| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate-to-severe rheumatoid arthritis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Rheumatoid Arthritis is a disease which causes joint inflammation and pain. The study is done in patients with rheumatoid arthritis of moderate to severe activity. |
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| 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 | 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 |
Primary study objective is to demonstrate a 3-way pharmacokinetic similarity between MabionCD20, EU-approved MabThera and US-licensed Rituxan following i.v. administration to patients with moderate-to-severe rheumatoid arthritis.
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary study objectives are to comparatively assess secondary PK parameters, efficacy, pharmacodynamics, safety and immunogenicity following i.v. administration of MabionCD20, EU-approved MabThera and US-licensed Rituxan in patients with active, moderate-to-severe RA.
The study will also investigate long-term safety, immunogenicity and efficacy outcomes following re-treatment with MabionCD20 (vs. re-treatment with MabThera); and safety and tolerability of switching the treatment from Rituxan to MabionCD20.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Patients must be 18 to 80 years of age inclusive, at the time of signing the informed consent.
2.Body Surface Area (BSA) between 1.5 and 2.2 m2, calculated according to the DuBois and DuBois formula: BSA in m2 = (weight (Kg)0.425 * height (cm) 0.725) * 0.007184).
3.Patients with confirmed rheumatoid arthritis, diagnosed according to the revised (2010) ACR/EULAR classification criteria, with a disease duration minimum of 6 months prior to the Screening Visit.
4.Patients with currently moderate to severe disease activity despite ongoing administration of an adequate methotrexate regimen. Moderate-to-severe activity is defined here as the presence of the following two
criteria:
a.Six or more swollen joints and ≥6 tender/painful joints (based on 66/68 joint count, not including distal interphalangeal joints), verified by a physician during screening and re-confirmed at baseline visit (Day 1).
b.DAS28-ESR score ≥3.2 at screening.
5.No history of treatment with TNF-α inhibitors (innovative or biosimilar, authorized or investigational) at any time before the screening i.e. patients naïve to TNF-α inhibitors.
6. Male or female.
7. Male patients must agree to use highly effective contraception, as detailed in Section 10.1. of this protocol, from the Screening Visit, during the intervention period, and for at least 12 months after the last dose of study intervention and refrain from donating sperm during this period.
8.Female patients are eligible to participate if not pregnant, not breastfeeding, and at least one of the following
conditions applies:
•Not a woman of childbearing potential (WOCBP)
•Patient is a WOCBP, but she and her partner agree to follow the contraceptive guidance outlined in Section 10.1 from the Screening Visit, during the intervention period, and for at least 12 months after the last dose of the study intervention.
9.Able to provide written informed consent as described in Appendix 2: Regulatory, Ethical, and Study Oversight Considerations after receiving information about benefits and potential risks of the study, as well as details of the insurance covering the patients of the study.
10. Patients receiving treatment with MTX 7.5–25 mg/week for at least 12 weeks, with the last 4 weeks at a stable dose, and willing to remain at this dose for the entire study duration.
11. For WOCBP: negative serum and urine pregnancy test.
12. Ability and willingness to comply with the requirements of the Clinical Study Protocol (CSP).
|
|
| E.4 | Principal exclusion criteria |
1.History of or current inflammatory joint disease other than RA.
2.History of or a current systemic autoimmune disorder with the exception of the secondary Sjögren's syndrome. Patients with a history of or current autoimmune disease confined to a single organ (e.g. thyroiditis or vitiligo) can be considered for enrollment, provided that other eligibility criteria are met.
3.American College for Rheumatology functional Class IV disease
4.History of psychiatric disorder that would interfere with normal participation in this protocol
5.Patient is positive for the current, clinically active or latent infection with human immunodeficiency virus (HIV), hepatitis B virus or hepatitis C virus, as determined by the validated serologic, molecular or antigen testing methods and interpreted according to the international diagnostic guidelines
6.History of or current active tuberculosis, with typical symptoms of M. tuberculosis infection confirmed by positive results of TB screening tests or documented diagnosis prior to screening.
7.Latent tuberculosis, as documented in subject's medical records or shown by a positive or indeterminate QuantiFERON test performed at screening, in absence of the typical symptoms of tuberculosis. However, a patient with latent Mycobacterium tuberculosis infection may become eligible for the study, if the following safety criteria are met:
•Patient completed a standard TB prophylaxis prior to the screening and had no active TB or contact with active TB case after completion of the most recent prophylactic regimen. OR
•Patient received at least four weeks of standard TB prophylactic regimen prior to the screening visit and is capable and willing to continue on this regimen while participating in the study
•Patient has no active TB at the time of screening, which must be confirmed through referral to a TB specialist if >1 year has passed since the completion of the last prophylaxis or if the prophylaxis is still being received by the time of screening
•Patient had no positive findings on chest X-ray examination at screening and within three months prior to screening. Patient identified as latently infected with tuberculosis on the screening test may be later re-screened for the study if he/she receives appropriate anti-TB prophylaxis
8.Serious AND/OR uncontrolled coexisting diseases which are recognized as: major contraindications to the administration of rituximab, MTX or any of the pre-medication components OR important risk factors for the development of severe or life-threatening SARS-CoV2 infection OR others, which in the Investigator's opinion, would
preclude patient's participation
9.Treatment with any of the authorized or investigational TNF-α inhibitors at any time before the screening.
10.Recent use of biologic DMARDs or non-biologic DMARDs other than MTX within the washout periods specified in Table 6 2.
11.Prior treatment with a B cell modulating or B cell depleting therapy such as, but not limited to, rituximab or other anti CD20 mAb (ocrelizumab, ofatumumab, obinutuzumab), belimumab, atacicept, tabalumab, epratuzumab and other experimental treatments.
12.Use of systemic glucocorticoids at a dose higher than 10 mg prednisolone daily or equivalent, within 2 weeks prior to Screening OR between Screening and administration of the first IMP dose.
13.Use of intraarticular hyaluronic acid injection within 28 days before the screening OR between Screening and administration of the first IMP dose.
14.Recent vaccination with inactivated/non-live (<4 weeks prior to study intervention infusion on Day 1) or live (<6 weeks prior to study intervention infusion on Day 1) vaccine.
15.Planned vaccination with live vaccine during the study follow-up.
16.Chronic intake of narcotic analgesics (e.g. morphine, fentanyl, hydrocodone, oxycodone, codeine).
17.Use of any drug or vaccine that has not received regulatory approval for any indication within 4 weeks or a minimum of 5 half lives, whichever is longer, prior to the Screening Visit or planned receipt of unauthorized
drug or vaccine during the study
18.Participation in a clinical study during the 2 months prior to enrolment in the study (exemption – previously failed screening procedures in MabionCD20 003RA study)
19.Serious abnormal laboratory findings, specifically:
a)White blood cell count <3,000/µL OR neutrophil count <1,500/µL
b)Platelet count <75,000/µL
c)Aspartate aminotransferase or alanine aminotransferase >2.5 times ULN.
d)Hemoglobin <8.0 g/dL
e)IgG below 5.0 mg/mL or IgM below 0.4 mg/mL
f)Any other clinically significant laboratory abnormality, that in the opinion of Investigator could endanger the safety and well-being of participant OR affect the analysis and interpretation of study results.
For other Exclusions please refer to Clinical Study Protocol v.2.0, Section 5.2 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Co-primary PK endpoint 1:
• AUC 0-inf (Day 1 to Week 24)
Co-primary PK endpoint 2:
• AUC 0-t (Day 1 to Day 15)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
• Day 1, 2, 3, 7, 15, 16, 17, 22, 28, 56, 84, 112, 168
• Day 1, 2, 3, 7, 15 |
|
| E.5.2 | Secondary end point(s) |
Secondary pharmacokinetic endpoints:
• AUC0-t (Day 1 to Week 24)
• AUC0-inf (Day 15 to Week 24)
• Cmax (2nd dose), Cmax (1st dose)
• Ctrough
• Tmax (2nd dose), Tmax (2nd dose)
• t1/2
• Kel
• Vd
• CL
Efficacy endpoints:
• Mean change from baseline in DAS28-ESR score
• Mean change from baseline in DAS28-CRP score
• Percentage of patients with low disease activity (DAS28 <3.2)
• Percentage of patients with disease remission (DAS28 <2.6)
• Achievement of ACR 20%, 50% and 70% improvement from baseline (ACR20/50/70)
• Percentage of patients with good or moderate response on the EULAR scale
• Simplified Disease Activity Index (SDAI)
• Clinical Disease Activity Index (CDAI)
• Patient’s global assessment of disease activity
• Physician’s global assessment of disease activity
• Health Assessment Questionnaire Disability Index (HAQ DI)
Safety endpoints:
• Adverse events
• Treatment-emergent AEs (any, related, serious, leading to discontinuation)
• Adverse events of special interest [Infusion-related reactions (IRRs), Hypersensitivity and allergic reactions, Serious Infectious Events (SIEs), Infusion-associated cardiovascular events, SARS-CoV-2 infections, Progressive multifocal leukoencephalopathy (PML)]
• Clinical laboratory data
• Physical examinations
• Vital signs
• ECG abnormalities
• Concomitant medication use
Immunogenicity endpoints:
• ADA positive response (Treatment-induced and treatment-boosted anti-drug antibodies)
• Persistent ADA positive response
• Transient ADA positive response
• Neutralizing antibodies (NAb)
• Median ADA titer
Pharmacodynamic endpoints:
• Absolute CD19+ B-cell counts by visit
• Percentage of patients with undetectable levels of CD19+ B-cells
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Days 1,2,3,7,15,16,17,22,28,56,84,112,140,168,182,195,251,335 |
|
| 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 | Yes |
| 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 |
|
| 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 | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Georgia |
| Serbia |
| Belgium |
| Bulgaria |
| 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
|
| The end of the study will be defined as the date of the last visit of the last patient in the study. |
|
| 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 | 9 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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