| 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] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 18.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10042952 |
| E.1.2 | Term | Systemic rheumatoid arthritis |
| E.1.2 | System Organ Class | 100000004859 |
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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 |
The objectives of Part 1 of the study are to compare the efficacy and safety of CHS 0214 manufactured in the EU, to Enbrel (EU) at 24 weeks in subjects with RA who have an inadequate response to methotrexate and no more than 3 other non-biologic disease modifying anti rheumatic drugs and who are naïve to biologic therapies.
The objectives of Part 2 of the study are to evaluate the longer term safety and the durability of response to open-label CHS 0214.
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| E.2.2 | Secondary objectives of the trial |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet the following criteria to be enrolled in Part 1 of the study:
1.Male or female adult ≥ 18 years of age (≥ 20 years of age in Japan);
2.Have a diagnosis of RA, as defined by the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 or 1987 criteria for RA with disease duration of at least 6 months prior to Screening;
3.Have had an adequate trial of MTX defined as having been on MTX for at least 3 months and on a stable, dose (≥ 8 mg/week to ≤ 25 mg/week, not to exceed local approved dose level) for at least 6 weeks prior to Screening;
4.Have active disease, defined as: ≥ 6 tender joints, ≥ 6 swollen joints (based on 66 swollen joint count (SJC) and 68 tender joint count (TJC))
5.DAS28-CRP[4] ≥ 3.2 ;
6.Have had an IR to MTX and may have failed no more than 3 other conventional non-biologic DMARDs (eg, hydroxychloroquine, oral or injectable gold, azathioprine, D penicillamine, sulfasalazine, and leflunomide or approved kinase inhibitors), and are candidates for tumor necrosis factor alpha (TNF α) inhibitor therapy;
7.Have discontinued treatment with all DMARDs, except MTX, at least 2 weeks prior to Screening, For subjects taking leflunomide, cholestyramine should be administered 2 weeks prior to Screening to accelerate elimination of leflunomide as described in the approved label;
8.Women who meet one of the following:
a.Women of childbearing potential with a negative urine pregnancy test at Screening who agree to use one or more approved methods of birth control during the study. Approved methods of birth control are: hormonal contraception, intrauterine device, diaphragm plus spermicide, condom plus spermicide. Abstinence from heterosexual intercourse will be acceptable only if it is the preferred and usual lifestyle of the subject regardless of study participation; abstinence should be practiced for the duration of the study (study duration includes the Follow-up Visit) after taking the last dose of study drug;
b.Women who have been postmenopausal for at least 2 years (with amenorrhea for at least 1 year) or have had a hysterectomy, bilateral salpingo-oophorectomy, or tubal ligation prior to signing the informed consent; and
9.Able and willing to give written informed consent prior to performance of any study related procedures.
Part 2: Subjects must meet the following criteria to be enrolled in Part 2 of the study:
1.Completed the evaluations and achieved at least an ACR20 response at Week 24;
2.Tolerated study drug in Part 1 with no SAEs or unresolved Grade 3 or higher adverse events related to study drug. |
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| E.4 | Principal exclusion criteria |
1.Use of parenteral glucocorticoids within 4 weeks prior to initiation of Screening or use of intra articular glucocorticoids within 4W prior to randomization
2.Use of oral glucocorticoids (such as > 10 mg prednisone per day (or equivalent corticosteroid), or a change in dosage within 2W prior to initiation of Screening (Note: the dose of prednisone ≤ 10 mg per day [or equivalent corticosteroid] should remain stable throughout Screening and should be expected to remain stable during the study for the subject to be eligible)
3.Use of more than 1 NSAID or use of a single NSAID at greater than the recommended daily dose for that NSAID
4.Prior treatment with any biologic for any indication (including but not limited to: tocilizumab [RoACTEMRA, Actemra], certolizumab pegol [CIMZIA], etanercept [Enbrel], adalimumab [HUMIRA], anakinra [Kineret], abatacept [ORENCIA], infliximab [REMICADE], rituximab [MabThera, Rituxan], and golimumab [SIMPONI]); (Note: insulin for diabetes mellitus and hormonal replacement therapy and hormonal birth control are allowed)
5. Administration of a live vaccine within 4W prior to screening
6.Participation in an investigational drug or device trial within 30 days prior to randomization or a period equal to 5 times the half-life of the investigational agent, whichever is longer
7.Functional class IV RA according to ACR revised classification, 1991, ie, limited ability to perform usual self care, vocational, and avocational activities
8.Diagnosis of other rheumatic disease, autoimmune disease, connective tissue disease, or immune deficiency disease (eg, psoriasis, psoriatic arthritis, primary Sjögren’s syndrome, systemic lupus erythematosus, or demyelinating diseases such as multiple sclerosis)
9.History of alcohol or drug abuse within 2Y prior to Screening
10.White blood cell count < 3500 cells/mm3, lymphocyte count < 1000 cells/mm3, platelet count ≤ 125,000 cells/mm3, serum creatinine ≥ 2 mg/dL (177 µmol/L), alanine transaminase or aspartate transaminase ≥ 2.0 × the upper limit of normal of the reference range, or hemoglobin ≤ 8.5 g/dL at Screening
11.Presence or history of malignancy (except for successfully treated non metastatic basal or squamous cell carcinoma of the skin and carcinoma in situ of the cervix)
12. Presence of TB based on positive blood test (QuantiFERON®-TB Gold Test for TB) during Screening or subjects with known recent exposure to
patient with active TB; Note: QuantiFERON®-TB Gold test can be repeated one time using a fresh sample in patients with an indeterminate result or low positivity defined as Quantiferon TB Antigenm minus Nil value = 0.35-2 IU/mL. If the repeat test is negative, the subject may participate in the study. If the repeat test is positive or indeterminate, the subject does not qualify to participate in the study
13.Abnormal chest x-ray obtained within 6M prior to randomization demonstrating active lung disease processes other than RA (eg, evidence of TB)
14.History of positive test results for fungal or other infections required by regional guidelines prior to start of biologic drugs within 3M prior to randomization
15.Major systemic infections (eg, positive for hepatitis B surface antigen [HBsAg], hepatitis B core antibody [HBcAb], hepatitis C virus [HCV], or human immunodeficiency virus [HIV])
16.Class III or IV congestive heart failure as defined by the New York Heart Association criteria
17.Presence of significant comorbid medical condition(s), including, but not limited to:
a.uncontrolled diabetes mellitus (hemoglogin A1c [HgbA1c] ≥ 8% within the past 3M prior screening or history of diabetic ketoacidosis or hypoglycemic reactions requiring hospitalization within the past 12M prior to screening)
b.uncontrolled hypertension (systolic blood pressure > 160 mmHg and diastolic blood pressure > 100 mmHg) within the past 3M prior screening;
c.severe kidney disease requiring hemodialysis or peritoneal dialysis
d.advanced liver disease such as hepatitis or liver cirrhosis
e.severe congestive heart failure or history of ejection fraction ≤ 30%
f.severe lung disease requiring home oxygen or
g.active unstable angina requiring daily treatment with nitrates or other medications or
18.Presence of any other major medical or psychiatric illness that in the opinion of the Investigator would put the subject at increased risk or affect the ability to participate in the study
19.Known or suspected sensitivity or allergic reactions to latex or latex-containing products or product excipients
20.History of MTX associated clinically significant toxicity such as interstitial lung disease or persistently elevated transaminases; or
21.Women who are pregnant or nursing.
22. Men whose partners may become pregnant (do not agree to use contraception or who are not post-menopausal). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. The primary efficacy endpoint in Part 1 will be the percentage of subjects who achieve 20% improvement according to American College of Rheumatology Criteria (ACR20) at Week 24 compared to Baseline (initiation of treatment). Subjects will be considered an ACR20 responder if: compared to Baseline (Day 0), they achieve: 20% decrease in swollen joint counts (SJC), 20% decrease in tender joint counts (TJC), and 20% improvement in 3 of the following 5 measures
• C-reactive protein (CRP);
• Health Assessment Questionnaire – Disability Index (HAQ DI);
• Subjects pain assessment using a visual analoguie scale (VAS);
• Subject global assessment of disease activity (SGA);
• Physicians global assessmetn of disease activity (PGA).
2.The primary response duration endpoint will be the percentage of subjects who maintain ACR20 response from week 24 (durable effect) or who have a continued improvement in response (ACR50 response, ACR70 response) and DAS28-CRP(4) to < 3.2(low disease activity) and < 2.6 (remission) assessed at weeks 28. 36 and 48
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. From baseline - Day 0 to week 24
2. Part 1 - weeks 0, 4, 8, 12, 18, and 24 and for Part 2 - weeks 28, 36, and 48.
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| E.5.2 | Secondary end point(s) |
The secondary efficacy variables will include
1. ACR20 at Weeks 4, 8, 12, and 18;
2. The average percent improvement from Baseline (Day 0) in individual ACR response criteria: TJC, SJC, HAQ-DI;
3. Subject’s pain assessment (subject’s pain-VAS), SGA, PGA and CRP at Weeks 4, 8, 12, 18 and 24;
4. 50% and 70% improvement according to American College of Rheumatology criteria (ACR50 and ACR70, respectively) and DAS28-CRP(4) < 3.2. ;
5. Remission rate (defined as DAS28 CRP(4) < 2.6 on all subsequent visits after DAS28 CRP(4) < 2.6 is achieved).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Weeks 4, 8, 12 and 18
2. From Basline
3. Weeks 4, 8, 12, 18, and 24
4. Weeks 4, 8, 12, 18, and 24
5. At all subsequent study visists after required DAS28 CRP(4) is reached |
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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 | 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) | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| 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 |
| Belarus |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Japan |
| Poland |
| Russian Federation |
| South Africa |
| 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 | 1 |
| 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 | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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