Primary Objective: • The primary objective of the study is to evaluate the efficacy of three doses of atacicept to reduce CNS inflammation in subjects with RMS as assessed by frequent MRI.Secondary Objectives: • Evaluate safety and tolerability of…
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Brief title
(ATAMS)
Condition
- Central nervous system infections and inflammations
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• The primary endpoint is the mean number of T1 gadolinium (Gd)-enhancing
lesions per subject per scan from week 12 to 36, inclusive.
Secondary outcome
Secondary Endpoints:
MRI Endpoints
• Mean number of T1 Gd-enhancing lesions per subject per scan from week 24 to
36, inclusive
• Number of new T1 hypointense lesions per subject at weeks 12, 24, and 36
Clinical Endpoint
• Proportion of subjects free from relapses during the 36-week treatment period
Safety Endpoints
• Nature, severity, and incidence of adverse events and infections
• Incidence and severity of laboratory abnormalities
• Injection site reactions
• Changes in vital signs, ECGs
• Proportion of subjects who develop antibodies to atacicept during the course
of the study.
Tertiary Endpoints:
MRI Endpoints
• Number of T1 Gd-enhancing lesions per subject at weeks 12, 24 and 36,
respectively
• Total cumulative number of T1 Gd-enhancing lesions per subject from week 12
to 36, inclusive
• Proportion of subjects free from Gd-enhancing lesions at week 36
• T1 lesion volume:
o Total cumulative volume of T1 Gd-enhancing lesions per subject (monthly scans
per subject, from week 12 to 36, inclusive)
o Volume of T1 Gd-enhancing lesions per subject at week 36
• T2 lesion volume:
o Change in T2 lesion volume per subject at week 36 compared to baseline/SD1
• Mean number of combined unique (CU) active MRI lesions per subject per scan
(monthly scans per subject, from week 12 to 36, inclusive)
• Number of combined unique (CU) active MRI lesions per subject at weeks 12, 24
and 36
• Number of new T2 lesions per subject at weeks 12, 24, and 36
• Change in brain volume per subject at week 36 compared to baseline/SD1
Clinical Endpoint
• Annualised relapse rate over 36 weeks of treatment
Exploratory Endpoints
• EDSS change (relative to baseline/SD1) at Week 36
• MSFC change (relative to baseline/SD1) at Week 36
• Pharmacogenomic / pharmacogenetic (PGx) analysis in a sub-group of subjects
signing separate informed consent.
• Pharmacokinetic (PK) measures: free atacicept, composite atacicept (free
atacicept + atacicept BLyS complex), total atacicept (free atacicept +
atacicept-BLyS complex + atacicept-April complex), atacicept-BLyS complex
• Pharmacodynamic (PD) measures: free APRIL and free BLyS (contingent on
availability of appropriate assays for post-dose samples), ESR, CRP, total
immunoglobulin and immunoglobulin isotypes, anti-myelin antibody, and
lymphocyte subpopulations.
Background summary
Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of
the central
nervous system (CNS) and is one of the most common causes of neurological
disability in
young adults. It is characterised by multi-focal recurrent attacks (relapses)
of neurological
symptoms and signs with variable recovery. Eventually, the majority of subjects
develop a
progressive clinical course.
Approximately one and a half million adults are affected worldwide. The disease
is twice as
prevalent in women as in men, causes considerable disability over time and
continues for the
lifetime of the patient.
The exact cause of MS is unknown, although an autoimmune process has been
implicated. It
appears genetic susceptibility may very well play a role in disease initiation,
but currently
unidentified environmental factors are also likely involved. It is assumed that
T cells
autoreactive to CNS antigens are stimulated in the peripheral circulation and
recruited into the
CNS. Upon restimulation by antigen presenting cells, autoreactive T cells
proliferate, and
initiate a pro-inflammatory cascade within the brain. The inflammation results
over time in
demyelination and ultimately loss of axons and brain volume.
The paradigm of MS being a mainly T-cell mediated disease has shifted during
recent years
(8-11). There is a common understanding in the medical community that B-cells
contribute to
MS pathology by mainly two mechanisms: 1) on a cellular level by serving as
antigen
presenting cells that restimulate CD4 T-cells and produce pro-inflammatory
cytokines, and 2)
on the level of humoral immunity by producing antibody directed against CNS
components.
The expression of BLyS and APRIL is upregulated in peripheral blood monocytes
and T cells
of MS patients (32;33). These findings support the potential therapeutic
utility of BlyS / APRIL inhibitors in MS.
Given the above, it is warranted to explore agents targeting B cell immunity as
MS therapy.
Study objective
Primary Objective:
• The primary objective of the study is to evaluate the efficacy of three doses
of atacicept to reduce CNS inflammation in subjects with RMS as assessed by
frequent MRI.
Secondary Objectives:
• Evaluate safety and tolerability of three doses of atacicept in subjects with
RMS including incidence and severity of infections.
• Evaluate three doses of atacicept in order to determine a minimally effective
dose (MED) in subjects with RMS
Tertiary and Exploratory Objectives:
• Obtain further information on the involvement of B cell immunity in the
pathology of RMS by correlating the pharmacodynamic (PD) profile of atacicept
in RMS subjects with disease activity
• In a subset of subjects pharmacogenomic / pharmacogenetic (PGx) studies will
be performed to identify possible associations between gene polymorphisms or
gene expression profiles and drug response, respectively
• Evaluate the pharmacokinetics (PK) of atacicept at the doses and dose
regimens (loading phase: BW for the first 4 weeks; maintenance phase: QW for 32
weeks) tested.
Study design
This is a four-arm randomised, double-blind, placebo-controlled, multicentre
phase II study to evaluate the safety, tolerability and efficacy as assessed by
frequent MRI measures of three doses of atacicept monotherapy versus matching
placebo in subjects with RMS over a 36 weeks treatment course.
Subjects meeting the eligibility criteria during a screening period of up to 28
days will be randomly assigned in a 1:1:1:1 randomization ratio to receive
either one of three doses of atacicept or placebo. One arm will provide
atacicept with a loading dose of 150 mg SC twice a week (BIW) during the first
4 weeks, followed by a dose of 150 mg SC weekly (QW) over the next 32 weeks.
The other two atacicept arms will follow an identical regimen but the doses
will be 75 mg and 25 mg, respectively. The control arm will receive matching
placebo. The study treatment period will be 36 weeks with a safety follow- up
visit at 48 weeks (12 weeks after the last dose).
For all randomised subjects, there will be a rescue option of treatment with
Rebif (44 mcg three times a week [TIW] for 1 year, starting from the first
injection of Rebif), if the subject experiences more than one relapse, and/or
experiences a sustained increase in their EDSS of more than one point (over a
period of three months or greater), and if the investigator considers the
treatment with disease modifying drugs indicated.
Any subject accepting rescue medication will be withdrawn from IMP, but will
remain in the study, performing all scheduled assessments according to the
visit schedule.
Intervention
Hiervoor verwijzen wij graag naar de study flowchart in het protocol, pagina
93-94 en pagina 48-49 van het protocol (dosage and administration).
Study burden and risks
Experience in humans includes more than 170 subjects exposed to atacicept to
date (of which
more than 130 were healthy volunteers or subjects with RA, SLE respectively,
the others
subjects with B-cell malignancies). The maximum single dose tested by
subcutaneous
injection was 630 mg in healthy volunteers or subjects with RA, 9 mg/kg in
subjects with SLE
and 10 mg/kg in B-cell malignancies. The maximum single dose tested by IV
injection was 18
mg/kg in SLE subjects and 20 mg/kg in B-cell malignancies. The maximum duration
of
treatment was 4 weeks in the SLE studies and 12 weeks in the RA study. The
highest total
exposure was 10 mg/kg for a total of 20 weeks in subjects with multiple
myeloma. The results
from the completed clinical studies indicate that atacicept raises no safety
concerns across a
wide range of doses studied.
Atacicept affects the immune system, which may lead to increased susceptibility
to infections
due to downregulation of B-cell function and decrease of immunoglobulins. There
is currently
no data on the tolerability of atacicept treatment in autoimmune diseases
beyond three months
treatment duration. However, there was no indication of an increasing risk of
infections over
the treatment periods studied. Therefore, subjects with known risk for
infections will not be
included in the study. Furthermore, IgG levels will be monitored throughout the
study and
constitute a withdrawal criterion if below 3g/l, i.e. at a level in which the
risk of infection may
increase. Subjects may experience side effects or be at risk for symptoms,
illnesses or
complications that could not be foreseen by the Sponsor based on the current
data. However,
the standard safety monitoring procedures implemented in this protocol and the
visit structure
should allow a close monitoring of the subjects* wellbeing. As with other
medications, people
treated with atacicept may be at risk of developing allergic reactions or
anaphylaxis.
Trial procedures include chest X-rays and regular blood sampling for
measurement of safety
parameters and biological markers. Some minor risks are associated with these
procedures.
Efficacy measures regarding MRI and clinical evaluations are all non-invasive
and no specific
risks are associated with them, except those related to the use of Gadolinium
as a contrast
agent. However, subjects with known hypersensitivity to Gadolinium or with
inadequate renal
functions cannot participate in this trial.
Atacicept has not yet been tested in MS subjects. It is therefore unknown
whether subjects can
expect a clinical benefit from taking part in this trial. Nevertheless, there
is sufficient data
from the literature suggesting a contribution of B-cell immunity to the
inflammatory processes
typical for RMS. MRI and clinical data from a recent clinical study with
rituximab strongly
support this notion. Furthermore there is also data suggesting that B-cell
immunity may
contribute to the degeneration of neuronal structures that may also play a role
in optic neuritis
or MS, respectively. Treatment with atacicept may be also beneficial in this
regard. This
hypothesis is planned to be tested in a separate clinical study in optic
neuritis.
In case of relevant disease activity, IMP can be withdrawn and the subject may
receive
standard immunomodulatory treatment for the rest of the trial. This will allow
containing the
risk of uncontrolled disease in an individual subject.
An independent Data Monitoring Committee (DMC) will be monitoring safety data
throughout the trial, in order to evaluate the overall benefit/risk ratio. The
DMC will assume
the following responsibilities: (i) periodically review interim safety data
(ii) make
recommendations for the safe conduct of the study and (iii) determine whether
additional
safety monitoring procedures are needed. Details will be outlined in the
respective charter. As
appropriate, the DSMB will provide written recommendations to the sponsor as to
whether to
continue, modify or discontinue the study.
Taken together there seems to be an adequate benefit risk ratio in this phase
II trial.
Tupolevlaan 41-61
119 NW Schiphol-Rijk
Nederland
Tupolevlaan 41-61
119 NW Schiphol-Rijk
Nederland
Listed location countries
Age
Inclusion criteria
All subjects must satisfy the following entry criteria prior to baseline/SD1 (the first
day of dosing):
1. Diagnosis of Relapsing Multiple Sclerosis (per McDonald criteria, 2005);
2. Fulfill at least one of the following: two or more documented relapses during the
previous 2 years, one or more documented relapses in the year before enrolment, or one or more Gd- enhancing lesions detected on MRI at screening.
3. Male or female between 18-60 years old, at the time the informed consent is obtained.
4. Have an EDSS from 0-5.5, inclusive.
5. Women of childbearing potential must not be breast feeding and have a negative
serum/urine pregnancy test at initial screening and at Study Day 1 (SD1) before
dosing. For the purposes of this trial, a woman of childbearing potential is defined as: *All female subjects after puberty unless they are post-menopausal for at least two
years, or are surgically sterile*.
6. Female subjects of childbearing potential must be willing to avoid pregnancy by
using an adequate method of contraception for approximately four (4) weeks prior to SD1, during and for twelve (12) weeks after the last dose of trial medication. This
requirement does not apply to surgically sterile subjects or to subjects who are
postmenopausal for at least 2 years. Adequate contraception is defined as two barrier methods, or one barrier method with spermicide or intrauterine device or use of the oral female contraceptive.
7. Subject is willing and able to comply with study procedures for the duration of the
study;
8. Voluntarily provide written informed consent (obtained before any trial related
procedure), including, for USA, subject authorization under Health Insurance
Portability and Accountability Act (HIPAA), prior to any study-related procedure that
is not part of normal medical care, and with the understanding that the subject may
withdraw consent at any time without prejudice to their future medical care.
Exclusion criteria
To be eligible for inclusion in this study the subjects must not satisfy any of the
following criteria:
1. Have primary progressive MS.
2. Have secondary progressive MS without superimposed relapses.
3. Any condition, including laboratory findings and findings in the medical history or in the pre-study assessments, that in the opinion of the Investigator, constitute a risk or a contraindication for the participation in the study or that could interfere with the study objectives, conduct or evaluation.
4. Prior treatment with B cell modulating therapies, such as rituximab or belimumab.
5. Exposure to immunomodulatory therapy, such as interferon beta or glatiramer acetate, within 3 months prior to SD1.
6. Discontinuation of prior immunodulatory therapy due to perceived lack of efficacy.
7. Prior exposure to immunosuppressive or cytotoxic agents including but not restricted to cladribine, mitoxantrone, alemtuzumab cyclophosphamide, mycophenolate mofetil, azathioprine, methotrexate, or natalizumab.
8. Prior myelosuppressive / cytotoxic therapy, such as lymphoid irradiation, or bone
marrow transplantation.
9. Prior use of cytokine or anti-cytokine therapy, intravenous immunoglobulin (IVIg) or plasmapheresis within 6 months prior to SD1.
10. Treatment with oral or systemic corticosteroids or adrenocorticotropic hormone within 28 days prior to SD1.
11. Require chronic or monthly pulse corticosteroids during the study
12. Participation in any interventional clinical trial within 2 months prior to SD1, or within 5 half-lives of the investigated compound, whichever is longer.
13. Allergy or hypersensitivity to atacicept or to any of the components of the formulated atacicept.
14. Diagnosis or family history of Creutzfeldt-Jakob disease (CJD).
15. Moderate to severe renal impairment (creatinine clearance <50ml/min according to Cockcroft-Gault equation).
16. Allergy or hypersensitivity to gadolinium.
17. History or presence of uncontrolled or New York Health Association (NYHA) class 3 or 4 congestive heart failure Please add definition.
[NYHA class 3: Cardiac disease resulting in marked limitation of physical activity. Subjects are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnoea, or anginal pain.
NYHA class 4: Cardiac disease resulting in inability to carry on any physical activity without discomfort.
Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort is increased. (Source: The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston,
Mass: Little, Brown & Co; 1994:253-256.)];
18. History of cancer, except adequately treated basal cell carcinoma of the skin, cervical
dysplasia or carcinoma in situ of the skin or the cervix.
19. Aspartate aminotransferase (AST) alanine aminotransferase (ALT) or alkaline
phosphatase (AP) level >2.5 x ULN. Total bilirubin >1.5 x ULN at screening.
20. Clinically significant abnormality in any haematological test (e.g. haemoglobin <100 g/L (6,21 mmol/L), WBC <3*109/L, lymphocytes < 0.8*109/L, platelets <140*109/L) at screening.
21. Clinically significant abnormality on chest X-ray performed within 3 months prior to SD1 or on ECG performed at screening.
22. Immunisation with live vaccines within one month prior to SD1 or need for such
treatment during the study.
23. Known active clinically significant acute or chronic infection, or any major episode of infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks of SD1
24. Positive HIV, hepatitis C or hepatitis B (HBsAg) serology (test performed at screening).
25. Presence of active or latent tuberculosis within the past year prior to screening. Subjects should be evaluated and screened for active or latent tuberculosis according to national and/or local recommendations
26. Serum IgG below 6 g/L at screening.
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 | EUCTR2007-003936-50-NL |
| CCMO | NL20692.003.08 |