A study to investigate and compare the efficacy, safety, tolerability and pharmacodynamic (biochemical and physiological effects of the drug) of TL011 and MabThera® (rituximab) in patients with severe, active rheumatoid arthritis treated with methotrexate (MTX)

• Register: EUCTR
• Last refreshed on: 7 April 2014
• Main ID: EUCTR2011-005021-48-CZ
• Date of registration: 15/02/2012
• Prospective Registration: Yes
• Primary sponsor: Teva Pharmaceutical Industries
• Public title: A study to investigate and compare the efficacy, safety, tolerability and pharmacodynamic (biochemical and physiological effects of the drug) of TL011 and MabThera® (rituximab) in patients with severe, active rheumatoid arthritis treated with methotrexate (MTX)
• Scientific title: A multicenter, double-blind, randomized, active controlled, parallel-group study to evaluate the efficacy, safety, tolerability and pharmacodynamic profiles of TL011 infusions compared with MabThera® (rituximab) in subjects with severe, active rheumatoid arthritis treated with methotrexate (MTX) - ALTO
• Date of first enrolment: 23/05/2012
• Target sample size: 544
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2011-005021-48
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: no Other: no Number of treatment arms in the trial: 2

Countries of recruitment

Bulgaria, Czech Republic, Georgia, Germany, Hungary, Macedonia, the former Yugoslav Republic of, Netherlands, Poland, Romania, Russian Federation, Serbia, Spain, Ukraine

Contacts

• Name: Dr. Ronit Haviv
• Affiliation: Teva Pharmaceutical Industries

• Name: Dr. Ronit Haviv
• Affiliation: Teva Pharmaceutical Industries

Key inclusion & exclusion criteria

Inclusion criteria:
1. Aged 18-80 years (inclusive) at screening.
2. Rheumatoid arthritis for at least 6 months, as defined by the Revised Criteria ACR 1987 (adult onset RA).
3. Severe, active, seropositive (plasma RF level of at least 20 IU/mL and/or ACPA/anti-CCP positive) disease as defined by the following, revealed in screening tests:
• Active disease defined as presence of at least 8 swollen and 8 tender joints (at the screening visit).
• A serum CRP level of >=15 mg/L (>=1.5 mg/dL) and/or an ESR (Westergren method) of >= 28 mm per hour at screening.
4. Inadequate response or intolerance DMARDs other than MTX and/or TNFi therapies (1 or more).
5. Treatment with MTX (10 to 25 mg/week) for at least 12 weeks prior to screening, with at least 4 weeks before screening at a stable dosage that will remain stable throughout the study period (up to Week 48).
6. Willing and able to provide written informed consent prior to performing study procedures.
7. Women or men of reproductive potential must use (or have his/her partner use) effective contraceptive methods starting from screening and until 12 months following the last infusion (acceptable methods of birth control in this study include: surgical sterilization, intrauterine devices, oral contraceptive, contraceptive patch, long-acting injectable contraceptive, partner’s vasectomy or double-barrier method [condom or diaphragm with spermicide]).

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 354
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 190

Exclusion criteria:
1. Documented rheumatic autoimmune disease or inflammatory joint disease other than RA (eg, psoriatic arthritis or ankylosing spondylitis).
2. Significant systemic involvement secondary to RA (eg, vasculitis, pulmonary fibrosis, or Felty’s syndrome) or American Rheumatism Association (ARA) functional class IV disease.
3. Hypersensitivity to active ingredients, excipients (sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid, water for injections) and murine proteins.
4. Active uncontrolled infection (viral, bacterial or fungal infection) requiring systemic therapy or clinically significant infection, at screening and/or at Day 1 (baseline), or a history of recurring or chronic infections or with underlying conditions that may, according to the Investigator’s judgment, further predispose subjects to serious infection.
5. Known immunodeficiency syndrome, including total immunoglobulins (IgG, IgA and IgM) lower than the lower limit of normal (LLN).
6. Positive human immunodeficiency virus (HIV) serology (in case of positive result an additional HIV RNA test should be performed), positive hepatitis B surface antigen or positive hepatitis C antigen (in case of positive result an additional hepatitis C virus [HCV] RNA test should be performed).
7. History of cancer in the past 5 years prior to screening (except 8. Immunization with live viral vaccines less than 4 weeks prior to Day 1 (baseline) and/or planned live viral vaccination during the core
9. Use of oral/intravenous/intramuscular systemic corticosteroids
• Oral corticosteroids at a dose higher than 10 mg prednisone daily (or an equivalent dose of other oral steroids) within the 4 weeks prior to screening and between screening and Day 1 (baseline)
OR
• Oral corticosteroids at a dose equal to or lower than 10 mg prednisone daily (or an equivalent dose of other oral steroids) that were not kept at a stable dose within 4 weeks prior to screening and between screening and Day 1 (baseline).
• Use of intravenous/intramuscular/intra-articular or parenteral glucocorticoids <4 weeks prior to screening.
10. Use of any cytotoxic therapies and immunosuppressants, (except for allowed dosage of MTX) or other DMARDs within the 4 weeks prior to screening or between screening and Day 1 (baseline).
11. Prior use of MabThera (rituximab) and/or participation in a previous clinical trial with the investigational study drug TL011.
12. Use of TNFi and any other biological agent for the treatment of autoimmune diseases less than 8 weeks prior to Day 1 (baseline) or use of etanercept and anakinra less than 4 weeks prior to Day 1.
13. Participation in a previous clinical trial and/or use of an investigational drug within 90 days of screening.
14. Clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation based on the Investigator’s judgment. Conditions may include cardiovascular disease (including severe heart failure of New York Heart Association [NYHA] class IV or severe, uncontrolled cardiac disease) pulmonary, hepatic, renal, or neurological disease as determined by medical history, physical examination, laboratory tests, chest X-ray, or ECG.
15. Likely to be non-compliant or uncooperative during the study in the judgment of the Investigator.
16. History of tuberculosis, latent tuberculosis tested as required by the local regulations, and/or positive chest X-ray for tuberculosis at screening

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

adult patients with severe, active rheumatoid arthritis patients treated with methotrexate (MTX)
MedDRA version: 14.1 Level: PT Classification code 10039073 Term: Rheumatoid arthritis System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders

Therapeutic area: Diseases [C] - Immune System Diseases [C20]

Intervention(s)

Product Name: TL011
Product Code: TL011
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: TL011
Current Sponsor code: TL011
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Trade Name: MabThera®, 100 mg concentrate for solution for infusion
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: RITUXIMAB
CAS Number: 174722-31-7
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 10-

Primary Outcome(s)

Primary end point(s): Determination of therapeutic equivalence of TL011 to rituximab (MabThera®)
Primary efficacy endpoint: proportion of subjects (%) who meet the ACR criteria for 20% improvement (ACR20) from baseline

Secondary Objective: To assess the pharmacodynamics (PD), immunogenicity, safety, and tolerability of TL011 in comparison with MabThera® (rituximab) in subjects with severe, active RA treated with MTX

Timepoint(s) of evaluation of this end point: At week 24

Main Objective: to demonstrate equivalence of the efficacy of TL011 in comparison with the reference product MabThera® (rituximab) in subjects with severe, active RA treated with MTX

Secondary Outcome(s)

Secondary end point(s): ACR20, ACR50, ACR70

Timepoint(s) of evaluation of this end point: At week 24 and 48

Secondary ID(s)

TL011-RA-301

Source(s) of Monetary Support

Teva Pharmaceutical Industries