| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Rheumatoid Arthritis Patients With Inadequate Response to Methotrexate |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 23.1 |
| 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 |
The primary objective of the study is to demonstrate equivalent efficacy
of BAT1806 and RoActemra in subjects with rheumatoid arthritis (RA)
that is inadequately controlled by methotrexate (MTX). |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy profile ofBAT1806 compared with RoActemra over time based on secondary efficacy endpoints.
- To evaluate the safety and tolerability profile ofBAT1806 compared with RoActemra over the entire study period.
- To evaluate the irnmunogenicityprofile ofBAT1806 in terms of anti-drug antibody (ADAs) production compared with RoActemra.
- To evaluate the steady-state pharmacokinetics (PK) ofBATl 806 compared with RoActemra
- To assess safety and imrnunogenicity following transition from RoActemra to BAT1806. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects 18 years of age or older who fulfil the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 revised classification criteria for RA diagnosis for at least 6 months before screening, based on the medical history record.
2. Subject presents with active RA, as defined by:
a. 2: 6 out of 68 tender joints (at screening and randomization) AND
b. 2: 6 out of 66 swollen joints (at screening and randomization) AND
c. Serum C-reactive protein (CRP) >upper limit of normal (ULN) value or erythrocyte sedimentation rate (ESR) 2: 28 mm/hour at screening.
3. Subject must be receiving MTX therapy according to the following:
a. MTX treatment by any route of administration for 2: 12 weeks prior to randomization, with at least the last 4 consecutive weeks prior to randomization on a stable dose ranging between 10 to 25 mg/week.
b. Subjects will continue on their stable MTX dose and route of administration throughout the study.
4. If using oral corticosteroids, subject must be on a stable::=:: 10 mg dose ofprednisone/day equivalent for at least 4 consecutive weeks prior to randomization and willing to continue at this level throughout the study.
5. If taking nonsteroidal anti-inflammatory drugs, subject must be on a stable dose for at least 2 consecutive weeks prior to randomization and willing to continue at this level throughout the study.
6. Subjects are eligible if they have received not more than 2 biological agents other than interleukin-6 inhibitors or targeted synthetic DMARDs ( eg, tofacitinib) in total for RA treatment.
7. Female subjects of childbearing potential and male subjects with a female partner of childbearing potential must be willing to take reliable contraceptive precautions throughout the study period and continuing for at least 3 months after the last dose of study drug. Reliable methods of contraception include: intrauterine device, hormonal contraceptives (eg, oral, patch, or injectable), male vasectomy (if vasectomy was medically confirmed), a barrier protection method ( eg, condom or diaphragm) in association with spermicide cream, foam, or gel. Abstinence from heterosexual intercourses is accepted when this is the usual lifestyle of the subject and must be continued for at least 3 months after the last dose of study drug. A female subject is considered not of child-bearing potential when postmenopausal (at least 12 consecutive months without menses without an alternative medical cause) or surgically sterilized (bilateral tubal ligation, bilateral oophorectomy with or without hysterectomy).
8. If female of childbearing potential, subject should have a negative pregnancy test result at Screening and Baseline visit.
9. Subjects must be willing to provide written consent and to comply with the requirements of the study protocol.
|
|
| E.4 | Principal exclusion criteria |
1. Has RA of ACR functional class IV or is wheelchair/bed bound.
2. Known hypersensitivity to tocilizumab or to study treatment excipients.
3. Previous exposure to any authorized or investigational interleukin-6 inhibitor
4. Subject has received any biological agents other than those prohibited or any targeted synthetic DMARDs
5. Subject has received any cell-depleting therapy (eg, rituximab) ::=:: 12 months prior to randomization.
6. Subject has been treated with an investigational drug other than those prohibited or device :S 8 weeks or 5 half-lives of the drug (whichever is longer) prior to randomization.
7. Subject has received any conventional DMARDs other than MTX (eg, hydroxychloroquine, sulfasalazine, iguratimod, etc.)::=:: 4 weeks prior to randomization. For leflunomide, the washout period before randomization must be a minimum of 12 weeks or a minimum of 4 weeks is accepted
after documented completion of standard cholestyramine or activated charcoal washout procedure.
8. Previous exposure to alkylating agents such as cyclophosphamide or chlorambucil.
9. Subject has received IV imrnunoglobulins or plasmapheresis ::=:: 6 months prior to randomization.
10. Subject has been treated with intra-articular or parenteral corticosteroids ::=:: 4 weeks prior to randomization (inhaled corticosteroids for stable medical conditions are allowed).
11. Subject has received any herbal remedies, traditional medicines, or other not approved medications for RA :S 4 weeks prior to randomization.
12. Subject has undergone joint surgery :S 12 weeks prior to randomization (on any joint to be assessed during the study) or has any surgery planned during the study.
13. Evidence of malignancy, lung infection, or abnormalities suggestive of active tuberculosis (TB) on chest radiography performed within 12 weeks prior to the Screening Visit or during the screening period.
14. Subject meets any of the following criteria relative to latent or active TB infection:
a. History of active TB :S 3 years prior to screening. If> 3 years, documentation of completion of adequate therapy must be available.
b. Presence of signs or symptoms suggestive of active TB upon medical history and/or physical examination during screening.
c. Recent close contact with a person with active TB.
d. Positive interferon-gamma release assay (IGRA) result at screening.
15. History of invasive infection (eg, histoplasmosis, coccidioidomycosis, blastomycosis).
16. Presence of active infection at screening, or history of infection requiring intravenous antibiotics and/or hospitalization :S 4 weeks prior to randomization or oral antibiotics :S 2 weeks prior to randomization. Minor fungal infections (eg, minor nail infections) will be allowed.
17. Any recurrent bacterial, fungal, or viral infection that based on the investigator's clinical assessment makes the subject unsuitable for the study, including recurrent/disseminated herpes zoster.
18. Current or history of diverticulitis, complications of diverticulitis, history of diverticulosis requiring antibiotic treatment, current or history of chronic ulcerative lower gastrointestinal tract diseases or any other lower gastrointestinal condition that may predispose to perforation.
19. Any history of malignancy or lymphoproliferative disease at any tin1e, except curative treatment for nonmelanoma skin cancer or resected carcinoma in situ of the cervix.
20. Have a transplanted organ/tissue or stem cell transplantation.
21. Significant medical problems, including but not limited to the following: uncontrolled hypertension (systolic pressure 2: 160 and/or diastolic pressure 2: 95 mmHg), congestive heart failure (New York Heart Association status of class III or IV), history of unstable angina pectoris, myocardial infarction, or cerebrovascular accident within the past 12 months, uncontrolled diabetes, renal or liver disease.
22. Presence of any of the following abnormal laboratory test results at screening:
a. Abnormal liver function.
b. Serum total bilirubin > 1.5 x ULN.
c. Abnormal renal function defined as serum creatinine level 2: 1.5 x ULN.
d. Total white blood cell count :S 3,000/μL, absolute neutrophil count :S 2,000/μL, platelet count < 100,000/μL, or hemoglobin < 8.5 g/dL.
e. Positive HIV, hepatitis B, or hepatitis C serological result.
For European sites, HBsAg-positive AND I OR HBcAb-positive subjects will be excluded.
For Chinese sites:
• HBsAg-positive subjects will be excluded;
• IfHBsAg is negative:
- HBcAb is also negative, subjects will be included;
- HBcAb is positive:
• HBsAb-positive subjects will be included;
• HBsAb-negative subjects will be tested for HBV DNA:
- IfHBV DNA is negative, the subjects will be included.
- If HBV DNA is positive, the subjects will be excluded.
23. Subject has a history of acute inflammatory joint disease of different origin other than RA. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for the study is the percentage of subjects
achieving an American College of Rheumatology 20% (ACR20) response |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Two timepoints (Week 12 or Week 24) will be analyzed independently as
primary for this measure, depending on the regulatory agency for
submission (ie, for the European Medicines Agency [EMA] this will be
Week 12 and for the US Food and Drug Administration [FDA] and China
National Medical Products Administration [NMPA] this will be Week 24
during TP1). |
|
| E.5.2 | Secondary end point(s) |
The following secondary endpoints will be assessed.
Efficacy
• Change from baseline in Disease Activity Score on 28 Joints (DAS28; C- reactive protein [CRP]) and DAS28 (erythrocyte sedimentation rate [ESR]) over the course of the study
• Percentage of subjects achieving ACR20, ACR50, and ACR 70 response over the course of the study
• Change from baseline in ACR and DAS28 individual components over the course of the study, including Swollen Joint Count in 66 joints (SJC66), Tender Joint Count in 68 joints (TJC68), pain VAS, total Health Assessment Questionnaire - Disability Index (HAQ-DI), Subject's Global Assessment of Disease Activity visual analogue scale (VAS), Physician's Global Assessment of Disease Activity VAS, CRP, and ESR
Pharmacokinetics
• Trough serum concentration of tocilizumab at predose over the course of the study for both arms
Immunogenicity
• Proportion of subjects developing ADAs to RoActemra or BAT1806 over the course of the study
Safety:
• Adverse events (AEs), including treatment-emergent AEs (TEAEs), SAEs, related AEs and related SAEs
• Laboratory parameters, including hematology, chemistry with lipids panel, and urinalysis
• Vital signs
• Physical examination
• 12-lead ECG |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | 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) | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Bulgaria |
| China |
| Georgia |
| Poland |
| Ukraine |
|
| 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
|
| Last Visit of Last Subject will be end of 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 | 11 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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