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 | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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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 |
Part A: To evaluate the safety and tolerability of LY3337641 at 5, 10, and 30 mg qd in subjects with RA
Part B: To evaluate the efficacy, safety, and tolerability of LY3337641 at 5, 10, and 30 mg qd versus placebo at Week 12 for the treatment of subjects with moderately to severely active RA |
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E.2.2 | Secondary objectives of the trial |
Part A: N/A
Part B:
• To evaluate the efficacy of LY3337641 at 5, 10, and 30 mg qd versus placebo at Week 12 on RA clinical endpoints
• To characterize the PK of LY3337641 in subjects with RA |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Female subjects of childbearing potential: test negative for pregnancy at screening and agree not to breastfeed
• Female subjects: agree to use a reliable method of birth control from the start of screening until 28 days after the last dose of study drug or be of nonchildbearing potential:
o are postmenopausal
o have undergone bilateral tubal ligation, bilateral oophorectomy, and/or hysterectomy
o have another medical cause of female infertility
• Male subjects: agree to use a reliable method of birth control from the start of screening until 2 weeks after the last dose of study drug or have undergone vasectomy at least 6 weeks prior to screening
• Have a diagnosis of RA based on the 2010 ACR/European League against Rheumatism criteria
• Have at least 1 of the following:
o rheumatoid factor or anti-citrullinated peptide antibodies (ACPA) at screening OR
o radiographs documenting bony erosions
• have active RA, defined as:
o Part A: ≥3 swollen joints (based on 66-joint counts)
o Part B:
o ≥6 swollen joints (based on 66-joint counts)
o ≥6 tender joints (based on 68-joint counts)
o hsCRP greater than the upper limit of normal (ULN) OR positive for ACPA
• Part B only: have had inadequate response, loss of response, or intolerance to at least 1 synthetic or biologic DMARD treatment for RA, regardless of treatment duration |
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E.4 | Principal exclusion criteria |
• Have received any of the following synthetic immunosuppressive therapies under the defined conditions:
o methotrexate (MTX), hydroxychloroquine, sulfasalazine, or leflunomide at an UNSTABLE PRESCRIBED DOSE (defined as a change in prescription) within 28 days prior to baseline
o concomitant treatment with MTX PLUS leflunomide within 28 days prior to baseline
o gold salts, kinase inhibitors (such as tofacitinib), cyclophosphamide, mycophenolic acid, azathioprine, cyclosporine, sirolimus, or tacrolimus within 28 days prior to screening
o Part B only: any prior treatment with a product directly targeting BTK (marketed or investigational)
• Have received any of the following biologic immunosuppressive therapies:
o etanercept, adalimumab, or anakinra within 14 days prior to baseline
o infliximab, certolizumab pegol, golimumab, abatacept, or tocilizumab within 4 weeks prior to baseline
o belimumab, natalizumab, or vedolizumab within 6 months prior to baseline
o Part A only: B-cell–depleting agents (such as rituximab) or other cell-depleting biologics (eg, anti-CD3 antibody) within 12 months prior to screening
o Part B only: B-cell–depleting agents (such as rituximab) or other cell-depleting biologics (eg, anti-CD3 antibody) at any time prior to screening
• Have received any of the following:
o parenteral corticosteroids within 28 days prior to baseline (A single intra-articular corticosteroid injection is permitted within 28 days prior to baseline if no more than 40 mg triamcinolone [or equivalent])
o oral prednisone (or equivalent) >10 mg/day or UNSTABLE PRESCRIBED DOSE within 28 days prior to baseline
o a chronic narcotic drug at an UNSTABLE PRESCRIBED DOSE within 28 days prior to baseline
o gemfibrozil or alfentanil, dihydroergotamine, dofetilide, ergotamine, fentanyl, pimozide, or quinidine within 28 days prior to baseline
• Have known hypogammaglobulinemia or a screening serum immunoglobulin G (IgG level) <565 mg/dL (<5.65 g/L)
• Have hepatitis C virus (HCV) at screening. Subjects who are anti-HCVAb positive and HCV ribonucleic acid (RNA) negative can be enrolled in the study.
• Have hepatitis B virus (HBV) at screening, defined as (1) positive for hepatitis B surface antigen OR (2) positive for anti-hepatitis B core antibody (HBcAb) AND positive for HBV DNA. Have human immunodeficiency virus antibody
• Have active tuberculosis (TB)
• Are at high risk of infection or have recent evidence of clinically significant infection
• Have had lymphoma, leukemia, or any malignancy within the previous 5 years except for basal cell or squamous epithelial carcinomas of the skin
• Have received a live (attenuated) vaccine within 28 days prior to baseline or plan to receive one during the study
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A:
• The safety endpoints evaluated will include but are not limited to the following:
o TEAEs, AESIs, SAEs
o Clinical laboratory tests, vital signs, physical examinations
Part B:
• proportion of subjects who achieve ACR20
• The safety endpoints evaluated will include but are not limited to the following:
o TEAEs, AESIs, SAEs
o clinical laboratory tests, vital signs, physical examinations
Long Term Extension (LTE):
• The safety endpoints evaluated will include but are not limited to the following:
o TEAEs, AESIs, SAEs
o Clinical laboratory tests, vital signs, physical examinations |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: Week 4
Part B: Week 12
LTE: Week 64 |
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E.5.2 | Secondary end point(s) |
Part A: N/A
Part B:
• Proportions of subjects achieving ACR50 and ACR70
• Change from baseline in the DAS28-hsCRP
• Proportion of subjects achieving LDA based on DAS28-hsCRP
• Proportion of subjects achieving clinical remission based on DAS28-hsCRP
• Population PK model estimate of clearance
LTE: N/A
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
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 | Yes |
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 | Yes |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Argentina |
Australia |
Austria |
Germany |
Italy |
Japan |
Korea, Republic of |
Mexico |
Poland |
Slovakia |
South Africa |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |