Primary objective:To evaluate the long-term safety of BI 695500 in adult patients with moderate tosevere active rheumatoid arthritis (RA) who have successfully completed treatment inTrial 1301.1.Secondary objective:* To assess the long-term efficacy…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Joint disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary efficacy endpoint:
The primary endpoint of Trial 1301.4 is safety; efficacy will be evaluated as
secondary and other endpoints.
Primary safety endpoint:
The primary endpoint is defined as the number (proportion) of patients with drug
related adverse events during the treatment phase
Secondary outcome
Secondary efficacy endpoints:
* The change from Baseline in Trial 1301.1 in DAS28 (erythrocyte sedimentation
rate [ESR]) at Week 48 of Trial 1301.4;
* The proportion of patients meeting the American College of Rheumatology 20%
(ACR20) response criteria (based on improvement since Baseline in Trial
1301.1) at Week 48 of Trial 1301.4;
* The proportion of patients who meet the ACR/European League Against
Rheumatism (EULAR) definition of remission (based on improvement since
Baseline in Trial 1301.1) at Week 48 of Trial 1301.4;
* The proportion of patients who meet the EULAR response (good response,
moderate response, or no response) (based on DAS28 improvement since
Baseline in Trial 1301.1) at Week 48 of Trial 1301.4.
Other efficacy endpoints:
* The change from Baseline in Trial 1301.1 in DAS28 (ESR) at Week 24 of Trial
1301.4;
* The proportion of patients meeting ACR20 response criteria (based on
improvement since Baseline in Trial 1301.1) at Week 24 of Trial 1301.4;
* The proportion of patients who meet the ACR/EULAR definition of remission
(based on improvement since Baseline in Trial 1301.1) at Week 24 of Trial
1301.4;
* The proportion of patients who meet the EULAR response (good response,
moderate response, or no response) (based on DAS28 improvement since
Baseline in Trial 1301.1) at Week 24 of Trial 1301.4;
* ACR50 and ACR70 responders (based on improvement since Baseline in Trial
1301.1) at Week 24 of Trial 1301.4;
* ACR50 and ACR70 responders (based on improvement since Baseline in Trial
1301.1) at Week 48 of Trial 1301.4;
* The change from Baseline in Trial 1301.1 in DAS28 (C-reactive protein [CRP])
at Week 24 of Trial 1301.4;
* The change from Baseline in Trial 1301.1 in DAS28 (CRP) at Week 48 of
Trial 1301.4;
* Individual parameters of the ACR improvement criteria (based on improvement
since Baseline in Trial 1301.1): swollen joint count, tender joint count,
patient*s
and physician*s global assessments of disease activity, patient*s assessment of
pain, Health Assessment Questionnaire - Disability Index (HAQ-DI) and acute
phase reactant (CRP) at Week 24 of Trial 1301.4;
* Individual parameters of the ACR improvement criteria (based on improvement
since Baseline in Trial 1301.1): swollen joint count, tender joint count,
patient*s
and physician*s global assessments of disease activity, patient*s assessment of
pain, HAQ-DI and acute phase reactant (CRP) at Week 48 of Trial 1301.4;
* The change from Baseline in Trial 1301.1 in 36-item Short Form Health Survey
(SF-36) at Week 24 of Trial 1301.4;
* The change from Baseline in Trial 1301.1 in SF-36 at Week 48 of Trial 1301.4;
* The change from Baseline in Trial 1301.4 in DAS28 (ESR) at Week 24 of Trial
1301.4;
* The change from Baseline in Trial 1301.4 in DAS28 (ESR) at Week 48 of Trial
1301.4;
* The proportion of patients meeting ACR20 response criteria (based on
improvement since Baseline in Trial 1301.4) at Week 24 of Trial 1301.4;
* The proportion of patients meeting ACR20 response criteria (based on
improvement since Baseline in Trial 1301.4) at Week 48 of Trial 1301.4;
* The change from Baseline in Trial 1301.4 in SF-36 at Week 24 of Trial 1301.4;
* The change from Baseline in Trial 1301.4 in SF-36 at Week 48 of Trial 1301.4.
Other endpoints/parameters of interest:
* Immunogenicity (proportion of patients with ADAs) at Weeks 24 and 48;
* Pharmacodynamic analysis of CD19+ B-cells, CD3+, CD4+, and CD8+ T-cells,
total RF, RF immunoglobulin (Ig) isotypes, Igs (total Ig, IgG, IgA and IgM).
* A PPK analysis with sparse blood sampling throughout the treatment period and
at follow-up will be carried out to assess the PK of BI 695500 in the underlying
population.
Other safety endpoints include:
* Infusion reaction adverse events
* Rate of infections/serious infections (seriousness of infection defined as
requirement of IV antibiotics for treatment and/or meeting seriousness criteria
to
be qualified as an SAE)
Additional safety criteria include physical examination, vital signs (blood
pressure,
pulse rate, respiratory rate, body temperature), 12-lead electrocardiogram,
laboratory
tests, concomitant medication, and tolerability.
Relevant findings in these safety assessments will be reported as adverse
events.
Background summary
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease
characterized by
synovial inflammation in the joints and consequently, progressive joint
destruction.
Depending on the severity of the disease, systemic manifestations may occur
including lung
disease, rheumatoid nodules and cardiovascular system effects. If left
untreated, RA may lead
to severe functional disabilities, and therefore a considerable reduction in
quality of life for
the patient. The prevalence of RA varies with factors such as gender, race and
smoking status and is approximately 0.5-1%.
B lymphocytes (B-cells) are thought to play a crucial role in the pathogenesis
of RA. B-cells
are highly efficient antigen-presenting cells and therefore contribute to the
auto-immune
response through downstream activation of T-cells via co-stimulatory molecules.
B-cells
respond to, and produce, chemokines and cytokines that facilitate lymphocyte
infiltration into
joints, formation of ectopic lymphoid structures (e.g., the formation of T-cell
* B-cell
follicles with germinal center reactions in the synovium of affected joints),
angiogenesis, and
synovial hyperplasia that characterize the pathology observed in the rheumatoid
joint. They are also the primary source of rheumatoid factors (RFs) and
anti-cyclic
citrullinated peptide (anti-CCP) antibodies which contribute to the formation
of immune
complexes and complement activation in inflamed joints. Thus, B-cell targeted
therapy could
play an important role in RA through a reduction in the B-cell count as well as
a reduction in
B-cell-mediated downstream effects on other cell types involved in the
inflammatory
response.
BI 695500 is a monoclonal antibody being developed as a proposed biosimilar to
rituximab
(MabThera® in the European Union [EU]; Rituxan® in the United States [US]
). BI 695500 is a genetically engineered chimeric mouse/human monoclonal
antibody (mAb) representing a glycosylated immunoglobulin (Ig) with human IgG1
constant
regions and murine light-chain and heavy-chain variable region sequences. The
active
substance of BI 695500 is rituximab and, like MabThera® and Rituxan®, BI 695500
has been
shown, in vitro, to lead to the elimination of B-cells by means of several
different
mechanisms, including antibody-dependent cellular cytotoxicity (ADCC),
complementdependent
cytotoxicity (CDC), and apoptosis. Rituximab causes rapid peripheral B-cell
depletion in vivo.
BI 695500, as a proposed biosimilar product, may be seen to provide comparable
PK,
efficacy, safety and tolerability in patients with RA and may present an
opportunity to
improve healthcare.
In conclusion, these data support the continued evaluation of the PK, efficacy
and safety of
BI 695500 in patients with RA over an additional 48 weeks.
Study objective
Primary objective:
To evaluate the long-term safety of BI 695500 in adult patients with moderate to
severe active rheumatoid arthritis (RA) who have successfully completed
treatment in
Trial 1301.1.
Secondary objective:
* To assess the long-term efficacy of BI 695500 in patients with moderately to
severely active RA. These analyses will be displayed by the groups the patients
were randomized in Trial 1301.1 as well as overall.
Other objectives:
* To assess population pharmacokinetics (PK), pharmacodynamics (PD) and
immunogenicity of BI 695500 in patients with moderately to severely active RA.
* To evaluate the safety, efficacy and tolerability of BI 695500 in patients
with
moderately to severely active RA, who were initially randomized to receive
Rituxan®/MabThera® in the clinical Trial 1301.1 compared with patients who
continued to receive BI 695500. For this analysis baseline as measured in
Trial 1301.4 will be considered.
Study design
To assess the continued safety and efficacy of repeated courses with BI 695500,
patients from the initial randomized controlled Trial 1301.1 who are eligible
for
further treatment courses, will receive two 1000 mg drug infusions of BI
695500: the
first on Day 1 and the second on Day 15. This includes patients who were
initially
randomized to receive Rituxan®/MabThera® in Trial 1301.1, who will be
transitioned
to treatment with BI 695500 in Trial 1301.4.
Patients are eligible to receive another course of treatment at 24 weeks if the
investigator considers the patient as having benefited from previous treatment
course(s).
The second course of treatment will consist of one infusion of BI 695500 at
Week 24
and one infusion of BI 695500 at Week 26.
Intervention
patients from the initial randomized controlled Trial 1301.1 who are eligible
for
further treatment courses, will receive two 1000 mg drug infusions of BI
695500: the
first on Day 1 and the second on Day 15. This includes patients who were
initially
randomized to receive Rituxan®/MabThera® in Trial 1301.1, who will be
transitioned
to treatment with BI 695500 in Trial 1301.4.
Patients are eligible to receive another course of treatment at 24 weeks if the
investigator considers the patient as having benefited from previous treatment
course(s).
The second course of treatment will consist of one infusion of BI 695500 at
Week 24
and one infusion of BI 695500 at Week 26.
Study burden and risks
Rituximab causes rapid peripheral B cell depletion in vivo. Therefore, CD19+ B
cell counts will be monitored at frequent
intervals throughout the trial for each of the trial medications.
Common adverse reactions reported in greater than 10% of patients include
infusion related reactions, upper respiratory tract
infections and urinary infections. Overall, infusion-related reactions in
clinical trials with MabThera and Rituxan occurred in up
to one third of patients approximately, with the first infusion and decreased
with subsequent infusions. Serious infusion-related
reactions were uncommon (<1% of patients) and were predominantly seen during
the initial course.
Although rare, a potential for drug-induced liver injury (DILI) is under
constant surveillance by sponsors and regulators.
The use of MabThera and Rituxan has been shown to be associated with an
increased risk of progressve multifocal
leukoencephalopathy (PML). On the basis of limited experience with MabThera and
Rituxan in RA patients the present data do
not suggest an increased risk of malignancy, however, the possible risk for the
development of solid tumors cannot be
excluded.
BI695500, as a proposed biosimilar product, may be seen to provide comparable
PK, efficiacy, safety and tolerability in
patients with RA and may present an opportunity to improve healthcare.
Binger Strasse 173
Ingelheim am Rhein D-55216
DE
Binger Strasse 173
Ingelheim am Rhein D-55216
DE
Listed location countries
Age
Inclusion criteria
1. Must give written informed consent and be willing to follow this CTP.;2. Male or female patients, with moderately to severely active RA who have previously participated in the double-blind randomized clinical Trial 1301.1.;3. Current treatment for RA on an outpatient basis: ;a) Patients must continue to receive and tolerate oral or parenteral methotrexate (MTX) therapy at a dose of 15-25 mg per week (dose may be as low as 10 mg per week if the patient is unable to tolerate a higher dose). The dose must have been stable for at least 4 weeks prior to Day 1. ;b) Patients must be willing to receive oral folic acid (at least 5 mg/week or as per local practice) or folinic acid (at least 1 mg per week or as per local practice) or equivalent during the entire trial (mandatory co-medication for MTX treatment).;c) If receiving current treatment with oral corticosteroids (other than intra-articular or parenteral), the dose must not exceed 10 mg/day prednisolone or equivalent. During the 4 weeks prior to Baseline (Day 1) the dose must remain stable.;d) Intra-articular and parenteral corticosteroids are not permitted throughout the trial, with the exception of IV administration of 100 mg methylprednisolone 30 to 60 minutes prior to each infusion as this is part of the trial procedures.;e) Any concomitant non-steroidal anti-inflammatory drugs (NSAIDs) must be stable throughout the trial.;f) Patients may be taking oral hydroxychloroquine provided that the dose is not greater than 400 mg/day, or chloroquine provided that the dose is not greater than 250 mg/day. These doses must have been stable for a minimum of 12 weeks prior to Day 1. The hydroxychloroquine or chloroquine treatment will need to be continued at a stable dose with the same formulation until the end of the trial.;4. For participants of reproductive potential (males and females), use of a medically acceptable method of contraception during the trial, i.e., a combination of 2 forms of effective contraception (defined as hormonal contraception, intrauterine device, condom with spermicide, etc.). Females of childbearing potential must also agree to use an acceptable method of contraception (see above) for 12 months following completion or discontinuation from the trial medication.
Exclusion criteria
1. Patients receiving current treatment with corticosteroids must not be receiving a dose exceeding 10 mg/day prednisone or equivalent.;2. Serious underlying medical conditions, which, per the investigator*s discretion, could impair the ability of the patient to participate in the trial (including but not limited to ongoing severe infection, severe immunosuppression, severe heart failure, uncontrolled hypertension, uncontrolled diabetes mellitus, gastric ulcers, active autoimmune disease).;3. Pregnancy or breast feeding. For women of childbearing potential, a positive serum pregnancy test at the Screening Visit.;4. Patients who have significant cardiac disease, including but not limited to congestive heart failure of Class III or IV of the New York Heart Association (NYHA) classification; uncontrolled angina or arrhythmia; any uncontrolled or severe cardiovascular or cerebrovascular disease; or uncontrolled hypertension. ;5. Treatment with IV or intramuscular corticosteroids. The only exception will be the administration of 100 mg IV methylprednisolone 30 to 60 minutes before each infusion as part of the trial procedures.;6. Any condition or treatment (including biologic therapies) that, in the opinion of the investigator, may place the patient at unacceptable risk during the trial.;7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times upper limit of normal (ULN).;8. Hemoglobin <8.0 g/dL.;9. Levels of IgG <5.0 g/L.;10. Absolute neutrophil count <1500/*L.;11. Platelet count <75000/*L.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2013-002622-23-NL |
| ClinicalTrials.gov | NCT01955733 |
| CCMO | NL47012.048.14 |