| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe Rheumatoid Arthritis (RA) |
|
| 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10039075 |
| E.1.2 | Term | Rheumatoid arthritis and associated conditions |
| E.1.2 | System Organ Class | 100000004870 |
|
| 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 compare the pharmacokinetics
(PK) of SAIT101 (proposed rituximab biosimilar) versus rituximab
licensed in the European Union (MabThera®, brand name in EU) versus
rituximab licensed in the United States (Rituxan®, brand name in US) in
patients with RA. |
|
| E.2.2 | Secondary objectives of the trial |
| The secondary objectives of the study are to compare the safety, additional PK , pharmacodynamics (PD), efficacy, tolerability and immunogenicity of SAIT101 versus MabThera® versus Rituxan® in in patients with rheumatoid arthritis (RA). With the extension phase of the study, the descriptive evaluation of the long-term safety and immunogenicity of SAIT101 is also included. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Parts A and B:
1. Male or female outpatient, between 18 and 80 years of age at Screening
2. Severe RA defined as:
- Diagnosis of RA according to the revised (1987) ACR criteria for the classification of RA for at least 3 months prior to screening visit.
- And ≥6 swollen joints and ≥6 tender/painful joints (from the 66/68 joint count system)
- And C-reactive protein (CRP) ≥1.0 mg/dL or an ESR ≥28 mm/hour at Screening
- And positive RF (≥20 units/mL) or anti-CCP antibodies (≥10 units/mL) at Screening
3. Patients with severe RA who have had an inadequate response to at least 3 months’ treatment (according to the approved treatment and dosage) or intolerance (at Investigator's discretion and/or experience of intolerable AE or toxicity such as infusion related reaction, hypersensitivity, anaphylaxis or severe toxicity) to anti-TNF therapy (experience of severe AE or toxicity).
4. Current treatment for RA on an outpatient basis:
- Receiving MTX 7.5 - 25mg/week (oral or parenteral) for at least 12 weeks, including the last 4 weeks prior to Day 1 at a stable dose, via the same route of administration, dose, and formulation. Patients receiving a lower dose of MTX (<10 mg/week), stable for 4 weeks prior to Day 1, should be doing so as a result of a documented evidence of intolerance to higher doses of MTX.
- Leflunomide must be withdrawn at least 12 weeks prior to Day 1 or a minimum of 4 weeks prior to Day 1 if after 11 days of standard cholestyramine washout.
- All DMARDs different from MTX and leflunomide must be withdrawn at least 4 ~ 8 weeks prior to Day 1.
- If receiving current treatment with oral corticosteroids, the dose must not exceed 10 mg/day prednisone or equivalent. During the 4 weeks prior to Day 1 the dose must be stable.
- The most recent IM/intra-articular steroid injection should be 6 weeks prior to Day 1.
- If receiving current treatment with NSAIDs at the time of Screening, the patient must remain on a stable dose for at least 3 weeks prior to Day 1.
- Patients are willing to receive oral folic or folinic acid or equivalent during the entire study (mandatory co-medication for MTX treatment), according to local standards and availability.
5. Men and women of childbearing potential must use highly effective methods of contraception during the course of the treatment period and for at least 12 months after the last infusion of study drug. A man or women is of childbearing potential if, in the opinion of the investigator, he or she is biologically capable of having children and is sexually active. Examples of highly effective contraception include:
- combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation 1:
* oral
* intravaginal
* transdermal
- progestogen-only hormonal contraception associated with inhibition of ovulation 1:
* oral
* injectable
* implantable
- intrauterine device (IUD)
- intrauterine hormone-releasing system (IUS)
- bilateral tubal occlusion
- vasectomised partner
- sexual abstinence
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.
6. Female patients of childbearing potential must have a negative serum pregnancy test at Screening (Visit 1) and a negative urine pregnancy test at each applicable visit thereafter. Females will be considered to be of non-childbearing potential if they fulfill one of the following criteria at Screening:
- Postmenopausal defined as amenorrheic for at least 12 months following cessation of all exogenous treatments
- Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
Part C only:
1.Patients who participated for the core study (Part A and B) without
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withdrawal or study treatment discontinuation.
2.Patients with active RA (CDAI > 2.8) at Week 52. CDAI = SJC (28) +
TJC (28) + Patient's Global Assessment (1-10, in cm) + Physician's
Global Assessment (1-10, in cm). All of these are from Week 52
assessment.
3.Men and women of childbearing potential must use highly effective
methods of contraception during the course of the treatment period and
for at least 12 months after the last infusion of study drug.
4. Female patients of childbearing potential must have a negative urine
pregnancy test at each applicable visit thereafter. |
|
| E.4 | Principal exclusion criteria |
Parts A and B:
1 Females who are pregnant, breastfeeding, or planning a pregnancy
during the Treatment Period of and 12 months after the last infusion of
study drug.
2 Class IV as per the Classification of Global Functional Status in Rheumatoid Arthritis (as per ACR 1991 Revised Criteria) or wheelchair/bed-bound.
3 History of or current inflammatory joint disease other than RA
4 History of or current systemic autoimmune disorder with the exception of the secondary Sjögren's syndrome.
5 Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection or positive test at screening.
Part C only:
1. Females who are pregnant, breastfeeding, or planning a pregnancy
during the Treatment Period of and 12 months after the last infusion of
study drug.
2. Patients with IgG levels at Week 36 <300 mg/dL. IgG may be
repeated one time to establish eligibility upto 4 weeks prior to the 1st
infusion of the 3rd course.
3. Patients with ANC at Week 36 <1,500 cells/μL. ANC may be repeated
one time to establish eligibility upto 4 weeks prior to the 1st infusion of
the 3rd course.
4. Any significant cardiac disease.
5. Patients who, based on the Investigator's judgment, have a clinically
significant or unstable medical or surgical condition that may preclude
safe and complete study participation. Conditions may also include
cardiovascular, vascular, pulmonary, hepatic, renal, endocrine or
neurological conditions as determined by medical history, physical
examination, or laboratory tests or electrocardiogram (ECG).
6. Patients who, in the judgment of the Investigator, are likely to be
non-compliant or uncooperative during the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetics
1. Area under the concentration-time curve from time 0 (immediately predose on Day 1) to last quantifiable concentration
2. AUC from time 0 to infinity
3. AUC from time 0 to Day 15 prior to infusion
4. Maximum concentration (Cmax) after Day 15 infusion
5. Trough concentration (Ctrough) before the second infusion on Day 15
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetics: Baseline Day 1 (time 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (Part A) and Day 169 (Part B), as applicable
|
|
| E.5.2 | Secondary end point(s) |
Pharmacokinetics
1.AUC from Week 2 to Week 24
2. AUC from time 0 (immediately predose on Day 1) to Week 12
3. Time of maximum concentration (Tmax) post infusion on Day 15
4. Systemic clearance (CL)
5. Volume of distribution (VD)
6. Terminal half-life (t½)
Pharmacodynamics
1. Depletion of CD19+ B cell count at Week 24
2. Time needed to B cell depletion
3. Duration of CD19+ B cell depletion
4. % CD19+ B-cell count vs. baseline at Week 24
5. AUC of CD19+ B-cell count change at Week 24
6. Change from Baseline in CD19+ B cell count during the study period
7. Change from Baseline in IgG, IgM, and IgA levels at Weeks 24 and 52
8. Change from Baseline in CRP levels at Weeks 8, 16, 24, 36, and 52
Efficacy:
1. Change in DAS28 score
2. ACR20 response rates
3. ACR50 response rates and ACR70 response rates
4. Individual components of the ACR improvement criteria
5. Change in DAS28-CRP
6. Major clinical response (continuous ACR70 for at least 24 weeks)
7. Clinical remission (defined by SDAI < 3.3)
8. Proportion of patients with European League Against Rheumatism (EULAR) response
Immunogenicity
1. Incidence of HACA and neutralizing antibody
Safety
SAEs, AEs, ADRs, Vital signs, Clinical laboratory parameters including hematology, chemistry and urinalysis, Physical findings, Concomitant medication, incidence of rescue medication, where rescue medication is defined as the use of non-biologic DMARDs after Week 16 of the study, B cell recovery measured by a CD19+ B cell count after Week 24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetics: Baseline Day 1 (time 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (Part A) and Day 169 (Part B), as applicable
Pharmacodynamics: Baseline Day 1 (time 0), 3, 8, 15, 17, 29, 57, 85, 113, 141 (Part A) and Day 169, 253, 365 (Part B), as applicable
Efficacy:
Efficacy: Baseline, Week 24 // Baseline, Weeks 8, 16, 36, and 52
Immunogenicity: Day 1 predose and at Week 1, 2, 4, 12, 16, 24, 36, and 52, 54, 64, 76, 78, 88, and 100
Safety: continuously
|
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | Yes |
| 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 | Yes |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Part C: open-label extension to evaluate long term safety and immunogenicity of SAIT101 |
|
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| Bosnia and Herzegovina |
| Bulgaria |
| Czech Republic |
| Germany |
| Hungary |
| India |
| Italy |
| Korea, Republic of |
| Mexico |
| Poland |
| Russian Federation |
| Spain |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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