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 |
|
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 |
|
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. |
|
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 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 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. |
|
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 |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout study, Week 12 |
|
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 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout study, Week 12 |
|
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 | Yes |
E.7.1.3.1 | Other trial type description |
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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 | 1 |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |
E.8.9.2 | In all countries concerned by the trial days | 0 |