| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Rheumatoid arthritis is a chronic, inflammatory disorder that may affect many tissues and organs |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| 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 |
|
| 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 evaluate the efficacy of LY3009104 as assessed by the aggregate proportion of patients in the 4 mg and 8 mg dose groups who achieve an ACR20 response compared to placebo over 12 weeks in patients with active RA despite ongoing MTX therapy. |
|
| E.2.2 | Secondary objectives of the trial |
| 1 Characterize dose-response relationship of LY3009104 on ACR (20/50/N) response rates over 12wks & evaluate model-predicted responses for each dose vs placebo to identify efficacious doses. 2 Evaluate efficacy of each LY3009104 dose compared to placebo over 12wks. 3 Evaluate efficacy of once-daily doses of 2,4,8mg LY3009104 over 24wks. 4 Evaluate safety/tolerability of LY3009104 compared to placebo. 5 Evaluate efficacy/safety of twice-daily dosing of 2mg of LY3009104 compared to once-daily dosing of 4mg of LY3009104. 6 Characterize pharmacokinetics of LY3009104. 7 Evaluate impact of LY3009104 compared to placebo over the 12wk study period with regard to patient-reported outcomes. 8 Evaluate patient-reported measures at baseline with natural course of disease progression & response to treatment with LY3009104 compared to placebo. 9 Evaluate safety/tolerability of long-term administration of once-daily dose of 4mg/8 mg LY3009104 (Part C) and once-daily dose of 4mg LY3009104 (Part D). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Addendum I4V-MC-JADA(1), dated 23 May 2011 August 2010. This is the MRI imaging sub-study as an addendum to main protocol. A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging, Parallel-Group, Phase 2b Study of LY3009104 in Patients with Active Rheumatoid Arthritis on Background Methotrexate Therapy. Exploratory objectives:
To evaluate the efficacy of each dose of LY3009104 compared to placebo at Week 12 as assessed by changes in synovitis, osteitis, bone erosion score, and joint space narrowing as measured by MRI of the hand and wrist.
|
|
| E.3 | Principal inclusion criteria |
Parts A & B
[1] Ambulatory males or females between the ages of 18 and 75 years, inclusive, at time of study entry.
[1a] Male patients:
Agree to use two forms of highly effective methods of birth control with female partners of childbearing potential during the study.
[1b] Female patients:
Females must not be pregnant, breastfeeding, or at risk to become pregnant during study participation.
Female patients of childbearing potential, must have a negative serum
pregnancy test at the time of enrollment and agree to use two forms of
highly effective methods of birth control or remain abstinent for at least 28 days following the last dose of study drug. OR Must be female patients of non-childbearing potential, defined as:
• women who have had surgical sterilization (hysterectomy or bilateral
oophorectomy or tubal ligation),
• women ≥60 years of age,
• women ≥40 and <60 years of age who have had a cessation of menses for at least 12 months and a follicle-stimulating hormone (FSH) test confirming non-childbearing potential (FSH ≥40 mIU/mL), or
• women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome (also
referred to as Congenital Absence of Uterus and Vagina [CAUV]).
[2] Diagnosis of adult-onset RA (of at least 6 months duration but not longer than 15 years prior to screening) according to the ARA 1987 Revised Criteria for the Classification of RA.
[3] Have active RA defined as at least 8 swollen and at least 8 tender joints based on the 66/68 joint count.
[4] Regular use of MTX for at least 12 weeks, and treatment at a stable dose of 10 to 25 mg/week for at least 8 weeks prior to baseline. The dose of MTX should remain stable throughout the study, but may be adjusted for safety reasons. Local standard of care should be followed for concomitant administration of folic acid.
[5] For patients receiving corticosteroids, they must be on a dose not to exceed 10 mg of prednisone daily (or equivalent) and have been on a the same dosing regimen for at least 6 weeks prior to randomization.
[6] ACR functional class I, II, or III.
[7] Have C-reactive protein (CRP) measurement > 1.2 times upper limit of normal (ULN) or Erythrocyte Sedimentation Rate (ESR) > upper limit of normal (28 mm/hr). The CRP and ESR may be repeated once during the screening period at the discretion of the investigator, and the repeat results may be accepted for study eligibility purposes.
[8] Have laboratory values that in the opinion of the investigator do not pose an unacceptable risk to the patient if study drug would be administered.
[9] Venous access sufficient to allow blood sampling as per the protocol.
[10] Are reliable and willing to be available for the duration of the study and are willing to follow study procedures.
[11] Are able to read, understand, and give written informed consent approved by Lilly (or designee) and the ethical review board (ERB) governing the site, and are able to read and understand all questionnaires given at study visits.
Study Part C
[12] Continue to meet inclusion criteria [1a] or [1b] and [8] to [10] of Parts A and B.
[13] Have completed the 24 weeks (Visit 1 to Visit 10) of participation in Parts A and B of the study without permanent study drug discontinuation. Patients who complete Part A and Part B before amendment (a) is active will be eligible to enter Part C of the study only if Part C becomes active prior to the patient’s Follow-Up Visit (28 days after the last dose of study drug).
[14] Give written informed consent approved by Lilly (or designee) and the ERB governing the site for Part C.
Study Part D
[53] Continue to meet inclusion criteria [1a] or [1b] and [8] to [10] of Parts A and B.
[54] Have completed the 52 weeks (Visit 10 to Visit 17) of participation in Part C of the study without permanent study drug discontinuation and have not completed the Follow-Up Visit (approximately 28 days after the last dose of study drug).
[55] Give written informed consent approved by Lilly (or designee) and the ERB
governing the site for Part D. |
|
| E.4 | Principal exclusion criteria |
Parts A & B
[15] Received any parenteral corticosteroid administered by intra-articular, intramuscular, or IV injection within 6 weeks prior to baseline.
[17] Used NSAIDs for less than 4 weeks prior to baseline. If on NSAIDs , must be on a stable dose for at least 4 weeks prior to baseline and must remain on a stable dose throughout Part A and Part B of the study.
[18] Received any prior biologic DMARD therapy (such as TNFα, IL-1, IL-6, T-cell or B-cell targeted therapies).
[20] Received prior treatment with an oral JAK inhibitor.
[21] Used DMARDs (for example, gold salts, cyclosporine, azathioprine, or any other immunosuppressives) other than stable treatment of MTX, hydroxychloroquine (up to 400 mg/day), and/or sulfasalazine (up to 3000 mg/day) in the 8 weeks prior to baseline.
[22] Use of leflunomide in the 12 weeks prior to baseline (or a minimum of 4 weeks prior to baseline will be required if the standard 11 days of chlolestyramine is used to washout leflunomide).
[23] Have active fibromyalgia that would make it difficult to appropriately assess RA activity for the purposes of this study or have a diagnosis of any systemic inflammatory condition other than RA. Patients with secondary Sjogren's syndrome with RA are not excluded.
[24] Evidence of active vasculitis.
[25] Diagnosis of Felty’s syndrome.
[26] Had surgical treatment of a joint that is to be assessed in the study within 2 months of study baseline or will require such during the study.
[27] An abnormality in the 12-lead ECG that in the opinion of the investigator increases the risk of participating in the study.
[28] Uncontrolled arterial hypertension characterized by repeated systolic BP >160 mmHg or repeated diastolic BP >100 mmHg, measured twice during the screening visit.
[30] History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders that in the opinion of the investigator could constitute a risk when taking the study drug or of interfere with the interpretation of data. Patients on a stable dose of thyroid replacement therapy during the 6 months preceding baseline who are clinically or biochemically euthyroid may enroll.
[32] Current or recent (<30 days prior to screening) viral, bacterial, fungal, or parasitic infection.
[33] Had a serious infection or atypical mycobacterial infection within 6 months prior to screening.
[34] Symptomatic herpes zoster or herpes simplex infection within 90 days prior to baseline.
[35] History of disseminated/complicated herpes zoster (for example,
multidermatomal involvement, ophthalmic zoster, CNS involvement).
[36] Evidence of human immunodeficiency virus (HIV) infection and/or positive human HIV antibodies.
[37] Hepatitis C virus (HCV; positive for anti-hepatitis C antibody with confirmed presence of HCV).
[38] Evidence of active hepatitis B (positive for hepatitis B surface antigen [HBsAg+]) OR are positive for hepatitis B core antibody and negative for hepatitis B surface antibody.
[39] Evidence of active tuberculosis (TB) or evidence of latent TB
[41] Have any significant hematological abnormalities listed below:
o Hemoglobin less than 10.0 g/dL,
o Total platelet count less than 100,000/μL ,
o Total white blood cell (WBC) count less than 2500/μL,
o Neutrophil count equal to or less than 1200/μL
o Lymphocyte count equal to or less than 750 cells/μL.
[42] Have estimated glomerular filtration rate (GFR) from serum creatinine using the Modification of Diet in Renal Disease method of <50 mL/minute.
[44] Have any history of chronic liver disease or current serum aspartate
aminotransferase (AST) or alanine aminotransferase (ALT) concentration >3x the ULN or total bilirubin is ≥1.5x ULN.
Part C
[50] Presence of significant uncontrolled cerebro-cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic or neuropsychiatric disorders or abnormal laboratory values during Part A and/or Part B of the study that in the opinion of the investigator pose an unacceptable risk to the patient if study drug would be administered.
[51] Have had study drug permanently discontinued during Part A or Part B or study drug interrupted at Week 24 due to laboratory parameters.
Part D
[56] Presence of significant uncontrolled cerebro-cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic or neuropsychiatric disorders or abnormal laboratory values during Part C of the study that in the opinion of the investigator pose an unacceptable risk to the patient if study drug would be administered.
[57] Had study drug permanently discontinued during Part C or interrupted at Week 76 due to laboratory parameters. The eligibility of patients who have study drug interrupted at Week 76 for reasons other than laboratory parameters is based on the clinical judgment of the investigator and agreement from Lilly (or designee).
Refer to protocol for full exclusion criteria. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary analysis will be a comparison of the combined 4 mg and 8 mg dose groups with placebo on the ACR20 response rate at 12 weeks. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
[1] In Part A, a Bayesian dose-response model will be used to estimate the ACR20 response rate for each treatment group and to compare each LY3009104 dose group to placebo.
[2] From the final Bayesian model, posterior probabilities will be obtained for each dose group's response rate being superior to the placebo group's response rate. For the purposes of this analysis, posterior probabilities will be considered "significant" if they exceed 85% for the evaluation of superiority of a dose group to placebo.
[3] Analyses of ACR50 and ACR-N will be conducted using the same Bayesian dose-response methodology as for ACR20. A supportive doseresponse analysis of ACR-N, as a continuous measures, will be conducted using nonlinear regression of the standard Emax model.
[4] Additional characterizations of the dose-response relationship on ACR indices up to 24 weeks will be made by quantifying the percent of responders (for ACR20/50) or the mean response (for ACR-N).
[5] Mean or median responses (for continous measures) or percent of responders (for dichotomous measures) over time will be presented for ACR20/50/N and selected ACR core components by treatment group.
[6] In Part A, ACR70 through 12 weeks will be analyzed for each dose against placebo.
[7] Individual core components of the ACR indices, DAS28 (actual value and change from baseline), EULAR28, assessments of low disease activity and remission based on DAS28, assessment of clinical remission based on the ACR/EULAR criteria, and duration of morning stiffness through 12 weeks.
[8] In Part B, treatment with 2 mg twice daily will be compared to treatment with 4 mg once daily with regard to the standard efficacy assessments for RA: DAS28, ACR indices and core components, EULAR28, and measures of low disease activity and remission.
[9] In Part C, the number of patients requiring a change to their LY3009104 treatment dose, either as dose interruptions or dose escalations, will be summarized. These summaries will include reason for dose change and frequency and length of dose interruption, if applicable.
[10] Safety and efficacy assessments will be summarized as actual values
or long-term changes from baseline.
[11] In Part D, the number of patients requiring a dose interruption will be summarized.
[12] Radiographic progression of structural joint damage, as assessed by changes in the van der Heijde modified Total Sharp Score, from baseline to the end of Part C will be summarized across the combined treatment groups or within specific subgroups of interest (eg, in those patients treated with 4 mg throughout the majority of Study Parts A, B, and C). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At various timepoints - at 12 weeks, through 12 weeks, through 24 weeks, Part B weeks 13-24, through Part C (weeks 25-76) and through Part D (weeks 77-128). |
|
| 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 | 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 | Yes |
| 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 | 5 |
| 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 | 32 |
| 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 |
| Croatia |
| Czech Republic |
| Hungary |
| India |
| Mexico |
| Peru |
| Poland |
| Romania |
| Ukraine |
| United Kingdom |
| United States |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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