subcutaneous (SC) dose administrations of AMG 592 in subjects with active RA Phase 2a • To evaluate the efficacy of AMG 592 at week 12 as measured by the American College of Rheumatology 20% improvement criteria (ACR 20) in adult subjects with moderate to severe RA |
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E.2.2 | Secondary objectives of the trial |
Phase 1b • To characterize the pharmacokinetic (PK) profile following treatment with AMG 592 • To evaluate the incidence of anti-AMG 592 antibody formation and cross-reactivity to human IL-2. Phase 2a • To evaluate the effect of treatment with AMG 592 on other measures of disease • To evaluate the safety of AMG 592 • To characterize the PK of AMG 592 in subjects with RA activity at week 12 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 to day 1. - Phase 1b only. Normal or clinically acceptable 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. |
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E.4 | Principal exclusion criteria |
Disease Related: - Class IV RA according to ACR revised response criteria - Diagnosis of Felty’s Syndrome (RA, splenomegaly and granulocytopenia) Other Medical Conditions - 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 - Positive for hepatitis B surface antigen, hepatitis B core antibody . - Phase 1b only: Positive for Human Immunodeficiency Virus (HIV) at screening or known to be HIV positive. Phase 2a only: Known history of HIV - Positive drug or alcohol urine test at screening. - 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 - 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. - Phase 1b only: Subject unwilling to limit alcohol consumption 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 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 inhibitiors • ≤ 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 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. 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. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 1b • Treatment-emergent adverse events. • Clinically significant changes in vital signs, laboratory safety tests, and electrocardiograms (ECGs)
Phase 2a • ACR 20 at week 12 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout study, Week 12 |
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E.5.2 | Secondary end point(s) |
Phase 1b • AMG 592 serum concentration and PK parameters including, but not limited to, maximum observed concentration (Cmax), the time of maximum observed concentration (Tmax), and area under the concentration-time curve (AUCtau) after the first and last doses. Area under the concentration-time curve over the dosing interval will be calculated & reported for each dosing regimen. • Anti-AMG 592 antibodies and cross-reactivity to IL-2. • Anti-AMG 592 and anti-IL 2 neutralizing antibodies Phase 2a • ACR 50/70 at weeks 12 • Disease activity score (28 joint) calculated using the erythrocyte sedimentation rate formula (DAS28-ESR) score and change from baseline at week 12 • Disease activity score (28 joint) calculated using the C-reactive protein formula (DAS-28-CRP) score and change from baseline at week 12 Treatment-emergent adverse events. • Clinically significant changes in vital signs, laboratory safety tests - AMG 592 serum concentration and PK parameters |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout study, Week 12 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Bulgaria |
Czech Republic |
Germany |
Mexico |
New Zealand |
Poland |
Romania |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 15 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |