Primary objective:* To assess the safety and tolerability of combined treatment with atacicept and rituximab insubjects with active rheumatoid arthritis receiving re-treatment with rituximab.Secondary objectives:* To evaluate the effect of combined…
ID
Source
Brief title
Condition
- Autoimmune disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints:
* Nature, incidence and severity of adverse events (AEs); in particular,
proportion of
subjects with treatment-emergent infection-related AEs and proportion of
subjects with
serious infections.
* Proportion of subjects who develop IgG <3 g/L.
* Changes and abnormalities in vital signs and routine safety laboratory
parameters.
* Changes over time in vaccine immunisation status, assessed through
anti-tetanus
toxoid, anti-pneumococcus and anti-diphtheria toxoid antibody titres.
Secondary outcome
Secondary endpoints:
* B cell subsets, T cell subsets and natural killer (NK) cells measured by flow
cytometry, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), IgG,
IgM, IgA, rheumatoid factors (RFs) * IgM-RF, IgG-RF and IgA-RF, anti-cyclic
citrullinated peptide antibodies (ACPA or anti-CCP antibodies) and
disease-related
cytokines.
* Levels of free BLyS and free APRIL.
* PK profiles of free atacicept, atacicept·BLyS complex, composite atacicept
(free
atacicept + atacicept·BLyS complex) and *total atacicept* (free atacicept +
atacicept·BLyS complex + atacicept·APRIL complex).
PK profile of rituximab.
* ACR core measures, and morning stiffness, enabling calculation of ACR and
DAS28 composite scores.
* Time to loss of response.
* Incidence of antibodies to atacicept, both binding and neutralising.
* Incidence of antibodies to rituximab.
* Gene expression profiles and/or genetic variations that would predict drug
response
and/or that would explain the drug*s mechanism of action.
Background summary
Rheumatoid arthritis is a chronic inflammatory disease of the joints of unknown
cause. Certain mechanisms that lead to joint inflammation are becoming better
understood and research in rheumatoid arthritis suggests that B cells play an
important role in the development of the inflamation activity in the joints.
Decreasing the B cell population could give a positive effect on the
inflamation, which could result in a decrease of the inflamation activity,
pain, swelling and destruction of the joints. Atacicept recombinant fusion
protein functions as an antagonist to B-Lymphocyte Stimulator (BLys) and A
Proliferation Inducing Ligand (APRIL), these take care of the growing of the
B-cells in the bone marrow.
Study objective
Primary objective:
* To assess the safety and tolerability of combined treatment with atacicept
and rituximab in
subjects with active rheumatoid arthritis receiving re-treatment with rituximab.
Secondary objectives:
* To evaluate the effect of combined treatment with atacicept and rituximab on
levels of
peripheral blood B cell populations over time.
* To gain further information on the effect of combined treatment with
atacicept and
rituximab on biomarkers reflecting their mechanism of action (MoA) and disease
activity.
* To characterise the pharmacokinetic (PK) profiles of atacicept and rituximab
when given
in combination.
* To identify potential associations between gene polymorphisms and drug
response, at a
genome scale and with a focus on BLyS, APRIL, BAFF-R, TACI, BCMA and HLADRB1.
* To investigate the preliminary efficacy of combined treatment with atacicept
and rituximab
compared to rituximab alone in the treatment of signs and symptoms in a
population of
subjects with active RA receiving re-treatment with rituximab
Study design
This is a randomised, placebo controlled, double-blind trial in subjects with
moderate to severe
active RA who have previously received rituximab and who are candidates for a
new course of
rituximab treatment. Candidates for re-treatment are subjects who have
previously responded
to rituximab and have significant residual disease activity or have
deteriorated clinically after
initial response. Response to a previous course of treatment should be
evaluated after an
observation period of at least 16 weeks from the initiation of treatment. The
previous course of
rituximab treatment should have been given at least 24 weeks before SD1.
Residual active
disease and clinical deterioration after initial response are defined by
disease activity with a
minimum of 8 swollen joints (66-joint count) and 8 tender joints (68-joint
count).
Screening will be performed within 28 days before Study Day 1 (SD1), defined as
the first day
of treatment with rituximab (Cohort 1) or atacicept/placebo (Cohort 2).
Following provision of
written Informed Consent and confirmation of eligibility for the trial,
subjects in Cohort 1 will
receive two doses of rituximab 2 weeks apart, followed by 28 days without
treatment then
subjects will be randomised to receive atacicept or placebo in a 2:1 ratio.
Following provision
of written Informed Consent and confirmation of eligibility for the trial,
subjects will be
randomised to receive atacicept or placebo in a 2:1 ratio (Cohort 2).
Subjects will receive atacicept 150 mg or placebo subcutaneously (SC) once
weekly for
25 weeks. There will be two different cohorts, which will differ in terms of
the start time of
atacicept/placebo treatment in relation to rituximab treatment.
Atacicept/placebo will
commence 4 weeks after the last infusion of rituximab in Cohort 1, and 9 days
before the first
infusion of rituximab in Cohort 2.
Cohort 1
Twenty-seven subjects will receive rituximab at a standard dosing regimen at
SD1 and SD15.
At SD43 (four weeks after the last infusion of rituximab), subjects will be
randomised to
receive atacicept 150 mg or placebo (2:1) given SC once weekly for 25 weeks and
will begin
atacicept/placebo treatment.
Trial assessments for Cohort 1 will take place before rituximab administration
on SD1 and on
SD 15 and at Weeks 7, 9, 12, 16, 20, 26 and 32. Post treatment follow-up
assessments will
take place at Weeks 40, 48, 56 and 64.
Cohort 2
Twenty-seven subjects will be randomised at SD1 to receive atacicept 150 mg or
placebo (2:1)
SC once weekly for 25 weeks; these subjects will begin atacicept/placebo
treatment at SD1.
Subjects will receive rituximab at a standard dosing regimen at SD10 and SD24,
rituximab
infusions will be given 2 days after the Weeks 2 (SD8) and 4 (SD22)
atacicept/placebo doses
to avoid dosing of atacicept and rituximab on the same day.
Trial assessments for Cohort 2 will take place before dose administration on
SD1, on SD10
and SD24 and at Weeks 8, 12, 16, 20 and 26. Post treatment follow-up
assessments will take place at Weeks 34, 42, 50, 58 and 66.
Subjects who withdraw prematurely from the trial should undergo the assessments
planned for
Week 32 (for subjects in Cohort 1) or Week 26 (for subjects in Cohort 2) at the
time of
withdrawal, and should then have a Follow-up visit for safety 12 weeks after
the last dose of
trial medication: this will involve the assessments planned for Week 48 (for
subjects in Cohort
1) or Week 42 (for subjects in Cohort 2).
Subjects will be followed up for approximately 60 weeks after the last dose of
rituximab.
Subjects who discontinue treatment and receive only rituximab or only
atacicept/placebo will
be followed up for at least 12 weeks after the last dose.
Intervention
In cohort 1, 27 patients will receive rituximab on study day 1 and on study day
15.
On study day 43 (four weeks after last rituximab infusion) the patients will be
randomized to receive either atacicept or placebo (2:1). This will be
administered once a week sub cutanous for 25 weeks.
In cohort 2, 27 patients will be randomized on study day 1 to receive atacicept
or placebo (2:1). This will be administered sub cutanous once a week for 25
weeks. Rituximab infusion will be on study day 10 and on study day 24.
Study burden and risks
From the patient information:
Approximately 54 trial subjects will be enrolled in this trial, which will be
conducted in several countries in the European Union. If you are accepted into
this trial, you will be participating for a total duration of 65 to 70 weeks
(approximately 16 months), which consist of the following:
- Screening period of 1 to 4 weeks before treatment
- Treatment period of 25 to 31 weeks (approximately 6-7 months)
- Follow-up period of between 32 and 40 weeks (approximately 8-10 months) after
completing treatment
Side effects, discomforts and inconveniences
As with any treatment, adverse effects are possible. Please review the
information regarding adverse effects and potential risks and ask your study
doctor if you have any questions or concerns.
Atacicept has been well tolerated when tested in healthy male volunteers and in
patients with rheumatoid arthritis, systemic lupus erythematosus and B-cell
cancers. The main adverse effects reported included viral respiratory tract
infections (colds and flu), fatigue, shortness of breath, reduced appetite,
nausea, and diarrhoea, but a causal relationship between atacicept and these
symptoms and illnesses has not been established. There have been short-lived
reactions at the injection site (bruising, redness and swelling).
Rituximab can lower your body*s ability to fight infections. Taking rituximab
can make you more prone to getting infections or make any infection you have
worse. Potential risks associated with treatment with rituximab include serious
infection (including fatalities), reactivation of hepatitis B, infusion
reactions, anaphylactic and other hypersensitivity reactions and the worsening
of pre-existing heart conditions.
The combination of rituximab and atacicept may result in excessive suppression
of the immune system, leading to an increased risk of infection.
Potential risks
Atacicept is a relatively new medication. To date, approximately 178 subjects
(including healthy volunteers and patients with rheumatoid arthritis, systemic
lupus erythematosus, and B cell malignancies-[cancers]) have received atacicept
at doses up to 1900 mg, which is much higher than you will receive in this
study. Atacicept affects the production of immunoglobulins (antibodies) and the
immune system, which may lead to increased susceptibility to infection.
As with other medications, people treated with atacicept may be at risk of
developing allergic reactions or anaphylaxis. Symptoms of an allergic reaction
generally include overall body itching, hives, skin flushing, or rash.
Anaphylaxis is a more serious allergic reaction that may involve dizziness, low
blood pressure (loss of consciousness is possible in the case of very low blood
pressure), difficulty breathing and swallowing, palpitations, abdominal pain
and vomiting. Prompt medical care is needed since serious allergic reactions
may be potentially life threatening. If you think you are having an allergic
reaction, you need to notify the study staff immediately.
Study procedures include a chest X ray and regular blood sampling for
measurement of safety parameters and biological markers; some minor risks are
associated with these procedures.
The standard chest X-ray will involve a small radiation exposure. The radiation
exposure is very low and is equal to that you would get from natural sources
(like the sun) in less than 2 weeks.
Blood will be drawn at each of the study visits. A number of laboratory tests
will be performed (depending upon the visit, tests will differ). These amounts
are unlikely to cause you any harm taken over the period of study. For your
safety your study doctor may want you to have blood tests more frequently than
your scheduled study visits. He/She will let you know if this becomes
necessary. The needles used to draw blood may cause local pain, bruising and
swelling. Some patients may also experience light-headedness, dizziness and
rarely fainting or a local infection.
ECGs and measurements of blood pressure, heart rate and body temperature are
safe and are unlikely to cause discomfort.
In some countries, study procedures will include a skin test for tuberculosis
(TB). There is a very small risk of severe redness and swelling of the arm in
individuals who have had a previous positive PPD test (tuberculin skin test)
and who undergo repeat testing. There have been a few cases of this reaction
also occurring in individuals who have not been previously tested.
In a pharmaceutical study like this one, every risk or side effect cannot be
predicted. Each person*s reaction to a test, drug, or procedure may be
different. You may have a side effect or be at risk for symptoms, illnesses
and/or complications that could not be predicted by the study doctor or the
makers of atacicept.
Basisweg 34
1043 AP Amsterdam
NL
Basisweg 34
1043 AP Amsterdam
NL
Listed location countries
Age
Inclusion criteria
The trial will enrol male and female subjects 18 years of age at the time of Informed Consent who have rheumatoid arthritis satisfying American College of Rheumatology criteria and a disease history of at least 12 months. Subjects must have active disease; defined by 8 swollen joints (out of 66), 8 tender joints (out of 68) and CRP 6 mg/L or ESR 28 mm/h. Subjects must have received previous treatment with rituximab and must be candidates for re-treatment
with rituximab: i.e. they must have a documented response after an observation period of at least 16 weeks from initiation of treatment to a previous course of rituximab treatment given at least 24 weeks before SD1 and they must have significant residual active disease after previous rituximab treatment or clinical deterioration after initial response (defined by satisfying the above criteria for active disease).
Female subjects of childbearing potential must be willing to avoid pregnancy by using an
adequate method of contraception for four weeks before SD1, during the treatment period and
for 12 months after the last dose of rituximab, and must have a negative urine pregnancy test
at the screening visit and at SD1.
Exclusion criteria
Main exclusion criteria are:
* Neurological disease.
* Inflammatory joint disease other than RA.
* Any contraindication to rituximab as per national label.
* Known presence of human anti-chimeric antibodies (HACA) to rituximab.
* Use of disease-modifying anti-rheumatic drugs (DMARDs; including methotrexate) for less than 3 months or change in dosing regimen within 28 days before SD1, or
methotrexate dose regimen >25 mg/week.
* Participation in any interventional clinical trial within 1 month before SD1 (or within
5 half-lives of the investigated compound before SD1, whichever is longer).
* Prednisone dose regimen >10 mg/day (or equivalent), or change in steroid dosing
regimen within 28 days before SD1.
* Active or latent tuberculosis within the year before screening or major infection requiring
hospitalisation or intravenous anti-infectives within 28 days before SD1.
* Serum IgG below 6 g/L.
* Known hypersensitivity to atacicept or to any of the components of the formulated
atacicept.
* Known hypersensitivity to rituximab, to any of the components of the formulated
rituximab or to murine proteins.
* Breastfeeding or pregnancy.
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 | EUCTR2007-003647-75-NL |
| CCMO | NL20485.018.07 |