| 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 |
|
| 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 | LLT |
| E.1.2 | Classification code | 10003268 |
| E.1.2 | Term | Arthritis rheumatoid |
| E.1.2 | System Organ Class | 100000004859 |
|
| 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 demonstrate the PK similarity of rituximab Pfizer, rituximab EU and rituximab-US in subjects with active rheumatoid arthritis on a background of methotrexate who have had an inadequate response to 1 or more TNF antagonist therapies. |
|
| E.2.2 | Secondary objectives of the trial |
• To assess PD parameters of rituximab Pfizer, rituximab EU and rituximab-US.
• To evaluate the overall safety, tolerability and immunogenicity of rituximab-Pfizer, rituximab-EU and rituximab-US.
• To evaluate measures of clinical response in subjects receiving rituximab-Pfizer, rituximab-EU, or rituximab-US.
• To evaluate health outcomes using HAQ DI in subjects receiving rituximab-Pfizer, rituximab-EU, and rituximab-US. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
1. Age 18 years or older.
2. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
3. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
4. Confirmed diagnosis of rheumatoid arthritis (RA) based on 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis.
5. Meets Class I, II or III of the ACR 1991 Revised Criteria for Global Functional Status in RA.
6. RA seropositivity as documented by a screening assessment for RF, and/or anti CCP.
7. Active disease as defined by:
a. ≥6 tender/painful joints (of 68 assessed) at screening and baseline, and
b. ≥6 swollen joints (of 66 assessed) at screening and baseline, and
c. hs CRP > ULN at screening, performed by central laboratory
OR
Patient’s Global Assessment of Arthritis score ≥50, and
d. Baseline DAS28-CRP >3.2.
8. Stable dose of oral or parenteral methotrexate 10 25 mg per week (depending on local practice and standard of care; in the case of prior poor tolerance, methotrexate doses as low as 7.5 mg per week are allowed). Subjects must have received methotrexate for at least 3 months, and with a stable dose for at least 4 weeks prior to first dose of study drug.
9. Inadequate response in the opinion of the investigator to 1 or more approved TNF antagonist therapies administered in accordance with local product label. Inadequate response is defined as:
a. Failure to achieve adequate clinical response during prior TNF antagonist therapy, or
b. Relapse following clinical response to TNF antagonist therapy, or
c. Adverse event to TNF antagonist therapy resulting in discontinuation from treatment.
Please refer to the Protocol for a full list of Inclusion Criteria |
|
| E.4 | Principal exclusion criteria |
Subjects presenting with any of the following will not be included in the study:
1. Any prior treatment with lymphocyte depleting therapies such as, but not limited to rituximab [Rituxan®, MabThera®], alemtuzumab (Campath®), total lymphoid irradiation.
2. Pregnant females; breast feeding females; males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 6 months after last dose of investigational product. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
3. Inadequate bone marrow, liver, renal and immune system functions at screening visit as defined by:
a. Absolute neutrophil count (ANC) ≤1500 cells/mm3.
b. Platelets <100 x 109/L.
c. Hemoglobin (Hgb) <8 g/dL.
d. Bilirubin ≥1.5 times the upper limit of normal (x ULN), unless a diagnosis of Gilbert’s Disease in which case ≥2.5 x ULN.
e. Aspartate aminotransferase/alanine aminotransferase (AST/ALT) ≥3 x ULN.
f. Serum creatinine ≥1.5 mg/dL.
g. Immunoglobulin G (IgG) or IgM < lower limit of normal (LLN).
4. Evidence of latent, inadequately treated or active infection with tuberculosis (TB) as defined by one or more of the following:
a. Screening TB according to local health authority guidance.
b. History of active TB infection.
• A Mantoux Purified Protein Derivative (PPD) test may be performed locally for subjects not having prior Bacille Calmette Guérin (BCG) vaccination and interpreted by the investigator according to local standards or country-specific guidelines. A QuantiFERON Gold®™ test is recommended and provided for subjects in this study with a history of BCG vaccination.
• Screening chest radiograph suggestive of active TB infection.
c. Untreated or inadequately treated latent TB infection. Subjects previously treated for potential latent TB must have completed a full course of treatment in accordance with local guidelines. General guidelines recommend 3 years elapsed since completing TB therapy.
5. Known or screen test positive for any of the following viruses or indicators of viral infection:
a. Known positive for human immunodeficiency virus (HIV).
b. Test positive for hepatitis B surface antigen (HBsAg) (unless previously immunized for hepatitis B).
c. Test positive for hepatitis B virus (HBV).
d. Test positive for core antibody associated with positive HBV DNA.
e. Test positive for hepatitis C.
f. History of disseminated or recurrent herpes zoster (single, limited episode in the past is not exclusionary).
g. History of disseminated herpes simplex.
6. Primary or secondary immunodeficiency.
7. History of recurrent inflammatory joint disease other than rheumatoid arthritis (eg, other autoimmune diseases, vasculopathies, spondyloarthropathies, severe osteoarthritis, post infectious arthritis, gout).
8. History of lymphoproliferative disorder (eg, Epstein Barr Virus (EBV) related lymphoproliferative disorder, lymphoma, leukemia).
9. Infection requiring hospitalization, parenteral antimicrobial therapy, or judged clinically significant by the investigator within 3 months prior to first dose of study drug.
10. Vaccination with live or attenuated vaccines within 6 weeks prior to the first dose of study drug or plan/need to administer these vaccines during study participation or within 4 weeks following discontinuation of study drug.
11. Current or recent history of uncontrolled clinically significant renal, hepatic, hematological, gastrointestinal, endocrine, metabolic, pulmonary (eg, uncontrolled COPD), cardiac, neurological disease, or addiction or dependence on non prescribed substances.
12. History of a malignancy except for non-melanoma skin cancer (removed prior to entry), in situ carcinoma, or those having non hematological tumors treated with curative intent with no evidence of disease for 5 years.
13. Significant trauma or surgical procedure within 4 weeks prior to first dose of study drug.
14. Requirement for treatment during study with prohibited concomitant medications listed in Appendix 4.
15. History of corticosteroid induced psychosis or significant hyperglycemia.
16. Participation in other therapeutic studies within at least 4 weeks or 5 half lives, whichever is longer, prior to first dose of study drug.
17. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
18. Subjects who are investigational site staff members or relatives of those site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PK parameters Cmax, and AUC0-∞ |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PK parameters Cmax, and AUC0-∞. Timepoint: The parameters will be assessed after Day 85 for the primary endpoint. |
|
| E.5.2 | Secondary end point(s) |
• PK parameters AUC0-2wk, AUC0-8wk and AUC0-12wk.
• PD parameters of drug effect including CD19+ B-cell count, circulating IgM and kinetics of early clinical response using DAS28-CRP.
• Type, incidence, severity, timing, seriousness, and relatedness of adverse events, and laboratory abnormalities.
• Incidence of anti rituximab antibodies (ADA), including neutralizing antibodies (Nab), and safety associated with immune response.
• Mean change from baseline in DAS28-CRP, EULAR response (reduction ≥1.2), LDAS (≤3.2), and DAS remission (<2.6).
• ACR response at End of Treatment (EOT).
• Outcome measure using HAQ DI. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PK parameters: AUC0-2wk Day 15: AUC0-8wk Day 57: AUC0-12wk Day 85
PD parameters: CD19+ B-cell count and IgM Day 1, 4, 8, 15, 22, 29, 57, 85, 113, 141, 169 and follow-up as needed every 3 months DAS28-CRP Day 15, 29, 57 and 85
• Type, incidence, severity, timing, seriousness, and relatedness of adverse events, and laboratory abnormalities throughout the study
• Incidence of anti drug antibodies and safety associated with immune response Day 1, 15, 29, 57, 85 and 169 with follow-up every 3 months if needed.
• Mean change from baseline in DAS28-CRP, EULAR response, LDAS, and DAS remission Day 15, 29, 57, 85, 113, 141 and 169.
• ACR response Day 169. |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability and immunogenicity |
|
| 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 | 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 | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Brazil |
| Canada |
| Colombia |
| France |
| Germany |
| Israel |
| Italy |
| Korea, Democratic People's Republic of |
| Mexico |
| Peru |
| Poland |
| Russian Federation |
| South Africa |
| Spain |
| Taiwan |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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