E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Chronic autoimmune disease that causes inflammation and deformity of the joints |
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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 | 14.0 |
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 |
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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 investigate the efficacy and safety of three different sc doses of the humanized anti-CD20 antibody veltuzumab as an add-on treatment to MTX over 24 weeks compared to MTX alone |
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E.2.2 | Secondary objectives of the trial |
To identify the dosage(s) of veltuzumab with the most favourable benefit-risk-ratio to be further evaluated in the subsequent Phase II/III clinical program in patients with moderate to severe RA. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Nested pharmacokinetic and exploratory biomarker study in a subset of 60 patients |
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E.3 | Principal inclusion criteria |
• Written informed consent obtained before any trial-related activities
• Outpatient, male or female, at least 18 years of age at Screening
• Active rheumatoid arthritis. Diagnosis of RA using the ACR criteria for the classification of RA for at least 6 months prior to trial entry (based on swollen and tender joint count; CRP and/or ESR; RF and/or anti-CCP)
• An inadequate response to previous or current treatment with either MTX alone or a combination of MTX plus anti-tumor necrosis factor alpha biologic agents.
• Receiving MTX 15-25 mg/week (oral or parenteral) for at least 20 weeks, including the last 6 weeks prior to Baseline at a stable dose
• Subjects of reproductive potential (females and males) must agree to use effective double-method contraception
• Female subjects must not be actively breast-feeding
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E.4 | Principal exclusion criteria |
Medical history/concurrent diseases
Joints
• Subjects who are wheel chair or bed bound
• Rheumatic autoimmune disease other than RA, or significant systemic involvement secondary to RA
• History of or current inflammatory joint disease other than RA
• Septic prosthetic joint within the last 48 weeks prior to Baseline or indefinitely if the prosthesis concerned remains in situ.
Infectious diseases
• Primary or secondary immunodeficiency, including human immunodeficiency virus (HIV) infection
• Evidence of acute or chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)
• Evidence and/or history of active tuberculosis (TB), prior to successfully completing an anti-TB treatment. Subjects with latent TB infection (LTBI) can be included
• Acute clinical manifestations of herpes zoster virus and history of severe herpes zoster
• History of active infection of any kind or any major episode of infection requiring hospitalisation or treatment with iv anti infective agents within 6 weeks prior to Baseline or oral anti-infective agents within 2 weeks prior to Baseline
• History of deep space/tissue infection within 48 weeks prior to Baseline
• History of osteomyelitis
• History of sepsis of any origin requiring intensive care
• History of serious recurrent or chronic infections not specified above.
Cardio-pulmonary
• Any significant cardiac disease
• History of severe chronic obstructive pulmonary disease (COPD) and/or history of severe COPD exacerbation(s) within the last 12 months prior to Screening .
Immune system/haematology/biochemistry
• History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to any component of veltuzumab injection solution
• Subjects with CD4 cell counts (< 250/µl) at Screening
• Hypogammaglobulinemia (IgG < 5.0 g/L, and/or IgM < 0.20 g/L) at Screening
• Splenectomy
• Subjects with haemoglobin < 9.0 g/dL, white blood cell (WBC) count < 3000 cells/µL, absolute neutrophil count (ANC) < 2000 cells/µL, lymphocyte count < 800 cells/µL or platelet count < 100,000/µL at Screening
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT) or alkaline phosphatase levels > 2.0 times the upper limit of normal (ULNR) at Screening
• Subjects with a serum creatinine > ULNR (e.g. > 1.2 mg/dL for males and > 1.0 mg/dL for females) at Screening
Other medical conditions
• Subjects with diabetes mellitus type 1 or unstable type 2
• History of solid-organ transplantation
• History of cancer within the last 5 years treated with anti-cancer chemotherapy
• Current active alcohol or drug abuse or history of alcohol or drug abuse within 24 weeks prior to Baseline. Opiate-containing medicines are not allowed
• Evidence of any significant and/or unstable concomitant diseases such as nervous system, renal, hepatic, endocrine, respiratory or gastrointestinal disorders which, in the Investigator’s opinion, would preclude subject participation
• Any other medical condition (e.g. clinically relevant abnormal laboratory values) that would, in the Investigator's opinion, make the administration of trial drug or trial procedures hazardous to the subject, or obscure the interpretation of AEs.
Skin
• Chronic skin ulcerations.
Previous and concomitant therapies and procedures
• Any planned, elective or emergency surgical procedure, including bone or joint surgery/synovectomy within 12 weeks prior to or planned within 52 weeks after Baseline
• Treatment with any investigational agent 12 weeks or five half-lives of the investigational drug or the duration of that agent’s PD effect (whichever is longer) prior to Baseline
• Previous treatment with any cell-depleting therapies, including investigational agents
• Persistent urinary catheter or regular intermittent catheterisation
Other
• Previous participation in this clinical trial
• Pregnancy
• Donation or loss of more than 400 mL of blood within less than 3 months before first IMP administration
• History of MTX toxicity (especially pulmonary, hepatic or haematologic toxicity) and unable to tolerate a stable dose of at least 12.5 mg/week
• Lack of peripheral venous access
• Employee at the investigational site, relatives or spouse of site staff
• Suspected inability, e.g. language problems, or unwillingness to comply with trial procedures
• Subjects enrolled in this trial will not be allowed to donate blood, germ cells, organs, or bone marrow during the trial and for at least 12 months after the last administration of the IMP
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable will be the ACR20 responder rate after 24 weeks of double blind treatment with the study medication. Responders will be defined as those whose improvement from baseline to endpoint fullfil the following criteria:
• more or equal to 20% reduction in the TJC (66/68)
• more or equal to 20% reduction in the SJC (66/68)
• more or equal to 20% reduction in three of the following additional measures:
- Subject assessment of pain (visual analogue scale [VAS])
- Subject global assessment of disease activity (VAS)
- Physician global assessment of disease activity (VAS)
- Degree of disability (HAQ-DI)
- Level of acute-phase reactant (CRP)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
ACR20 response rate at week 48, ACR50 and ACR70 response rate at week 24 and 48. Major clinical response. Safety parameters, Pharmacokinetic parameters, Pharmacodynamic/Exploratory biomarkers. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.9 | Dose response | Yes |
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) | 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 | 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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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 |
Canada |
Mexico |
United States |
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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
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last patient last visit (after 48 weeks) |
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |