The objectives of this study are to compare the safety and efficacy of 2 annual cycles of intravenous (IV) alemtuzumab to 3-times weekly subcutaneous (SC) interferon beta 1a (Rebif*) in patients with active relapsing-remitting multiple sclerosis (…
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Source
Brief title
Condition
- Demyelinating disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint will be time to SAD and relapse time.
The study will be considered to have met its primary efficacy objective if a
statistically significant difference between the alemtuzumab treatment group
and the interferon beta-1a group is observed for time to SAD or relapse rate.
Confidence intervals and p-values will be presented for all primary efficacy
endpoints for descriptive purposes regardless of the outcome of the Hochberg
procedure.
The comparison of the SAD co-primary endpoint will use a Cox proportional
hazards regression model with treatment group indicators, geographic region,
and baseline EDSS as the only covariates in the model.
The comparison of the relapse rate co-primary endpoint will use the
proportional means model. Treatment group indicators, geographic region, and
baseline EDSS will be the only covariates in the model.
Supportive analyses will be performed using all of the available follow-up
data, including data collected beyond Year 2, and will also include analyses
restricted to Year 1 follow up.
Secondary outcome
The secondary endpoint are:
• Proportion of patients who are relapse free at Year 2.
• Change from baseline in EDSS.
• Acquisition of disability as measured by the MSFC.
• Percent change from baseline in MRI-T2 hyperintense lesion volume at Year 2.
Hypothesis testing for the secondary efficacy analyses will be performed using
a closed testing procedure with the following rank order:
• Proportion of patients who are relapse free at Year 2.
• Change from baseline in EDSS.
• Acquisition of disability as measured by the MSFC.
• Percent change from baseline in MRI-T2 hyperintense lesion volume at Year 2.
The hypothesis testing will proceed from highest rank (1. Proportion of
patients who are relapse free at Year 2) to lowest rank (4. Percent change
from Baseline in MRI-T2 hyperintense lesion volume at Year 2), and if
statistical significance is not achieved at an endpoint (p*0.05), then
endpoints of lower rank will not be considered to be statistically
significant. Confidence intervals and p-values will be presented for all
secondary efficacy endpoints for descriptive purposes, regardless of the
outcome of the closed testing procedure.
Background summary
This study will compare an investigational medicine, called alemtuzumab, to an
approved medicine named Rebif® in people with early, active relapsing-remitting
multiple sclerosis. Rebif® is an approved treatment for multiple sclerosis in
the US, Canada, Australia, some South American countries and Europe.
Alemtuzumab (Campath/MabCampath) has been used as an experimental treatment of
multiple sclerosis since 1991. Currently, alemtuzumab is approved to treat some
types of leukemia but is not approved for the treatment of MS. As a leukemia
treatment it is given more often and at much higher doses than in this study.
Approximately 400 MS patients have been treated with Alemtuzumab in clinical
research studies conducted in Europe and the US. These studies have shown that
it may be an effective treatment for multiple sclerosis. For instance, there
has already been a study of alemtuzumab versus one of the standard treatments
for multiple sclerosis, interferon beta 1a (Rebif®), in people with
relapsing-remitting multiple sclerosis, study *CAMMS223*. This showed that two
years* treatment with alemtuzumab, used at the dose proposed for this current
study, reduced the risk of having a relapse, compared to Rebif®, by 72% and it
also reduced the risk of acquiring sustained disability by 88% compared to
Rebif®. But there were more side-effects associated with alemtuzumab compared
to Rebif®.
We now want to conduct a large study comparing alemtuzumab and Rebif®, to
carefully judge the balance between effectiveness and safety of alemtuzumab
compared to interferon beta 1a.
Study objective
The objectives of this study are to compare the safety and efficacy of 2 annual
cycles of intravenous (IV) alemtuzumab to 3-times weekly subcutaneous (SC)
interferon beta 1a (Rebif*) in patients with active relapsing-remitting
multiple sclerosis (RRMS) who have experienced at least 1 relapse while on
disease-modifying drug therapy for *6 months.
To investigate these objectives, alemtuzumab will be compared to SC interferon
beta-1a for efficacy in the time to sustained accumulation of disability (SAD),
relapse rate, time to first relapse, acquisition of disability as measured by
changes in the Multiple Sclerosis Functional Composite (MSFC) plus visual
function as measured by Sloan Charts, changes in magnetic resonance imaging
(MRI)-T2 hyperintense lesion volume, other MS-related endpoints, and
quality-of-life measures. Principal relapse analyses will be based on
determinations of relapse made by an independent Relapse Adjudication Panel
(RAP). Safety will be assessed by comparing alemtuzumab to SC interferon
beta-1a for frequency and intensity of adverse events (AEs), changes in
laboratory values for several hematologic and chemistry parameters, incidence
of autoimmune disorders*especially immune thrombocytopenic purpura (ITP) and
thyroid disorders*and incidence of infection.
The study will be considered to have met its efficacy objectives if a
statistically significant treatment effect of alemtuzumab over SC interferon
beta-1a is demonstrated in either or both of the co-primary efficacy endpoints:
time to SAD and relapse rate.
Study design
This is a randomized study with a blinded rater, who performs the EDSS and MSFC
tests with the patients. Approximately 573 eligible patients will be randomized
2:1. This is an open label study except for the blinded rater.
Intervention
Approximately 573 eligible patients will be randomized 2:1 to receive 2 annual
cycles of IV alemtuzumab or 3-times weekly injections of SC interferon beta-1a
for at least 2 years.
Alemtuzumab:
On Days 1, 2, and 3 of treatment (Month 0) and re-treatment (Month 12), all
patients will receive premedication with 1 gram of IV methylprednisolone
immediately prior to alemtuzumab infusion. Patients randomized to receive
alemtuzumab will receive 12 mg/day for 5 consecutive days at Month 0 and for 3
consecutive days at Month 12. All alemtuzumab patients will also receive a
course of acyclovir 200 mg twice daily (or therapeutic equivalent) beginning
with the first day of each alemtuzumab cycle and continuing for 28 days after
the last day of the cycle.
Rebif:
SC interferon beta-1a (44 mcg administered 3 times/week; a total 132 mcg/week)
will be self- or other-administered by SC injection for the duration of the
study period after the initial titration. Initial titration will occur over a
4-week period until the full dose of 44 mcg administered 3 times/week is
reached. The titration schedule for SC interferon beta-1a is, per the labeling,
20% dose the first 2 weeks, 50% dose the next 2 weeks, reaching the full dose
after 4 weeks of titration. The *Rebiject II** Rebif autoinjector may be used,
but will not be provided by Genzyme.
On Days 1, 2, and 3 of treatment initiation (Month 0) and again at Month 12, SC
interferon beta-1a-treated patients will receive premedication with 1 gram of
IV methylprednisolone.
Study burden and risks
During the study the following non-invasive assessments will be conducted:
neurological exams: a 500 meter walk, a timed 25 foot (7.63 meter) walk, a
9-hole peg test, an eye exam, and a test requiring you to add small numbers in
your head quickly (Paced Auditory Serial Addition Test), yearly brain scans
with MRI (Magnetic Resonance Imaging), monthly questionnaires to evaluate how
you are feeling, to determine health condition, and to find out about other
medical visits, standard urinalysis, physical examination and special
neurological exams: Expanded Disability Status Scale (EDSS) and the Multiple
Sclerosis Functional Composite (MSFC).
During the study the following invasive assessments will be done: monthly blood
samples taken from a vein in your arm. Additional blood samples may be taken
for medical testing.
The patients entering in the study may be subjected to the following invasive
treatments: Alemtuzumab: 5 days in a row intravenous infusion for approximately
4-6 hours. 1 Year later 3 days intravenous infusion for approximately 4-6
hours. Rebif®: 3 times a week a subcutaneous injection for a minimum of two
years, estimated between 2 and 3.5 years. Corticosteroids: 3 days infusion of
methylprednisolone for approximately 1 hour every day, repeat after 12 months.
Treatment with Alemtuzumab may cause side effects: for a few hours, worsening
of current or old symptoms from MS, rash in response to antihistamine
medication, fever, headache, and fatigue - may last for a few hours,
rigor/chills, nausea, vomiting, and/or diarrhea, shortness of breath and/or
spasms in the windpipe, especially in patients with asthma, hypotension.
In addition, Alemtuzumab treatment may cause low platelet count, possibly
leading to unusual bleeding, easy bruising, appearance of petechia Immune
Trombocytopenic Purpura (ITP), easy bleeding of the gums, nosebleeds, and
unusually heavy menstrual periods.
Alemtuzumab treated patients are at an increased risk of infections.
A small number, less than 1 %, of the patients who were treated with
Alemtuzumab suffered from anti-glomerular basement membrane disease, anti-GBM
or "Goodpasture*s disease".
Alemtuzumab treated patients may develop Graves* disease, an abnormality of the
thyroid gland, with symptoms: increased sweating; anxiety; weight loss; tremor;
and sometimes, pain in the neck.
Treatment with Rebif® may cause soreness, redness, pain, bruising, or swelling,
and in some cases tissue necrosis, which may occur at the place of the
injection. In addition, Rebif treatment may cause flu-like symptoms (fever,
chills, sweating, muscle aches, and fatigue) a few hours after each injection,
but this side-effect usually disappears after a few weeks. Rebif treatment may
also cause depression, liver problems, difficulty to fight an infection,
tiredness or sluggishness, unusual bruising or bleeding, very rarely severe
allergic reactions, leading to difficulty breathing and loss of consciousness,
thyroid disease much less frequent than after alemtuzumab treatment but with
similar symptoms.
The intravenous corticosteroid methylprednisolone may reduce or eliminate these
symptoms, and antihistamine medication may further reduce the risk of rash.
Methylprednisolone treated patients may experience nervousness and difficulty
sleeping, which resolves within a day of the last infusion. Severe damage to
bone, particularly the hip, is a rare side effect of high dose intravenous
steroid treatment.
The acyclovir serves to prevent herpes virus infection and is generally
well-tolerated. The most common side effects associated with acyclovir are
nausea and diarrhea.
The MRI contrast agent gadolinium may cause mild headache, nausea and local
pain, in less than 1% of the time low blood pressure and light-headedness
occurs. Less than one in one thousand patients are allergic to the contrast
agent, resulting in hives and itchy eyes, but more severe reactions have been
seen, which result in shortness of breath.
Other than the risks of side effects, known or unknown, one disadvantage of
this study is that you will be inconvenienced by blood tests, clinic visits,
and MRI brain scans.
There may be other risks or side effects which are unknown at this time.
Gooimeer 10
1411 DD Naarden
NL
Gooimeer 10
1411 DD Naarden
NL
Listed location countries
Age
Inclusion criteria
•Diagnosis of MS and MRI scan demonstrating white matter lesions attributable to MS
•Onset of MS symptoms within 10 years
•EDSS score 0.0 to 5.0
•>=2 MS attacks within 24 months, with >=1 attack within 12 months
•>=1 MS attack (relapse)during treatment with a beta interferon therapy or glatiramer acetate after having been on that therapy for at least 6 months within 10 years
Exclusion criteria
•Previous treatment with alemtuzumab
•Previous treatment with any investigational drug (i.e. a medication that is not approved at any dose or for any indication)
•Treatment with natalizumab, methotrexate, azothioprine or cyclosporine in the past 6 months
•Previous treatment with mitoxantrone, cyclophosphamide, cladribine, rituximab, or any other immunosuppressive, or cytotoxic therapy (other than steroid treatment)
•Any progressive form of MS
•Any disability acquired from trauma or another illness that could interfere with evaluation of disability due to MS
•Major systemic disease that cannot be treated or adequately controlled by therapy
•Active infection or high risk for infection
•Autoimmune disorder (other than MS)
•Impaired hepatic or renal function
•History of malignancy, except basal skin cell carcinoma
•Medical, psychiatric, cognitive, or other conditions that compromise the patient's ability to understand the patient information, to give informed consent, to comply with the trial protocol, or to complete the study
•Known bleeding disorder
•Of childbearing potential with a positive serum pregnancy test, pregnant, or lactating
•Current participation in another clinical study or previous participation in CAMMS323 
•Previous hypersensitivity reaction to any immunoglobulin product
•Known allergy or intolerance to interferon beta, human albumin, or mannitol
•Intolerance of pulsed corticosteroids, especially a history of steroid psychosis
•Inability to self-administer subcutaneous (SC) injections or receive SC injections from caregiver
•Inability to undergo MRI with gadolinium administration
•Unwilling to use a reliable and acceptable contraceptive method throughout the study period (fertile patients only)
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 | EUCTR2007-001162-32-NL |
| CCMO | NL21253.003.07 |
| Other | not available |