An Extension Protocol For Multiple Sclerosis Patients Who Participated in Genzyme-Sponsored Studies of Alemtuzumab

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.

Over 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 74% and it also reduced the
risk of acquiring sustained disability by 71% compared to Rebif®. But there
were more side-effects associated with alemtuzumab compared to Rebif®.

The two Phase 3 studies, CAMMS323 and CAMMS32400507 (hereafter: CAMMS324), were
developed to confirm the phase 2 results and collect additional information on
safety and efficacy. Both protocols specified that all patients treated with
alemtuzumab would be monitored for at least 4 years after their last cycle of
study medication for safety purposes. At least part of this monitoring will
take place under this separate extension protocol. In addition, patients who
had received SC IFNB-1a in one of the previous studies have the opportunity to
receive treatment with alemtuzumab in this extension study, provided the in-and
exclusion criteria are met.

The objectives of this study are to examine: (1) the long-term safety and
efficacy of alemtuzumab in multiple sclerosis (MS) patients who received
alemtuzumab during prior Genzyme-sponsored studies including CAMMS223,
CAMMS323, or CAMMS32400507 (referred to hereafter as CAMMS324); (2) the safety
and efficacy of as-needed alemtuzumab retreatment in these previously
alemtuzumab-treated patients; and (3) the safety and efficacy of 2 fixed annual
alemtuzumab cycles followed by optional as-needed retreatment in patients who
previously received subcutaneous interferon beta-1a (SC IFNB-1a) during these
studies. The efficacy of immediate alemtuzumab treatment (IAT, ie, alemtuzumab
initiated at onset of CAMMS323 or CAMMS324) vs. delayed alemtuzumab treatment
(DAT, ie, alemtuzumab initiated after completing 2 years of CAMMS323 or
CAMMS324) will also be examined.

This is an open-label, rater-blinded extension study for patients who
participated in CAMMS223, CAMMS323, or CAMMS324 (referred to hereafter as prior
studies).
Based upon prior study enrollment, patients will have a finite period of time
to enroll in this study:
• Patients who are participating in CAMMS323 or CAMMS324 should be told details
of the extension study and be provided with a copy of the informed consent form
(ICF) to review in advance of their CAMMS323 or CAMMS324 Month 24 visit,
preferably at the Month 21 visit. Informed consent should then be obtained at,
or following, the CAMMS323 or CAMMS324 Month 24 visit, but not sooner. Patients
[from CAMMS323 or CAMMS324] who do not provide consent at the Month 24 visit
will have 8 weeks from their scheduled Month 24 visit to consent to the
extension study.
• Patients who participated in CAMMS223 will have 6 months from the date their
site receives approval for this extension study to consent to the extension
study. Approval refers to the official notice from Genzyme to a site following
receipt of applicable approval from governing agencies (eg, Competent
Authorities, Institutional Review Board [IRB]/Ethics Committee [EC]), and other
required documentation that they are approved to start entering patients in the
extension study.
Patients randomized to and treated with alemtuzumab in one of these prior
studies will receive safety monitoring. They may also be eligible to receive
additional alemtuzumab upon documented evidence of resumed disease activity,
defined as >=1 protocol-defined relapse or >=2 new or enlarging brain or spinal
lesions on magnetic resonance imaging (MRI), provided they meet all of the
entry criteria and do not meet any of the disqualifying criteria in Section
9.2.3. All retreatment cycles will consist of 12 mg/day alemtuzumab
intravenously (IV) infused once daily for 3 days. Patients will have 47 months
from enrollment (ie, signing of the ICF) to qualify for and receive
retreatment.
Patients randomized to and treated with SC IFNB-1a in one of these prior
studies will be enrolled in this study only if they desire treatment with
alemtuzumab and meet all of the entry criteria. Eligible patients will receive
2 annual cycles of alemtuzumab. The first cycle should be administered at
study entry, provided the patient does not meet any of the disqualifying
criteria listed in Section 9.2.3. The second cycle should be administered 12
months later, provided the patient meets none of the disqualifying criteria.
SC IFNB-1a patients who cannot receive alemtuzumab at study entry should be
reassessed regularly at the discretion of the investigator and must qualify for
and receive alemtuzumab treatment by the end of the Month 2 visit window or
they will be discontinued from the study. SC IFNB-1a patients who complete 2
alemtuzumab cycles will be eligible for as needed alemtuzumab retreatment
according to the procedures described above for alemtuzumab patients.
Safety and efficacy assessments will be performed at scheduled visits for 48
months from enrollment in this extension study. Adverse events (AEs) and
concomitant medications will be monitored continuously. Once the extension
study ends, any additional safety follow-up may occur via a separate
mechanism.
The Expanded Disability Status Scale (EDSS), relapse, and MRI assessments will
be performed by raters who are blinded to patients* treatment history. The
annual MRIs will be read and interpreted locally by qualified site personnel
and/or designee (eg. neuroradiologist) for assessment of retreatment
eligibility and to rule out a non-MS pathology. Annual MRIs will also be read
and interpreted by blinded neuroradiologists at a central site for the analyses
of efficacy endpoints.
An independent, Data Monitoring Committee (DMC) will conduct interim monitoring
of data during this study until the lead-in Phase 3 studies (CAMMS323 and
CAMMS324) are concluded.
A sub-study to assess the potential effects of a 5-day, 12 mg/day, IV
alemtuzumab treatment cycle on cardiac repolarization as detected by
prolongation of the QT corrected (QTc) interval ("QT substudy") will be
performed at selected sites (excluding the Netherlands). Approximately 55
patients formerly treated with SC IFNB-1a in prior studies will be enrolled in
the QT sub-study (provided that they meet additional eligibility criteria for
QT assessment), in which they will have ECGs and corresponding PK samplings
performed surrounding the first cycle of alemtuzumab dosing. A single dose of
400 mg of moxifloxacin will be given orally 4 days prior to th first day of
alemtuzumab treatment, as a positive control to establish assay sensitivity.
For research purposes and on a voluntary basis, a blood sample will be
collected from consenting patients for subsequent exploratory analysis of
genetic variations related to MS disease and/or the effects of alemtuzumab. If
the sample is deemed unusable, a second sample would be obtained.

Alemtuzumab will be IV infused in a supervised medical setting. Patients
previously treated with alemtuzumab who show documented evidence of resumed
disease activity, do not meet any of the disqualifying safety criteria for
receiving alemtuzumab, and consent to alemtuzumab retreatment will receive 12
mg/day alemtuzumab once daily for 3 consecutive days. These patients may
subsequently receive additional cycles of alemtuzumab upon documented evidence
of resumed disease activity, but not within the same 12-month period. They
will have 35 months from enrollment to qualify for and receive retreatment.

SC IFNB-1a treated patients entering the extension study will receive 12 mg/day
alemtuzumab once daily for 5 days during the first cycle, and 12 mg/day for 3
days during the second cycle, 12 months later. SC IFNB-1a patients may qualify
for as needed retreatment, 12 mg/day for 3 consecutive days, after their second
fixed annual cycle if they meet the eligibility requirements and are within 35
months from entry into the extension study.
All patients will receive premedication with 1 gram of IV methylprednisolone
immediately prior to alemtuzumab on days 1-3 of any treatment cycle. All
patients will also receive a course of acyclovir, 200 mg twice daily (or
therapeutic equivalent), beginning with the first day of any alemtuzumab cycle
and continuing for 28 days after the last day of any cycle.

During the study the following non-invasive assessments will be conducted:
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 a special neurological exam, the Expanded Disability Status
Scale (EDSS).

During the study the following invasive assessments will be done: monthly blood
samples taken from a vein in your arm and monthly urinsampling. Additional
blood- and/or urinsamples 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. 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.
One person has developed *Goodpasture*s syndrome* after treatment with
alemtuzumab.
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.

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.

Herpes Simplex Type 1 and 2: An anti-viral medication (acyclovir or similar
medicine) designed to prevent herpes will be given to all alemtuzumab patients
starting on the first day of each alemtuzumab cycle and continuing for 28 days
after the last day of the cycle. Acyclovir is generally well-tolerated. The
most common side effects associated with acyclovir are nausea and diarrhea.
Abnormal kidney function has been reported in some patients, particularly
elderly patients with abnormal kidney function.

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.