E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
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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 |
To test the hypothesis that the ACR50 response after 24 weeks for the smallest dose that achieves at least 95% of the maximal efficacy (ED95) of LY2127399 is significantly greater than for placebo, when study drug is administered subcutaneously once monthly in patients with active RA despite ongoing MTX therapy. |
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E.2.2 | Secondary objectives of the trial |
• estimate maximum response to LY2127399, ED95, and smallest dose achieving maximum response of ACR20 and ACR50 at 24 weeks • determine whether there is a minimally effective dose (smallest dose with at least 25% absolute efficacy difference from placebo in ACR50 and ACR20) and to estimate that dose • evaluate LY2127399 dose-ACR50 response and dose-ACR20 response relationships at 24 weeks relative to placebo • characterize relationships between LY2127399 dose, exposure, and response of selected PD endpoints • evaluate LY2127399 safety and tolerability compared to placebo • evaluate PD of selected peripheral B cell subsets compared to placebo • explore potential associations between selected biomarkers and selected disease activity measures • further characterize LY2127399 PK in RA patients on MTX therapy • evaluate potential effect of LY2127399 compared to placebo on additional patient-reported outcomes as measured by the: ο FACIT Fatigue Scale ο Medical Outcomes SF-36
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
[1] Ambulatory males or females between the ages of 18 and 75 years, inclusive. [2] Women must not be pregnant or breastfeeding during study participation. Women of childbearing potential (not surgically sterilized and between menarche and 1 year postmenopause) must have a negative pregnancy test and must use an acceptable form of contraception during the study. Methods of contraception considered acceptable are oral contraceptives, contraceptive patch, intrauterine device (IUD), vaginal ring, diaphragm, or condom with contraceptive gel. [3] Diagnosis of RA according to the ARA 1987 Revised Criteria for the Classification of RA (Arnett et al. 1988). [4] Regular use of MTX for at least 16 weeks, and at a stable dose between 10 and 25 mg/wk, inclusive, for at least 8 weeks prior to baseline. Local standard of care should be followed for concomitant administration of folic acid. [5] History of, or current, positive rheumatoid factor (RF) test. [6] ACR functional class I, II, or III (Protocol Attachment BCDH.2). [7] Have active RA defined as at least 5 swollen and at least 5 tender joints based on the 28 joint count specified (Section 6.1.2.2 [Tender Joint Counts] and Section 6.1.2.3 [Swollen Joint Counts]). [8] Have a screening CRP of at least 1.2 times upper limit of normal (ULN). [9] Clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations as judged by the investigator. [10] Venous access sufficient to allow blood sampling as per the protocol. [11] Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures. [12] Are able to read, understand, and give written informed consent approved by Lilly or its designee and the ethical review board (ERB) governing the site. |
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E.4 | Principal exclusion criteria |
[1] Have received any parenteral corticosteroid administered by intraarticular, intramuscular, or IV injection within 4 weeks of baseline. [2] Within 4 weeks prior to baseline, either use of oral corticosteroids at average daily doses of >10 mg/day of prednisone or its equivalent, or use of variable doses of oral corticosteroids. [3] Have received any B cell biotherapies at anytime in the past, whether the indication for therapy was RA or not. [4] Have been treated for at least 3 months at approved doses with at least 1 biologic TNFα inhibitor therapy and have had an inadequate efficacy response to such treatment in the opinion of the investigator. Patients must have stopped etanercept ≥28 days, and infliximab, adalimumab, or other biologic TNFα inhibitor therapy ≥56 days prior to baseline. [5] Have had an inadequate response to treatment with 3 or more of the following DMARDs prescribed alone or in combination at approved doses for a minimum of 3 months: abatacept, leflunomide, azathioprine, cyclosporine, and sulfasalazine. [6] Use of other DMARDs other than MTX, hydroxychloroquine, or sulfasalazine, in the 8 weeks prior to baseline. If on hydroxychloroquine or sulfasalazine, must be on the drug for 16 weeks and at a stable dose for at least 8 weeks prior to baseline. [7] Use of leflunomide in the 12 weeks prior to baseline. Cholestyramine may be used to shorten the washout period for leflunomide, according to standard protocol [8] Use of NSAIDs for <2 weeks prior to baseline. [9] Diagnosis of any systemic inflammatory condition other than RA. [10] Evidence of active vasculitis. [11] Diagnosis of Felty’s syndrome. [12] Surgical treatment of a joint that is to be assessed in the study within 2 months of study enrollment, or will require such during the study. [13] Have previously completed or withdrawn from this study or any other study investigating LY2127399. [14] Abnormality in the 12-lead ECG that in the opinion of the investigator increases the risk of participating in the study or a Bazett’s corrected QT interval >450 msec for men and >470 msec for women. [15] Uncontrolled arterial hypertension characterized (sBP >160 mmHg or dBP >100 mmHg. [16] Lymphoma, leukemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease. [17] History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders constituting a risk when taking the study medication or of interfering with the interpretation of data. Subjects on a stable dose of thyroid replacement therapy during the 6 months preceding baseline who are clinically or biochemically euthyroid may enroll in the trial. [18] Evidence of significant active neuropsychiatric disease, in the opinion of the investigator. [19] Serious bacterial infection within 6 months of enrollment. [20] Symptomatic herpes zoster within 3 months of enrollment. [21] Evidence of HIV and/or positive human HIV antibodies. [22] Evidence of hepatitis C and/or positive hepatitis C antibody. [23] Evidence of hepatitis B and/or positive hepatitis B surface antigen. [24] Evidence or suspicion of active TB by medical history, physical examination and/or screening chest radiograph. [25] At the time of screening, a positive purified protein derivative (PPD) test for TB. For the purpose of this study, a positive test is defined as induration ≥10 mm, between approximately 2 and 3 days after test application. Exceptions to this criterion include patients with a history of a positive PPD who have been treated with isoniazid (INH) (documented) for at least 6 months, or patients with a previous diagnosis of TB who have received appropriate treatment (documented) and have not been re-exposed to TB since their treatment was completed. [26] Other recent or ongoing infection that in the opinion of the investigator poses an unacceptable risk to participate in the study. [27] Exposed to a live vaccine within 3 months of enrollment or expected to need/receive a live vaccine during the course of the study. [28] Significant hematological abnormalities, including hemoglobin <8.0 g/dL, total platelet count <100,000/μL, total white blood cell (WBC) count <3000/μL, neutrophil count <1000/μL, or lymphocyte count <200 cells/μL. [29] Screening serum creatinine >2.0 mg/dL. [30] Known hypogammaglobulinemia or a serum IgG, IgM, or IgA concentration less than lower limit of normal. [31] Any history of chronic liver disease or with serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) concentration >1.2x the ULN. The AST and ALT may be repeated once within a week. [32] Blood donation of more than 500 mL within the last month. [33] Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ACR50 responder index (based on the 28 joint count) at 24 weeks after baseline.
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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 | 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) | 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.8.3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 34 |
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 | Information not present in EudraCT |
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 |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 0 |