Primary ObjectiveThe primary objective for this study is to compare the clinical efficacy of weekly abatacept in combination with methotrexate to methotrexate alone in achieving Remission, defined as SDAI less than or equal to 3, at Week 24.…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint is the proportion of subjects in SDAI Remission
at Week 24.
Secondary outcome
The secondary endpoints below will be assessed in the order below in a
hierarchical fashion after the primary endpoint is met to preserve the type I
error of the study at 5%
(1) Proportion of subjects in DA28-CRP Remission at Week 24
(2) Proportion of subjects in SDAI Remission at Week 52
(3) Mean change from baseline in TSS at Week 52
(4) Proportion of subjects in Boolean Remission at Week 52
Background summary
Achieving remission in patients with rheumatoid arthritis has become an
important goal in the treatment of rheumatoid arthritis. This is because it has
been shown that improving the disease as early as possible after diagnosis can
result in less long term and irreversible damage to joints and physical
disability. Taking control of disease activity and reducing it as early as
possible is the current target approach. It has become important to evaluate
new and current rheumatoid arthritis therapies to see how the prevention of the
progression of this disease can be attained. Until recently, there has been no
defined standard of care for early stage rheumatoid arthritis other than
symptomatic treatment with NSAIDs and corticosteroids before starting
conventional DMARD therapy.
It is understood that there may be a *window of opportunity* for the effective
treatment of recently diagnosed rheumatoid arthritis patients, and this was
demonstrated in patients whom received early DMARD treatment had better
outcomes in regards to physical ability and ability to work than those in whom
therapy was delayed even by a few months. Based on current knowledge, patients
with early rheumatoid arthritis that are treated with abatacept, would be
expected to have a high chance of achieving an improvement in their disease.
The aim of this study is to determine if treatment with abatacept in
combination with methotrexate will achieve a higher rate of remission versus
methotrexate alone in adults, that have not yet been treated with methotrexate.
The first phase of the study (Induction Period) is designed to compare the rate
of disease improvement using some strict criteria.
There has also been an interest in decreasing or withdrawing treatment as a
patient improves. Retreatment would only be started again as necessary. This is
the aim of the second phase of the study called the De-escalation Period.
Study objective
Primary Objective
The primary objective for this study is to compare the clinical efficacy of
weekly abatacept in combination with methotrexate to methotrexate alone in
achieving Remission, defined as SDAI less than or equal to 3, at Week 24.
Secondary Objectives
1) To compare the efficacy of weekly abatacept + methotrexate to methotrexate
alone in achieving remission by DAS28 CRP Remission criteria at Week 24.
2) To compare the efficacy of weekly abatacept + methotrexate to methotrexate
alone in achieving remission by SDAI remission criteria at Week 52.
3) To compare the efficacy of weekly abatacept + methotrexate to methotrexate
alone in reducing joint damage by X-ray at Week 52.
4) To compare the efficacy of weekly abatacept + methotrexate to methotrexate
alone in achieving remission by Boolean remission criteria at Week 52.
Study design
This study is a phase 3, randomised, double-blind study which will be separated
into 2 phases. Firstly, an Induction Period, which will last for 56 weeks, and
treatment will be self-administered on a weekly basis. Patients will be
required to attend for hospital visits on a monthly basis. The second phase is
the De-escalation Period which will last for 48 weeks, and treatment will be
self-administered. Patients will be required to attend for hospital visits on a
monthly basis. Patients will be allowed to escape to open-label treatment at
specific time points during the study if they are not responding. A follow up
visit is required.
Intervention
In this study, investigational products are abatacept subcutaneous 125mg in 1
ml pre-filled syringes and oral methotrexate tablets and capsules at 2.5mg.
Placebo will given depending on what treatment the patient is randomised to.
In the Induction Period, all patients will be randomly assigned to one of two
treatment arms:
Arm A: Combination treatment: Active abatacept plus methotrexate weekly
Arm B: Methotrexate monotherapy (standard of care): Placebo abatacept plus
methotrexate weekly
Patients who achieve remission will be re-randomised to one of four treatment
arms in the De-escalation Period. To maintain the double-blind, a double-dummy
regimen will be used.
Patients who were assigned to a combination treatment during the Induction
Period have an equal chance of getting one of the following treatments in the
De-escalation Period:
1) Continue active abatacept weekly plus methotrexate weekly for 12 months
2) Reduce active abatacept to every other week plus methotrexate weekly for 6
months then reduce further to placebo abatacept weekly plus methotrexate weekly
for 6 months
3) Continue active abatacept weekly + convert to placebo methotrexate for 12
months
Patients who were assigned to methotrexate alone during the Induction Period
will continue to receive methotrexate alone for 12 months.
Study burden and risks
Burden: study procedures (physical examination, blood sampling, completing
questionnaires and diary, and regular pregnancy testing for women) and regular
attendance for hospital visits on a monthly basis. The patient will also be
required to have x-rays and self-administer weekly subcutaneous and oral
treatment themselves (or by a caregiver).
Risks: Abatacept was first approved in 2005. Post-marketing reports have not
altered the favourable benefit-risk profile for abatacept and its safety
profile remains generally similar to that established during the clinical
trials. Abatacept treatment in rheumatoid arthritis has an acceptable safety
profile regarding serious infections, malignancies and autoimmune reactions
that are usually a concern with agents acting on the immune system. The main
identified risks of abatacept therapy are infections (primarily bacterial),
autoimmune events (primarily psoriasis), and slightly increased risk of
infusion reactions versus placebo. The overall frequency of infections was
slightly increased in the abatacept treated population, but the severity,
treatment, and outcome of these infections was similar to those treated with
placebo. Serious viral, fungal, or mycobacterial infections were uncommon.
In order to minimise the overall risk to participating patients, this protocol
has inclusion and exclusion criteria appropriate to the population and proposed
treatments, exclusionary screening tests (chest x-ray, tuberculosis screening,
medical history), and specific follow-up safety assessments.
Benefit: Abatacept has demonstrated consistent and statistically robust effects
on all primary and secondary endpoints in Bristol-Myers Squibb rheumatoid
arthritis efficacy trials. Based on the data from three previous studies, the
use of abatacept (in combination with methotrexate) in early rheumatoid
arthritis has the potential to induce remission in a large proportion of
patients that is then sustained for months after cessation of biologic and
non-biologic DMARDs. The ability to sustain remission for a period of time
after stopping DMARDs would have the additional benefit of limiting exposure to
immunosuppressants. Finally, very early use of effective therapy may curtail or
even halt radiographic progression of disease which could lead to long-term
joint protection.
Group relatedness: knowledge gain from this study may also help other patients
in the future.
Orteliuslaan 1000
Urecht 3528 BD
NL
Orteliuslaan 1000
Urecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
1. Subjects that have early RA as defined as:
- Diagnosis made by the ACR/EULAR 2010 criteria for the classification of RA
- Diagnosis made within the past 6 months;2. Subjects must meet at least one of the following criteria:
- CRP greater than 0.3 mg/dL (ULN)
- ESR greater than or equal to 28 mm/h;3. Subjects that have at least 3 tender joints and at least 3 swollen joints using the 28 Joint Count Assessment at both screening and Day 1;4. Subjects are positive for anti-citrullinated protein antibodies (ACPA);5. Subjects receiving oral corticosteroids must be on a stable dose and at the equivalent of less than or equal to 10 mg prednisone daily for at least 4 weeks.;6. Men and women aged more than 18 years old;7. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within 24 hours prior to the start of study drug; must not be breastfeeding; agree to follow instructions for methods of contraception for the duration of treatment with study drug plus a total of 100 days post-treatment completion.;8. Men who are sexually active with WOCBP must agree to follow instructions for methods of contraception for the duration of treatment with study drug plus 160 days post-treatment completion.;9. At a minimum, subjects must agree to use of two methods of contraception, with one method
being highly effective and the other method being either highly effective or less effective as
listed in the protocol.
Exclusion criteria
1. Target Disease Exceptions
a) Subjects with autoimmune disease other than RA (eg, SLE, Juvenile Idiopathic Arthritis, vasculitis, seronegative spondyloarthritis, Inflammatory Bowel Disease). However, subjects with secondary Sjogren*s syndrome will be allowed.
b) Prior history of or current inflammatory joint disease other than RA (such as, systemic lupus erythematosus, gout, reactive arthritis, Lyme disease)
c) Subjects with active fibromyalgia
d) Subjects who have a history of Felty*s Syndrome;2. Medical History and Concurrent Diseases
a) Subjects at risk for tuberculosis (TB) defined as follows:
i) Current clinical, radiographic or laboratory evidence of active TB. Chest x-rays (PA and lateral) obtained within the 6 months prior to randomisation will be permitted. TB testing (interferon gamma release assay or PPD) performed in the past month prior to randomisation will be accepted.
ii) A history of active TB unless there is documentation that the subject had received prior anti-TB treatment that was appropriate in duration and type.
iii) Subjects with a positive TB screening test indicative of latent TB will not be eligible for the study unless they have no evidence of current TB on chest x-ray at screening and they are actively being treated for TB with isoniazid (INH) or other therapy for latent TB given according to local health authority guidelines. If permitted by local guidelines regarding treatment with biologic medications, subjects may be randomised prior to completion of treatment as long as they have completed at least 4 weeks of treatment and they have no evidence of current TB on chest x-ray at screening.;b) Subjects with recent acute infection defined as:
i) Any acute infection within 60 days prior to randomisation that required hospitalisation or treatment with parenteral antibiotics
ii) Any acute infection within 30 days prior to randomisation that required oral antimicrobial or antiviral therapy;c) Subjects with history of chronic or recurrent bacterial infection (such as chronic pyelonephritis, osteomyelitis, and bronchiectasis) or serious latent viral infections at the time of enrollment, including subjects with evidence of Immunodeficiency Virus (HIV) infection.;d) Subjects with any history of infection of a joint prosthesis or artificial joint.;e) Subjects who have a history of systemic fungal infections (such as histoplasmosis, blastomycosis, or coccidiomycosis);f) Subjects with history of recurrent herpes zoster (more than 1 episode) or disseminated (more than 1 dermatome) herpes zoster or disseminated herpes simplex, or ophthalmic zoster will be excluded. Symptoms of herpes zoster or herpes simplex must have resolved more than 60 days prior to screening;g) Subjects with history of primary or secondary immunodeficiency or a family history of a
primary immune deficiency in a first degree relative.;h) Subjects who have present or previous malignancies, except documented history of cured non-metastatic squamous or basal skin cell carcinoma, or cervical carcinoma in situ, with no recurrence in the 5 years prior to screening. Subjects who had screening procedure that is suspicious for malignancy, and in whom the possibility of malignancy cannot be reasonably excluded following additional clinical, laboratory or other diagnostic evaluations;i) Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, pulmonary, psychiatric, cardiac, neurological, or cerebral disease including severe and uncontrolled infections, such as sepsis and opportunistic infections. ;j) Subjects who have received any live vaccines within 3 months of the study drug administration or are scheduled to receive live vaccines during the study. In view of the long half-life of abatacept, study subjects should not be administered a live virus vaccine for a minimum of 3 months following the last dose of study medication. Subjects who are in close contact with others who have received a live vaccine may be enrolled at the investigator*s discretion.;k) Subjects who have undergone a major surgical procedure within the 60 days prior to randomisation.;l) Subjects for whom 5 or more joints cannot be assessed for tenderness or swelling (e.g, due to surgery, fusion, amputation, etc).;m) Subjects with a history of (within 12 months of signing informed consent), or known current problems with drug or alcohol abuse history or known cirrhosis including alcoholic cirrhosis;n) Subjects who are impaired, incapacitated, or incapable of completing study related
assessments.;3. Physical and Laboratory Test Findings
a) Hepatitis B surface antigen (HBsAg)-positive, or Hepatitis B core antibody (HBcAb) positive subjects with detectable hepatitis B viral DNA
b) Hepatitis C antibody (HcAb)-positive subjects with detectable hepatitis C viral RNA
c) Hemoglobin (Hgb) < 8.5 g/dl
d) White Blood Count (WBC) < 3,000/mm3 (3 x 109/L)
e) Platelets < 100,000/mm3 (100 x 109/L)
f) Serum creatinine > 2 times upper limit of normal
g) Serum ALT or AST > 2 times upper limit of normal;4. Allergies and Adverse Drug Reaction
a) Hypersensitivity to one of the investigational product excipients;5. Prohibited Therapies:
a) Subjects who have had prior exposure to abatacept (CTLA4-Ig)
b) Subjects who have been exposed to any treatment with an approved or investigational conventional (non-biologic) or biologic DMARD including but not limited to methotrexate, sulfasalazine, leflunomide, hydroxychloroquine/chloroquine, calcineurin inhibitors, tofacitinib, infliximab, etanercept, anakinra, adalimumab, rituximab, tocilizumab, golimumab, and certolizumab
c) Subjects who have received an IM, IV, or IA administration of a corticosteroid * 6 weeks prior to randomisation
d) If subjects are taking NSAIDs the dose must be stable, as assessed by the Investigator, for 14 days prior to randomisation
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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 | EUCTR2015-001275-50-NL |
| ClinicalTrials.gov | NCT02504268 |
| CCMO | NL54040.058.15 |