Clinical trial NCT03135249
Conditions: Multiple Sclerosis (MS)
Sponsor: University of Texas Southwestern Medical Center
Start date: 2018-05-01; Completion date: 2020-11-04
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine if a sequential combination therapy of natalizumab and alemtuzumab induces peripheral tolerance and reduces the annualized relapse rate (ARR) in patients with relapsing-remitting multiple sclerosis (RRMS).

Detailed description:
To determine if treatment with alemtuzumab after natalizumab reduces the ARR in patients with RRMS. The goal of this trial is to establish a disease-free state over a 24 months period in patients who received the natalizumab-alemtuzumab sequential therapy. The target population for this study are RRMS patients nearing the end of their natalizumab treatment regimen.Participants will be recruited from four different sites. Patients who meet all inclusion/exclusion criteria will be eligible for enrollment in the study.

Alemtuzumab (Lemtrada®) will be administered at a dose of 12 mg/d by intravenous (i.v.) infusion every day for five consecutive days within 14 days of the last dose of natalizumab. After 12 months, patients will be treated with a second course of alemtuzumab 12 mg/d by intravenous (i.v.) infusion every day for three consecutive days, and participants will be followed open-label for another 12 months per standard of care. Outside the scope of this study, the intention is to follow all study participants in participating centers long-term, and to record disease activity and treatment response.

Natalizumab treatment sequesters leukocytes out of the central nervous system (CNS) into the peripheral blood. Immediate sequential alemtuzumab therapy will deplete these cells more completely than alemtuzumab monotherapy, and prevent reactivation of disease activity previously treated with natalizumab. Thus, investigators hypothesize that sequential natalizumab - alemtuzumab therapy will prevent disease activation after cessation of natalizumab, and will provide sustained disease remission in many patients.

Clinical follow up by the treating physician will occur at months 0, 3, 6, 9, 12, 18 and 24 or immediately following clinical exacerbations months. During clinical visits, comprehensive medical history data will be obtained by the treating physician. Clinical visits due to suspected exacerbations associated with CNS (central nervous system) demyelination, and associated diagnostic studies and treatments, will be covered under the medical standard of care by third party payers. A recommendation to reevaluate the patient within 3 months following the clinical event to assess for extent of recovery will be made.

Standardized MRI studies of the brain will be performed at 0, 6, 12 and 24 months. Clinical imaging studies of the brain will be performed during or immediately following the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan costs covered under the medical standard of care. An end of study clinical MRI of the brain with and without contrast will be recommended to study participants at week 96 as medical standard of care.

Arms: arm 1: Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented:

Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution.

Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution.
Interventions: intervention 1: Alemtuzumab
Intervention descriptions: intervention 1: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.

Protocol documents:
Prot_SAP_001.pdf: 
Official title:  Sequential natalizumab – alemtuzumab therapy in patients 
with relapsing forms of multiple sclerosis (SUPPRESS) 
 
NCT number: NCT03135249 
Document date: June 14, 2019 


STU112016-060, Stuve, Form A, Mod_10, 06-14-19 (1) 
 
 
Sequential natalizumab – alemtuzumab therapy in patients with relapsing forms of 
multiple sclerosis (SUPPRESS) 
 
 
Primary Investigator: 
Olaf Stüve, M.D., Ph.D.  
Professor  
Department of Neurology and Neurotherapeutics  
University of Texas Southwestern Medical Center at Dallas  
6000 Harry Hines Blvd.  
Dallas, TX 75390-8813 
U.S.A.  
Tel: +1-214-6484559 
Fax: +1-214- 6456239 
 
 
 
 
 
Protocol Version:  
1.00  
Date of Creation:  
04/08/2016  
Release Date:  
12/08/2016 
 
 
 


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CONFIDENTIAL  
 
 


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Table of Contents 
 
Protocol Synopsis 
5 
1. Background 
9 
1.1 Biological rationale for proposed trial 
9 
1.1.1 Opportunistic Infections 
10 
1.1.2 Disease-reactivation after cessation of natalizumab therapy 
10 
1.2 Alemtuzumab in relapsing-remitting multiple sclerosis (RRMS) 
11 
1.2.1 Immune-reconstitution after alemtuzumab therapy in MS 
11 
1.3 A potentiation of efficacy through sequential natalizumab – alemtuzumab therapy
 
12 
2. Study Purpose 
13 
3. Study Objectives 
13 
3.1 Primary objective 
13 
3.2 Secondary objectives 
13 
4. Study Design 
13 
4.1 Study endpoints 
13 
5. Population 
14 
5.1 Inclusion/exclusion criteria 
14 
5.1.1 Inclusion criteria 
14 
5.1.2 Exclusion criteria 
14 
5.2 Consent 
15 
5.3 Privacy and confidentiality 
16 
5.4 Deviations 
16 
5.5 Premature patient withdrawal 
16 
6. Treatment 
17 
6.1 Patient numbering 
17 
6.2 Investigational drug 
17 
6.3 Treatment arms 
17 
6.4 Treating the patient 
17 
6.4.1 Baseline lab studies before starting alemtuzumab infusion 
18 
6.4.2 Prior to alemtuzumab infusion 
18 
6.4.2.1 Forms to complete 
18 
6.4.2.2 Laboratory assessments and procedures 
18 
6.4.2.3 Preparing the participant 
19 
6.4.2.3.1 Prescriptions 
19 
6.4.2.4 Day before infusion 
19 
6.4.3 Dispensing study drug 
20 
6.4.3.1 Days of infusion 
20 
6.4.3.2 Preparation for nurse on days of infusion 
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6.4.3.3 Monitoring parameters 
21 
6.4.4 Post-infusion 
21 
6.4.5 Reaction treatments 
22 
6.4.6 Monthly and quarterly labs and procedures 
23 
6.4.7 Annual labs and procedures 
23 
6.4.8 Treatment of MS relapses 
23 
6.4.9 Other concomitant treatment 
23 
6.4.10 Unexpected adverse event 
23 
6.4.11 Grading of adverse event 
24 
6.4.12 Relationship to study treatment 
24 
6.4.13 Serious adverse event reporting 
24 
6.4.14 Study drug discontinuation 
25 
6.4.15 Pregnancy 
25 
6.4.16 Study completion and post-study treatment 
25 
6.4.17 Role of key site personnel 
25 
6.4.18 Statement of compliance 
25 
7. Visit Schedule and Assessments 
26 
7.1 Study outline 
26 
7.2 Screening 
22 
7.3 Patient demographics and baseline characteristics 
27 
7.4 Treatment exposure and compliance 
27 
7.5 Efficacy 
27 
7.5.1 Definition of a relapse 
27 
7.5.2 Expanded Disability Status Scale (EDSS) 
27 
7.5.3 Magnetic resonance imaging (MRI) 
28 
7.5.4 Standard MRI protocol performed 
28 
7.5.5 Optic coherence tomography (OCT) 
29 
7.5.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
30 
7.5.7 Professional Quality of Life Scale (ProQOL) 
30 
7.5.8 Blood draw for mechanistic studies 
31 
8. Data Analysis 
31 
9. Reference List 
32 
10. Appendices 
34 
Appendix 1 
34 
Appendix 2 
52 
Appendix 3 
75 
Appendix 4 
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Protocol Synopsis  
 
Title of study:   
Sequential natalizumab – alemtuzumab therapy Trial (SUPPRESS) 
 
Study purpose:  
The purpose of this study is to determine if a sequential combination therapy of natalizumab and 
alemtuzumab induces peripheral tolerance and reduces the annualized relapse rate (ARR) in 
patients with relapsing-remitting multiple sclerosis (RRMS). 
 
Primary objective:  
To determine if treatment with alemtuzumab after natalizumab reduces the ARR in patients 
with RRMS.  The goal of this trial is to establish a disease-free state over a 24 months period in 
patients who received the natalizumab-alemtuzumab sequential therapy. 
 
Secondary objectives:  
To   evaluate the T cell, B cell, and autoreactivity characteristics of immune cells in RRMS 
patients before and after alemtuzumab treatment. 
 
Population:  
Relapsing MS patients will be recruited from four different sites:  UT Southwestern Medical 
Center (UTSW), Dallas VA Medical Center, Neurology Center of San Antonio, and the Multiple 
Sclerosis Treatment Center of Dallas. 
 
Inclusion criteria:  
Patients who meet all of the following inclusion criteria will be eligible for enrollment in the study:  
1. Age between 18 and 60 years, inclusive.  
2. Diagnosis of relapsing forms of MS using revised McDonald Criteria1.  
3. EDSS 0 - 6.5 (Functional system changes in cerebral (or mental) functions and in 
bowel and bladder functions not used in determining EDSS for protocol eligibility). 
4. Has had a minimum of 12 monthly doses of continuous natalizumab therapy (300 
mg/d), either regular or extended dosing. 
5. Understands and gives informed consent. 
 


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Exclusion criteria:  
Patients who meet any of the following exclusion criteria will not be eligible for enrollment in the 
study:  
1. Natalizumab failure based on clinician’s discretion. 
2. Has progressive MS. 
3. A diagnosis of PML. 
4. Known hypersensitivity to alemtuzumab.  
5. Any prior exposure to alemtuzumab. 
6. Initiation of new immunosuppressant treatment after the subject becomes protocol-
eligible (except for corticosteroids) or enrollment in a concurrent trial with immuno-
active pharmacotherapies. 
7. Uncontrolled diabetes mellitus defined as HbA1c > 8% and/or requiring intensive 
management. 
8. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome. 
9. Clinically significant autoimmune disease other than MS that may affect the CNS, 
including neuromyelitis optica (NMO), systemic lupus erythematosus (SLE, or Behcet 
disease. 
10. Active hepatitis B or C infection or evidence of cirrhosis. 
11. Human immunodeficiency virus (HIV) positivity. 
12. Uncontrolled viral, fungal, or bacterial infection.  
13. Positive pregnancy test or inability or unwillingness to use effective means of birth 
control. Effective birth control is defined as:  
a. Refraining from all acts of vaginal intercourse (abstinence), 
b. Consistent use of birth control pills, 
c. Tubal sterilization or male partner who has undergone vasectomy 
d. Placement of intrauterine device 
e. Use, with every act of intercourse, of a diaphragm with contraceptive jelly 
and/or condoms with contraceptive foam. 
14. Presence of metallic objects implanted in the body that would preclude the 
ability of the subject to safely have MRI exams. 
15. Psychiatric illness, mental deficiency, or cognitive dysfunction making 
compliance with treatment or informed consent impossible. 
 
 
 


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Investigational drug:  
Alemtuzumab 
 
Reference therapy:  
None.  This is a single arm trial. 
 
Study design:  
This is an open label, multicenter, efficacy pilot study. 
 
Key Efficacy Assessments:  
1. The primary endpoint is the annualized relapse rate (ARR) from the time of cessation of 
natalizumab treatment. 
2. A key secondary endpoint is freedom of relapse at 12 months.  
3. A key secondary endpoint is the number of new/enlarging T2 lesions on magnetic 
resonance imaging (MRI). 
4. A secondary endpoint is the number of gadolinium (Gd)-enhancing lesions on MRI. 
5. An exploratory endpoint is the Expanded Disability Status Scale (EDSS). 
6. An exploratory endpoint is retinal nerve fiber layer (RNFL) thickness assessment by optic 
coherence tomography (OCT).   
7. An exploratory outcome will be the assessment of quality of life (QoL) measures by a 
pre-defined, self-administered testing battery. 
 
Key Safety Assessments  
1. To minimize the risk of transitioning MS patients from natalizumab to alemtuzumab who 
already have progressive multifocal leukoencephalopathy (PML), all enrolled patients will 
undergo a brain MRI within 14 days prior to receiving alemtuzumab. 
2. To minimize the risk of herpetic infections while on alemtuzumab, anti-viral prophylaxis 
for herpetic viral infections should be administered on the first day of each treatment 
course and continued for a minimum of 2 months following treatment, or until the CD4 
lymphocyte count is > 200 cells/microliter, whichever occurs later. 
3. There may be an exaggerated cytokine response in some patients. Thus, patients will be 
monitored and management based on the treating physician’s best judgement from the 
final dose of natalizumab to the end of the first course of alemtuzumab treatment. 
4. Each relapse will be treated with pulse corticosteroids as per best clinical judgment.  


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5. Two or more confirmed clinical relapses during the trial would allow rescue therapy as per 
best clinical judgment.  
6. Five or more Gd+ lesions at the 6 month MRI assessment over the baseline assessment 
will result in a follow-up scan after 60 days and will count as one relapse. Should a 
confirmed clinical relapse occur within the 60 day period, it will still count as a single 
relapse.  
7. Sensitivity analyses will be conducted using intent-to-treat (ITT) principles for efficacy to 
ensure that safety considerations and withdrawals have not altered results.  
8. Patients who withdraw from study treatment will be observed as mandated by REMS.  
 
Data analysis:  
The sample size of 40 patients was chosen to obtain a clinically meaningful result as 
defined by neurologists.  
All outcome measures at 12 months prior to natalizumab treatment, on 
natalizumab treatment, and on alemtuzumab will be assessed and compared. We will 
control secondary and exploratory endpoints for multiple comparisons by testing 
sequentially the proportion of relapse-free patients, EDSS change, and T2-hyperintense 
lesion volume change. 
We will analyze the proportion of patients who are relapse-free with a proportional hazards 
model. We will analyze changes from baseline in EDSS at the pre-defined time points with a 
mixed model for repeated measures. We will make treatment comparisons of all available 3 
month assessments with a non-parametric test for repeated measures. We will analyze changes 
in T2-hyperintense lesion volume, and RNFL thickness with a ranked ANCOVA model. We will 
analyze proportions of patients with new or enlarged T2-hyperintense or Gd+ lesions with logic 
regression. 
 
 
 


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1 
Background  
Multiple sclerosis is an inflammatory disorder of the central nervous system (CNS). A pathological 
hallmark of this disorder is the infiltration of immune-competent leukocytes into the brain and 
spinal cord. Natalizumab is a humanized recombinant monoclonal antibody that binds to the alpha 
(α)4 chain of the integrin very late activation antigen (VLA)-4.  Natalizumab is currently considered the 
most effective approved therapy in reducing clinical and paraclinical MS disease activity. Our 
group has made several novel observations with regard to the pharmacodynamic properties of 
natalizumab: (1) Compared to controls, natalizumab-treated MS patients had significantly fewer 
white blood cells, CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD138+ plasma cells in 
cerebrospinal fluid (CSF); (2) CD4+:CD8+ ratios in the CSF of MS patients treated with 
natalizumab were reversed, and not statistically different from those in HIV-infected controls; (3) 
elevated serum anti-Human Herpesvirus (HHV)-6 IgG, and HHV-6A DNA were detected in the 
CSF of a subset of patients on natalizumab therapy. In summary, these data indicate that 
natalizumab therapy substantially alters the composition of immune-competent cells in the CSF of 
patients with MS.  
Since its first approval for patients with MS in November 2004, more than 200 patients 
treated with natalizumab have been diagnosed with PML, a CNS infection with the polyomavirus 
JC. PML is typically observed in the setting of prolonged and severe immunosuppression, most 
commonly in patients infected with HIV. Natalizumab is currently administered monthly as 
monotherapy to approximately 100,000 patients with MS, and treatment is recommended to 
continue indefinitely without treatment interruptions. 
 
1.1 Biological rationale for proposed trial  
Natalizumab is a humanized recombinant monoclonal antibody against alpha4-integrin that was 
first approved in November 2004 for patients with relapsing forms of multiple sclerosis (MS) 
based on the results of two phase III trials (1, 2).  Natalizumab blocks the egress of leukocytes 
from the peripheral blood into the CNS.  In the short term, the therapeutic benefits are likely due 
to its effect on lymphocytes as shown by our laboratory and other investigators (3-6).  Long-
term, the number of myeloid cells that serve as antigen presenting cells (APC) in perivascular 
spaces is likely also substantially reduced (7).  Despite its tremendous efficacy, there are two 
observations that have limited the use of natalizumab in patients with MS. 


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1.1.1 Opportunistic infections 
Approximately 1:250 patients with MS under natalizumab will develop progressive multifocal 
leukoencephalitis (PML), and infection with the human polyomavirus JC.  This potential side 
effect has substantially limited the use of an effective therapy.  An algorithm was recently 
developed to estimate PML incidence in MS patients considering or receiving natalizumab 
based on duration of natalizumab treatment (1-24 or 25-48 months), prior immunosuppressant 
use (yes or no), and anti-JCV antibody status (positive or negative) (8).  Based upon the two 
established risk factors for PML, PML risk was lowest in patients treated with natalizumab for 1-
24 months without prior immunosuppressant use, (0.19 cases per 1000 patients), and greatest 
in those with both risk factors, natalizumab treatment for 25-48 months and prior 
immunosuppressant use (4.3 cases per 1000).  When anti-JCV antibody status was included as 
a third risk factor, PML risk was lowest in patients who were anti-JCV antibody negative (0.11 
per 1000), and highest in patients with all three factors, (11 per 1000).  The most recent data 
indicate that MS patients on natalizumab with all three risk factors appear have a risk of 1:44 to 
develop PML (9, 10). 
1.1.2 Disease-reactivation after cessation of natalizumab therapy 
While natalizumab is a tremendously effective therapy, disease activity returns 3 to 6 months 
after treatment discontinuation in a predictable manner.  The best data in this regard were 
generated by O’Connor et al, who analyzed clinical relapses in 1,866 patients, and gadolinium 
(Gd)-enhancing lesions in 341 patients from the AFFIRM, SENTINEL, and GLANCE studies of 
natalizumab, and their respective safety extension studies (11).  Annualized relapse rates and 
Gd lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 
months.  A consistent return of disease activity was observed regardless of overall natalizumab 
exposure, whether or not patients received alternative MS therapies, and in patients with highly 
active MS disease. 
The return of disease activity may be explained by its biological activities.  Leukcoytes 
are sequestered out of the CNS into the peripheral blood, where they assume a more 
inflammatory phenotype.  Krumbholz et al. demonstrated that natalizumab therapy increased 
CD19+ mature B cells in peripheral blood 2-3-fold more than that of other lymphocytes and 
monocytes compared to pre-treatment levels (12).  The increase of immature CD19+CD10+ pre-
B cells in peripheral blood was 7.4-fold.  This pattern remained stable during treatment for up to 
16 months.  Kivisakk et al showed that the frequency of CD4+ T cells producing interferon 
gamma (IFNγ), tumor necrosis factor, and interleukin (IL)-17 upon anti-CD3 stimulation 
increased 6 months after initiation of natalizumab treatment and remained elevated throughout 


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the follow-up (13).  The frequency of CD4+ T cells expressing CD25, HLA-DR, and CCR6 ex 
vivo was increased at one or more time points during treatment.  Our lab showed in a cohort of 
23 patients that return of clinical disease activity in patients who stopped taking natalizumab 
correlated with the re-constitution of CD4+ T cells and CD8+ T cells in the cerebrospinal fluid (5). 
1.2 Alemtuzumab in RRMS 
Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes CD52+ 
cells.  Alemtuzumab is effective in ameliorating MS disease activity.  In the CARE-MS I phase III 
trial, a 55 % relapse rate reduction with alemtuzumab (12 mg/d) over interferon-beta (IFNβ) was 
observed for alemtuzumab treated patients after 24 months (14).  Significantly more (78 %) 
alemtuzumab treated patients remained relapse-free at month 24 compared with 59 % of 
IFNb1a-treated patients, which equates to a 55 % risk reduction.  In the CARE-MS II phase III 
trial a 49 % reduction in relapse rate was observed in patients treated with alemtuzumab (12 
mg/d) compared with those treated with IFNβ-1a over the two years (15).  Significantly more 
alemtuzumab treated patients remained relapse-free at month 24 compared with IFNβ-1a 
treated patients.  While these data provide a rational for the use of alemtuzumab in patients with 
MS, many experts considered the efficacy of this agent in the two phase III studies as perhaps 
somewhat disappointing.  Again, its biological effects may explain this incomplete treatment 
effect of alemtuzumab.  Mainly, there is currently no evidence that alemtuzumab has any 
biological effect in the CNS.  Thus, the number and function of autoimmune-prone lymphocytes 
and pre-inflammatory myeloid cells that reside in the brain and spinal cord is not reduced. 
1.2.1 Immune-reconstitution after alemtuzumab therapy in MS 
MS is considered an autoimmune disorder of the CNS.  However, an autoantigen has not 
been identified.  Thus, the creation of peripheral tolerance will best be inferred by the disease 
status.   
Recent data from an Immune Tolerance Network (ITN) trial that tested autologous 
hematopoietic stem cell transplant (HSCT) in patients with very aggressive MS (HALT trial) 
showed that the reconstitution of the T cell receptor repertoire predicts treatment responses: 
• 
Patients who failed treatment had a significantly less diverse TCR (CD4+ and CD8+) 
at 2 months post-transplant than “others” 
• 
Treatment effectively reduced dominant baseline CD4+ TCR clones, did not reduce 
dominant CD8 TCR clones 
• 
Patients who recovered CD8+ T cells at year 1 had a less diverse CD8+ TCR 
repertoire 
• 
The reconstituted CD8+ T cell repertoire was dominated by large clonal expansions 


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• 
There was up to a 100% “renewal” (ablatednew) of the CD4+ T cell repertoire;  
there was less renewal within the CD8+ T cell repertoire 
• 
Treatment resulted in a “new” Top 100 CD4+ TCR repertoire at 2 months post-
transplant 
Immune-reconstitution after alemtuzumab therapy is very similar to that after autologous 
HSCT.  This is perhaps not surprising, as in both treatment paradigms there is almost a 
complete re-constitution of the lymphocyte compartment that is driven by autologous CD34+ 
bone marrow cells.  As stated above, alemtuzumab targets CD52, which is a 12-amino-acid 
glycosylated GPI-bound membrane protein (16, 17).  CD52 is expressed on a number of cells 
derived from the lympho-monocytic cell lineage, including T and B cells, natural killer (NK) cells, 
dendritic cells and most monocytes and macrophages.  By contrast, neutrophils and precursors 
cells of the hematopoietic lineage do not express CD52 (18-20).  The exact biological function of 
CD52 is not fully understood; CD52 binding may induce T cell activation, and CD52 may be a 
stimulatory co-factor required for regulatory T cells (Treg) (18, 19).  Alemtuzumab depletes 
CD52+ cells through ADCC and likely also through activation of the complement cascade (20-
23).  Cellular depletion is initiated rapidly resulting in almost complete disappearance of CD52+ 
cells from the circulation shortly after alemtuzumab administration.  Experimentally, 
complement-mediated cell lysis of leukemic B cells occurs within 1-4 hours after addition of 
alemtuzumab in vitro (24).  Lympho-monocytic cells in the periphery are eventually repopulated 
from pools of stem cells and certain progenitor cells that do not constitutively express CD52.  
Monocytes and B cells reach pre-alemtuzumab levels in the peripheral blood approximately 
three to six months after treatment, with B cell levels exceeding baseline levels by 124-165% 
(21, 22, 25, 26).  T cells repopulate considerably slower; CD8+ T cells reach baseline levels only 
after a median of 30 months, and CD4+ T cells after a median of 61 months (21).  The lower 
limits of normal for CD4+ and CD8+ T cells are reached earlier with medians of 12 and 11 
months, respectively (27).  It is particularly noteworthy that Tregs repopulate distinctly before 
CD4+ and CD8+ T cells, resulting in their specific enrichment in the peripheral blood (21, 26). 
1.3 A potentiation of efficacy through sequential natalizumab – alemtuzumab therapy 
Natalizumab treatment sequesters leukocytes out of the CNS into the peripheral blood.  
Immediate sequential alemtuzumab therapy will deplete these cells more completely than 
alemtuzumab monotherapy, and prevent reactivation of disease activity previously treated with 
natalizumab. Thus, we hypothesize that sequential natalizumab – alemtuzumab therapy will 
prevent disease activation after cessation of natalizumab, and will provide sustained disease 


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remission in many patients. The goal of this trial is to establish a disease-free state over a 24 
months period in patients who received the natalizumab-alemtuzumab sequential therapy. 
 
2 
Study purpose 
The purpose of this study is to determine if a sequential combination therapy of natalizumab and 
alemtuzumab induces peripheral tolerance and reduces the AAR in patients with RRMS. 
 
3 
Study objectives 
 
3.1 Primary objective 
To determine if treatment with alemtuzumab after natalizumab maintains or reduces the ARR 
in patients with RRMS. The goal of this trial is to establish a disease-free state over a 24 
months period in patients who received the natalizumab-alemtuzumab sequential therapy. 
 
3.2 Secondary objectives 
To   evaluate the T cell, B cell, and autoreactivity characteristics of immune cells in RRMS 
patients before and after alemtuzumab treatment. 
 
4 
Study Design 
This is a one arm, open-label, multicenter, efficacy pilot study of sequential natalizumab-
alemtuzumab treatment in RRMS patients.  
 
4.1 Study endpoints 
The primary endpoint is the annualized relapse rate (ARR) from the time of cessation of 
natalizumab treatment. 
Key secondary endpoints are freedom from relapse at 12 months and the number of 
new/enlarging T2 lesions on MRI. 
Other secondary endpoints are:  Number of Gd-enhancing lesions on MRI. 
Other Exploratory endpoints: 
1. EDSS. 
2. RNFL thickness assessment by OCT. 
3. Assessment of quality of life (QoL) measures by a pre-defined, self-administered testing 
battery. 
 


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5 
Population 
The target population for this study are RRMS patients nearing the end of their natalizumab 
treatment regimen. Participants will be recruited from four different sites: UT Southwestern 
Medical Center (UTSW), Dallas VA Medical Center, the Multiple Sclerosis Treatment Center of 
Dallas, and the Neurology Center of San Antonio.  Recruitment will occur on a competitive basis. 
 
5.1  Inclusion/exclusion criteria 
5.1.1  Inclusion criteria 
Patients who meet all of the following inclusion criteria will be eligible for enrollment in the 
study:  
1. Age between 18 and 60 years, inclusive. 
2. Diagnosis of relapsing forms of MS using revised McDonald Criteria1. 
3. EDSS 0 - 6.5 (note: functional system changes in cerebral (or mental) 
functions and in bowel and bladder functions not used in determining EDSS 
for protocol eligibility). 
4. Has had a minimum of 12 monthly doses of continuous natalizumab therapy 
(300 mg/d), either regular or extended dosing. 
5. Understands English, and gives informed consent. 
5.1.2  Exclusion criteria  
Patients who meet any of the following exclusion criteria will not be eligible for 
enrollment in the study:  
1. Natalizumab failure based on clinician’s discretion. 
2. Any prior exposure to alemtuzumab. 
3. Progressive MS. 
4. A diagnosis of PML. 
5. Known hypersensitivity to alemtuzumab.  
6. Initiation of new immunosuppressant treatment after the subject becomes 
protocol-eligible (except for corticosteroids) or enrollment in a concurrent trial 
with immuno-active pharmacotherapies. 
7. Uncontrolled diabetes mellitus defined as HbA1c > 8% and/or requiring 
intensive management. 
8. History of cytopenia consistent with the diagnosis of myelodysplastic 
syndrome. 
9. Clinically significant autoimmune disease other than MS that may affect the 


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CNS, including neuromyelitis optica (NMO), systemic lupus erythematosus 
(SLE), or Behcet disease. 
10. Active hepatitis B or C infection or evidence of cirrhosis. 
11. HIV positivity. 
12. Uncontrolled viral, fungal, or bacterial infection.  
13. Positive pregnancy test or inability or unwillingness to use effective means of 
birth control. Effective birth control is defined as:  
a. Refraining from all acts of vaginal intercourse (abstinence), 
b. Consistent use of birth control pills, 
c. Tubal sterilization or male partner who has undergone vasectomy 
d. Placement of intrauterine device 
e. Use, with every act of intercourse, of a diaphragm with contraceptive 
jelly and/or condoms with contraceptive foam. 
14. Presence of metallic objects implanted in the body that would 
preclude the ability of the subject to safely have MRI exams. 
15. Psychiatric illness, mental deficiency, or cognitive dysfunction making 
compliance with treatment or informed consent impossible. 
 
5.2 Consent 
The informed consent form is a method of providing information regarding the trial to a 
prospective participant and allows for an informed decision about participation in the study. All 
participants (or their legally acceptable representative) must read, sign, and date a consent form 
before participating in the study, taking study drug, and/or undergoing any study-specific 
procedures. 
The informed consent form must be updated or revised whenever important new safety 
information is available, whenever the protocol is amended, and/or whenever any new information 
becomes available that may affect a participants' participation in the trial.  
A copy of the informed consent form will be given to a prospective participant for review. 
The attending physician, in the presence of a witness, will review the consent form and answer 
questions. The participant will be informed that their participation is voluntary and that they may 
withdraw from the study at any time, for any reason.  
 


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5.3 Privacy and confidentiality 
A participant's privacy and confidentiality will be respected throughout the study. Each participant 
will be assigned a unique identification number and these numbers, rather than names, will be 
used to collect, store, and report participant information.  
 
5.4 Deviations 
Any protocol deviations that impact patient safety will be reported within 7 days to the principal 
investigator and the IRB. Deviations from the inclusion and exclusion criteria will be minimized 
via eligibility criteria checks prior to initiation of alemtuzumab therapy. 
 
5.5 Premature patient withdrawal 
Patients may be withdrawn from the study for any of the following reasons:  
• 
Withdrawal of the informed consent  
• 
Lost to follow-up  
• 
Withdrawal at the investigator's discretion  
Patients should be withdrawn at any time if the investigator concludes that it would be in the 
patients' best interest for any reason. Patients may voluntarily withdraw from the study for any 
reason at any time. They may be considered withdrawn if they state an intention to withdraw, or 
fail to return for visits, or become lost to follow up for any other reason. Protocol violations should 
not lead to patient withdrawal unless they indicate a significant risk to the patient's safety. If 
premature patient withdrawal occurs for any reason, the investigator must determine the primary 
reason for a patient's premature withdrawal from the study and record this information on a CRF. 
For patients who are lost to follow-up (i.e., those patients whose status is unclear because they 
fail to appear for study visits without stating an intention to withdrawal), the investigator should 
show "due diligence" by documenting in the source documents steps taken to contact the patient, 
e.g., dates of telephone calls, registered letters, etc. In the case of death, a patient will be 
considered withdrawn. Patients who are prematurely withdrawn from the study will not be 
replaced.  
 
 
 


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6. Treatment 
 
6.1 Patient numbering 
Patients will be assigned a unique study number upon signing the informed consent form 
(PID#1). The PID#1 is used during screening. The numbering will be designated based on the 
recruitment site and will follow the convention: ccc-pppp, where ccc represents center and pppp 
participant. The PID#1 is numeric for the center and alphanumeric for the participant.  Patients 
will retain their PID#1 regardless of whether they enter the treatment arm of the trial or 
subsequently withdrawal. PID#2 will be assigned at randomization and has the form ccc-
ppppp.  PID#2 is numeric for the center and 5 digit numeric field for the participant. Assignment 
of PID#1 will be performed by the study data management system provided that an informed 
consent was signed and that screening evaluations can commence. Assignment of PID#2 will 
be performed by the study data management system at the time of study initiation. 
 
6.2 Investigational drug 
Alemtuzumab (Lemtrada®) will be administered at a dose of 12 mg/d by intravenous (i.v.) 
infusion every day for five consecutive days within 14 days of the last dose of natalizumab. After 
12 months, patients will be treated with a second course of alemtuzumab and they will be 
followed open-label for another 12 months per standard of care. Outside the scope of this study, 
the intention is to follow all study participants in participating centers long-term, and to record 
disease activity and treatment response. 
 
6.3 Treatment arms 
There is only one treatment arm in the trial, alemtuzumab treatment. 
 
6.4 Treating the patient 
All study participants will use commercial drug. All products will be labeled 
appropriately.  
Year One: Alemtuzumab 12 mg (1.2 ml) in 100 ml of sterile 0.9% sodium chloride (or 5% 
dextrose in water) IV Infusion via pump over a minimum of four hours daily for five days to be 
given within eight hours after dilution. Gently invert the bag to mix the solution. 


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Year Two: Alemtuzumab 12 mg (1.2 ml) in 100 ml of sterile 0.9% sodium chloride (or 
5% dextrose in water) IV Infusion via pump over a minimum of four hours daily for three days to 
be given within eight hours after dilution.  Gently invert the bag to mix the solution. 
 
6.4.1 Baseline lab studies before starting alemtuzumab infusion 
The following labs will be completed within 30 days of infusion: 
o Complete blood counts (CBC) with differential 
o Comprehensive metabolic panel (CMP), or only serum creatinine 
o CD4+ T cell counts (optional) 
o Complete urinalysis with cell count 
o Thyroid function test (TSH) 
o Free T4 (optional) 
o Other optional labs for endemic areas or patients-specific include human 
immunodeficiency virus (HIV), hepatitis B (HBcAb and HBsAg), hepatitis C virus 
antibody, Varicella Zoster virus (VZV), TB Quantiferon Gold, and human 
papilloma virus (HPV) screening. 
If all hepatitis B and C studies are negative, alemtuzumab can be administered. If laboratory 
assessments are completed more than 30 days before infusion, the only blood work that needs 
to be re-drawn is the CBC with differential, serum creatinine, TSH, and urinalysis with cell count. 
Perform baseline and yearly skin examinations to monitor for melanoma and annual HPV 
screening is recommended for female patients. 
6.4.2 Prior to alemtuzumab infusion 
6.4.2.1 Forms to complete (see Appendix 1) 
• 
Lemtrada® Services Form - to enroll patients in central laboratory 
program 
• 
Lemtrada® REMS Patient Enrollment Form  
• 
Lemtrada® Prescription Ordering Form  
• 
EMSI Request for Services Form- for traveling phlebotomist  
6.4.2.2 Laboratory assessments and procedures  
• 
CBC with differential 
• 
CMP 
• 
TSH 


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• 
MRI Brain W & W/O contrast (baseline) 
• 
VZV antibodies (as needed with first infusion only)  
• 
Urinalysis 
• 
Tuberculosis testing (as indicated) 
• 
A dermatology referral to screen for any suspicious lesions is 
recommended in the alemtuzumab package insert, but not absolutely 
required. 
• 
Appointment for gynecology exam and pap smear for women to rule 
out active HPV infection is recommended in the alemtuzumab 
package insert, but not absolutely required. 
• 
CD4+ T cell counts (optional) 
• 
Hepatitis screening blood tests 
6.4.2.3 Preparing the participant 
• 
Educate patients regarding the mild-to-moderate infusion-associated 
reactions that can occur commonly with alemtuzumab 
• 
Remind patients to bring all their routine medications, including 
inhalers, antihypertensive, anti-diabetes, etc. 
• 
Solumedrol 1000 mg in 100 ml of sterile 0.9% sodium chloride IV 
infusion via pump over 60 minutes daily for three days, starting 
immediately prior to the initial alemtuzumab infusion. 
• 
Solumedrol 250 mg in 100 ml of sterile 0.9% sodium chloride IV 
infusion via pump over 30 minutes on day 4 and 5. 
6.4.2.3.1 Prescriptions 
• 
Acyclovir 200 mg 1 tab BID #60 
• 
Hydroxyzine 25 mg, 1-2 tab every 6 hours as needed for 
itching/rash 
• 
Zolpidem 5 mg, 1-2 tab every night as needed for sleep 
(due to steroid) 
• 
Medrol® Dose Pack (1) – take as directed; if patient 
develops a diffuse rash after the alemtuzumab infusion 
6.4.2.4 Day before infusion 
• 
Patients will be encouraged hydrate with several liters of water. 


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• 
Ascertain that the patients have transportation to and from the clinic 
arranged for everyday of the alemtuzumab infusions. 
• 
Patients will be instructed to take cetirizine 10 mg & ranitidine 150 mg 
(start taking 3-5 days prior to infusion).  These medications should be 
continued after the infusion for 30 days. 
• 
Instruct the patient to rest.  Specifically, patients should pack a travel 
bag for the time of the infusion (food, snacks, water bottle, 
entertainment, blanket/sweatshirt) – it is a 4-6 hours infusion plus 2 
hours mandatory post-infusion monitoring 
• 
Have patient avoid these foods while on treatment:  
• 
Sushi  
• 
Raw Meat  
• 
Wash all fruits and vegetables well  
• 
Unpasteurized milk or foods  
• 
Ready to eat foods that have been unrefrigerated more than a 
1 day  
6.4.3 Dispensing study drug 
Study drug will be dispensed by the pharmacy at each study site. At each study visit, 
study medication will be administered by medical/research staff.  
6.4.3.1 Days of infusion 
• 
Patients will be instructed to bring their packed bags (please see 
above), and to wear layered, comfortable clothes. 
• 
Patients will be instructed to take cetirizine 10 mg & ranitidine 150 mg 
and to start acyclovir 200mg before arrival (or replacement 
medications as needed). 
• 
Patients will be asked to arrive early to the infusion clinic. 
• 
Patients will frequently be encouraged to stay hydrated before, during, 
and after their alemtuzumab treatments. 
• 
Patients will also be asked to adhere to a low-sodium diet to prevent 
corticosteroid-induced hypertension and peripheral edema. 
• 
In addition, patients will be requested to avoid high sugar foods to 
prevent corticosteroid-induced hyperglycemia. 


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• 
Prophylactic use of insomnia medication will be offered (please see 
above). 
• 
Patient will be monitored for at least 2 hours post-infusion every day 
of treatment. 
6.4.3.2 Preparation for nurse on days of infusion 
• 
A pregnancy test will be performed in all female patients. 
• 
1 gram of methylprednisolone will be infused IV over 60 minutes 
during the initial three days of treatment.  If the dosage is split three 
days and then two days (such as M/T/W then next M/T), then infuse 
125-250 mg methylprednisolone l IV on day four and five. 
• 
Five days of alemtuzumab needs to be infused within a 30 day period 
the 12 months of treatment. 
• 
Check blood pressure, pulse, and body temperature every hour during 
the infusions, and 2 hours after the infusions. 
• 
Administer IV or oral diphenhydramine 25-50mg every 8 hours as 
needed for persistent rash / hives / itching.  Administer 
acetaminophen 500-1000 mg every 4-6 hours as needed for fever / 
headaches / flulike symptoms. 
• 
Cover alemtuzumab with bag to protect from light exposure. 
• 
Alemtuzumab is to be infused over four hours at a rate of 25ml/hour. 
• 
Do not shake vial prior to use. 
• 
Do not freeze alemtuzumab.  Do not use alemtuzumab if vial has 
been frozen. 
6.4.3.3 Monitoring parameters 
• 
Monitor vital signs prior to infusion and every hour for at least 6 hours  
• 
For signs/symptoms of a hypersensitivity reactions 
(urticarial, dizziness, fever, rash, rigors, pruritus, flushing, 
hypotension, chest pain, dyspnea), slow or stop 
medication infusion, maintain IV access, notify physician.  
Follow reaction protocols. 
6.4.4 Post-Infusion  
• 
Observe and monitor patient for reactions 2 hours post-infusion. 


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• 
During the two hours of observation, use extra hydration of 100 ml bag (sterile 
sodium chloride or 5% dextrose in water) to keep IV open and infuse all the 
alemtuzumab out of the tubing. 
• 
Send patient home with over the counter prescriptions for additional anti-
histamine and anti-pyretic in case of rash, headache or fever after leaving the 
clinic. 
• 
Infusion-associated reactions during the first alemtuzumab treatment cycle 
typically are not allergic or anaphylactic in etiology.  Thus, patients can be re-
challenged once the initial reaction subsides, often with additional pre-
medications.  To temporarily stop or slow down the infusion rate will often resolve 
or minimize these adverse reactions. 
6.4.5 Reaction treatments 
• 
If patient experiences bronchospasm:  Administer B-adrenergic agonist inhaler 
• 
If anaphylactic reaction occurs: 
o Administer epinephrine 0.3 mg IV or IM or Epi-Pen; epinephrine 1:1000 (1 
ml):  Give 0.2-0.5 ml SQ, start with lower dose and may repeat in 3-5 
minutes 
o Diphenhydramine 50 mg (1 ml) - administer 50 mg in 100 ml 0.9% sodium 
chloride IV infusion via pump over 10-15 minutes 
o Sodium chloride 0.9% 500 ml infuse IV at a rate of 50 ml/hour 
• 
If bradycardia or hypotension occurs: 
o Stop infusion, or reduce infusion rate 
o Normal saline bolus of 500 ml IV 
• 
For severe bradycardia:  Atropine 0.5 mg IV push, and may repeat up to a total 
dose of 3 mg.  Epinephrine 2-10 µg/kg/minute can be used if atropine not 
effective 
• 
If fever occurs:  Administer acetaminophen 500-1000 mg PO PRN up to a total 
daily dose of 3 g per 24 hours. 
• 
If hypertension occurs:  Administer clonidine 0.1 mg PO, if BP is persistently > 
180/110 mmHG.  Administer an additional 0.1 mg if no success with the first 
dose. 
 
 


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6.4.6 Monthly/quarterly labs and procedures (all covered by Genzyme)  
• 
CBC with differential  
• 
CD4 counts (optional)  
• 
Serum creatinine level  
• 
Complete urinalysis  
• 
TSH (every 3 months)  
• 
Patient to F/U with physician 3 months, 6 months, and every 6 months thereafter 
(alemtuzumab patient status form to be filled out every 6 months) MS 1:1 will 
remind you every 6 months.  
6.4.7 Annual labs and procedures 
• 
Complete blood count with differential  
• 
Comprehensive metabolic panel, or serum creatinine  
• 
TSH  
• 
Complete urinalysis  
• 
A dermatology assessment is recommended in the alemtuzumab package insert, 
but not absolutely required. 
• 
Appointment with primary MD  
• 
Appointment for gynecological examination and PAP smear for female patients is 
recommended in the alemtuzumab package insert, but not absolutely required. 
6.4.8 Treatment of MS Relapses 
Each relapse will be treated with pulse corticosteroids as per best clinical judgment.  
Two or more confirmed clinical relapses during the trial would allow natalizumab re-initiation as 
rescue therapy or other therapies as per best clinical judgment. Five or more Gd+ lesions at the 
6 month MRI assessment over the baseline assessment will result in a follow-up scan after 60 
days and will count as one relapse. Should a confirmed clinical relapse occur within the 60 day 
period, it will still count as a single relapse.  
6.4.9 Other concomitant treatment 
All the concomitant medications used by participants will be recorded at each study visit on the 
relevant CRFs. The concomitant medications will be analyzed in regard to the use of 
corticosteroids, MS modifying therapies, and anti-inflammatory medications.  
6.4.10 Unexpected adverse event 
An adverse event is considered unexpected when the nature (specificity) or severity of the event 
is not consistent with applicable product information, such as safety information provided in the 


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package insert, the investigational plan, the investigator's brochure, the protocol, or the informed 
consent document.  
6.4.11 Grading of adverse event 
Toxicity grades are assigned by the study site to indicate the severity of adverse events occurring 
in study participants. The principal investigator (PI) has adopted the use of the National Cancer 
Institute's manual Common Terminology Criteria for Adverse Events v3.0 (CTCAE; published June 
10, 2003) for application in adverse event reporting. The purpose of using the CTCAE system is to 
provide a standard language to describe toxicities, to facilitate tabulation and analysis of the data, 
and to facilitate the assessment of the clinical significance of all adverse events. The CTCAE 
provides the following grades and descriptions in the CTCAE manual (v3.0). Adverse events 
should be recorded and graded 1 to 5 according to the CTCAE grades provided below:  
Grade 1 = Mild adverse event  
Grade 2 = Moderate adverse event  
Grade 3 = Severe and undesirable adverse event  
Grade 4 = Life-threatening or disabling adverse event  
Grade 5 = Death  
Note: In contrast to the CTCAE guidelines provided the National Cancer Institute's Common 
Terminology Criteria for Adverse Events v3.0 (published June 10, 2003) all adverse events are to 
be reported and graded whether or not they are related to disease progression or treatment.  
6.4.12 Relationship to study treatment 
The relationship or attribution between an adverse event and an investigational product is 
determined by the site investigator and recorded on the appropriate case report form and/or SAE 
reporting form. The Common Terminology Criteria for Adverse Events (CTCAE) provides the 
following descriptors and definitions (one category classified as unrelated [Code 1] and 4 
categories classified as related [Codes 2-5]) for assigning an attribution to each adverse event   
(for most recent update of terminology see http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_5x7.pdf). 
The investigator's determination of drug-relatedness (attribution) for each adverse event 
should be recorded in the source documentation.  
6.4.13 Serious adverse event reporting 
The following process for reporting a serious adverse event will ensure appropriate compliance 
with the ICH guidelines (http://www.ich.org/products/guidelines/quality/article/quality-
guidelines.html).  
Serious adverse event identification and determination of reporting timeline:  


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When an investigator identifies a serious adverse event (as defined above), he or she must notify 
the principal investigator, the IRB, and Genzyme pharmacovigilance.  In addition to telephone 
reporting, these events must be entered on the Serious Adverse Event Form (MedWatch). 
6.4.14 Study drug discontinuation 
At the initial clinic visit, study patients will be made aware of potential side effects of alemtuzumab. 
At each patient visit, patients will be inquired about any of these side effects. Should it be felt by 
the patient and the examining physician that these side effects warrant discontinuation of study 
drug, the offending therapeutic intervention will be terminated. 
6.4.15 Pregnancy (SAE reporting requirements)  
Any pregnancy that occurs during a clinical study with an investigational drug must be reported as 
an SAE for tracking purposes only. All pregnancies that are identified during this study need to 
be followed to conclusion and the outcome reported. Female participants should immediately 
inform the investigator of pregnancies and future treatment options should be discussed.  
The site investigator should report all pregnancies within 24 hours (as described above in 
SAE Reporting) using the SAE form. The site investigator should counsel the participant and 
discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
Monitoring of the participant should continue until conclusion of the pregnancy, and a follow-up 
SAE reporting form should be submitted detailing the outcome.  
6.4.16 Study completion and post-study treatment 
Outside the scope of this study, the intention is to follow all study participants in participating 
centers long-term, and to record disease activity and treatment response. 
6.4.17 Role of key site personnel 
The treating physician and other designated qualified personnel will see the participant. The 
physician will perform all neurological and non-neurological assessments, and will have access to 
laboratory results.  
6.4.18 Statement of compliance 
This trial will be conducted in compliance with the protocol, current Good Clinical Practice (GCP), 
adopting the principles of the Declaration of Helsinki, and all applicable regulatory requirements.  
Before study initiation, the protocol and the informed consent documents will be reviewed 
and approved by an appropriate ethics review committee or Institutional Review Board (IRB). Any 
amendments to the protocol or consent materials must also be approved before they are 
implemented.  
 


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7 Visit schedule and assessments  
7.1 Study outline 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Month 
Screening   
-1 
Baseline 
-15 
0 - 0.5 
3 
6 
9 
12 
18 
24 
Inclusion/exclusion 
x 
x 
 
  
  
  
  
  
  
Demographic 
information 
x  
 
  
  
  
  
  
  
Informed consent 
x 
 
 
  
  
  
  
  
  
Medical history 
x 
 
 
 
 
 
 
 
 
Concomitant meds 
x 
x 
 
x 
x 
x 
x 
x 
x 
Physical exam  
 x 
 
x 
  
x 
  
  
x 
Vitals 
x 
 
x 
x 
x 
x 
x 
x 
EDSS  
x 
 
  
x  
  
x  
  
x 
Alemtuzumab 
treatment 
(5 consecutive days, 
12 mg/d) 
 
 
x 
 
 
 
x 
 
 
Columbia Suicide 
Severity Rating Scale 
x 
 
 
x 
x 
x 
x 
x 
x 
QoL 
x 
 
 
x 
 
x 
  
x 
Neurological 
examination 
x  
 
x 
x 
x 
x 
  
x 
Blood draw for 
mechanistic studies 
x 
 
x 
x 
x 
x 
  
x 
Laboratory 
assessments for 
safety monitoring* 
x 
x 
 
 
 
 
 
 
 
Pregnancy test 
 
x 
 
  
  
  
  
  
  
OCT  
x 
 
  
x 
 
x 
 
x 
Visual acuity 
x 
 
 
x 
 
x 
 
x 
MRI 
x 
 
x 
  
x 
  
x 
Adverse events 
x 
x 
 
x 
x 
x 
x 
x 
x 
*Laboratory assessments for safety monitoring will be drawn monthly for until 48 months 
after the last dose of alemtuzumab as per REM.  These laboratory assessments include a 
CBC with differential, a serum creatinine, and urine analyses with cell count.  A thyroid 
function test such as a TSH will be obtained at baseline, and every 3 months thereafter. 
 
 


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7.2 Screening 
This research study will be explained in lay language to each potential research participant. The 
participant will sign an informed consent form before undergoing any screening study 
procedures. If the inclusion criteria are met at the screening visit, the participants will be enrolled 
in study. Each participant will be assigned a unique study ID.  
7.3 Patient demographics and baseline characteristics 
Each selected study site has a large population representing diverse age, backgrounds, and 
ethnicity. This study will enroll all patients that meet the inclusion criteria.  
7.4 Treatment exposure and compliance 
The participant will receive treatment at study visits 3 and 7 
 Because study drug is administered IV in the presence of research team members, participant will 
be 100% compliant. 
7.5 Efficacy 
Efficacy will be assessed by clinical evaluation and MRI scanning. Clinical evaluation includes 
neurological examination, and EDSS assessment. Brain MRI will assess T1 lesion load, T2 
number and lesion load, number of Gd+ lesions.  
7.5.1 Definition of a relapse 
A clinical relapse is defined as new neurologic symptoms, lasting at least 24 hours, is 
associated with an increase in the EDSS by ≥ 0.5 points, and consistent with new demyelination. 
Two relapses must be separated by at least 30 days. Due diligence to rule out 
pseudoexacerbations will be up to the PI in each individual case.  
7.5.2 EDSS 
A standard EDSS will be performed at certain study visits (screening or baseline, 6 months , 12 
months, and any relapse visits). This will include both a composite score and subsection score, 
recorded on a CRF. The EDSS is a scale providing a disability score (0 to 10) based on 
neurological examination and information about how the patient is able to perform tasks such 
as long walking. The EDSS may be conducted by a different doctor than the one the patient 
typically sees for treatment of MS. In order to make sure that this EDSS doctor is as objective 
as possible, the patient should not explain to this doctor how he/she is feeling that particular 
day, what symptoms may be bothersome at that time, or what treatment the patient is currently 
receiving for MS (see Appendix 2. 
 
 


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7.5.3 MRI 
All imaging data at UT Southwestern will be acquired on single 1.5 or 3 Tesla MRI unit within 
the Advanced Imaging Research Center (AIRC), located in the Bill and Rita Clements Advanced 
Medical Imaging Building within UT Southwestern Medical Center campus. Study participants at 
the Dallas VA. the Multiple Sclerosis Treatment Center of Dallas, and the Neurology Center of 
San Antonio will be scanned on similar scanners at their sites, using compatible software 
sequences.  All imaging data will be analyzed at the AIRC.  The AIRC, in partnership with other 
North Texas institutions, aims to further research in magnetic resonance imaging and translation 
of discoveries into clinical practice.  
 
7.5.4 Standard MRI protocol performed at all sites 
Standardized MRI studies of the brain will be performed at weeks 0 and 96.  Clinical imaging 
studies of the brain and/or spinal cord performed during or immediately following the onset of a 
clinical exacerbation will be performed at the discretion of the site PI with scan costs covered 
under the medical standard of care.  A clinical MRI of the cervical spinal cord with and without 
contrast will be recommended to study participants at week 0 and week 96 as medical standard 
of care.  The MS specialist with neuro-imaging expertise will be responsible for ensuring that a 
uniform protocol (“Dummy scans”) is implemented at specified sites for the collection of uniform, 
multi-center data for post processing.  In addition, this specialist will evaluate all MRI studies of 
the CNS for interval change (i.e. new and enlarging T2 lesion(s), gadolinium enhancement) 
during follow-up imaging studies and imaging studies acquired during clinical events.  At Year 2, 
changes in T2-lesion volumes, and brain atrophy (SIENA) will be determined. 
 
Standard imaging protocol: 
1.  Scout/Localizers 
Routine T1-weighted axial, coronal, and sagittal scout images will be 
acquired to assess the field of view and head positioning.   
2.  3D T2-Weighted Images  
A 3D T2-weighted imaging sequence will be performed to allow for a 
proper assessment of infratentorial lesions. 
- 1.0 x 1.0 x 1.0 mm3, TE/TR/TI=229/2500/1600, flip angle 90 degrees, 
250 x 250 x 180 FOV, NEX=1, 164 slices, 4:33 duration 
3.  3D Pre-Contrast T1-Weighted Volumetric Gradient Echo Images 
A 3D pre-contrast T1-weighted volumetric gradient echo sequence will be 
performed (anticipated acquisition time: 4-5 minutes) for future volumetric 


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analyses.  The sequence will generate approximately 180 slices with a 
1mm3 voxel size using the corresponding field of view and matrix.      
- 1.0 x 1.0 x 1.0 mm3, TE/TR/TI=3.7/8.1/864, flip angle 12 degrees, 256 x 
220 x 170 FOV, NEX=1, 170 slices, 4:11 duration 
4.  Following Series 3, Gadavist (0.1mmol/kg at a rate of 2cc/second) will be 
administered. 
5.  3D Fluid Attenuated Inversion Recovery (FLAIR) Images 
A 3D FLAIR sequence will be performed that will enable full appreciation 
of the brain surface.  The acquisition will be performed in sagittal or axial 
plane.  The anticipated acquisition time is 5 minutes. 
- 1.1 x 1.1 x 1.1 mm3, TE/TR/TI=350/4800/1600, flip angle 90 degrees, 
250 x 250 x 180 FOV, NEX=1, 163 slices, 5:02 duration 
6.  Post-Contrast 3D T1-Weighted Volumetric Gradient Echo Images 
A post-contrast 3D T1-weighted volumetric gradient echo image will be 
performed following Series 5 which will allow for at least 5 minutes to 
elapse prior to the acquisition of the post-contrast images to assess for 
blood brain barrier breakdown.  The expected acquisition time is 4-5 
minutes.   
7.5.5 OCT 
The OCT tests measure peripapillary RNFL thickness using the Spectralis OCT device 
(Heidelberg Engineering), the Cirrus OCT device (Carl Zeiss Meditec) or comparable devices.  
All scans will be performed by the same experienced operator.  An internal fixation target will be 
used because it provides the highest reproducibility. 
All participants will undergo testing using the RNFL image acquisition protocols on either 
Spectralis OCT (RNFL Circle Scan), the Cirrus OCT (200 x 200 ONH Scan), or a comparable 
device on each eye.  In addition, ganglion cell layer (GCL), and inner plexiform layer (IPL) will 
be assessed by measuring their combined thickness in a 4.8 × 4.0 mm oval with a longer 
horizontal axis.  Each patient will be longitudinally assessed on the same machine.  The 
database name should be de-identified with the study assigned identifier.  The default printing 
protocol will be used to print out the RNFL report on both eyes. 
RNFL protocols on the Spectralis OCT, the Cirrus OCT, or comparable devices generate 
a thickness map with mean thickness, thickness of the four quadrants (superior, nasal, inferior, 
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There are potential risks associated with OCT.  All of the proposed procedures are 
validated, safe, and standard assessments that are utilized in the clinical practice of neurology 
or ophthalmology.  In a limited number of participants, testing may require dilation of the eyes 
prior to assessment using standard ophthalmic solution if the data capture is not possible 
without dilating their eyes.  This may cause minimal discomfort to the participant.  Vision may 
become more sensitive to sunlight, the drops may cause a slight stinging sensation upon 
administration, and vision may be blurry for up to four hours after initial dilation. 
7.5.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is used extensively across primary care, clinical practice, surveillance, research, 
and institutional settings. It is a suicidal ideation rating scale to evaluate suicidality in ages 12 
and up. It rates an individual's degree of suicidal ideation on a scale, ranging from "wish to be 
dead" to "active suicidal ideation with specific plan and intent." This will be administered by 
research staff. See Appendix 3. 
 
7.5.7 Professional Quality of Life Scale (ProQOL) 
This is a self-administered assessment of quality of life. It measures the pleasure one derives from 
being able to do their work well, feelings of hopelessness and difficulties in dealing with work or 
in doing their job effectively, and work-related, secondary exposure to extremely stressful 
events. See Appendix 4. 
 
 
 
 


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7.5.8 Blood Draw for Mechanistic Studies  
Blood will be collected at each time point to assess the immune-modulating effects of the trial. 
Blood will be collected at the study sites, in Cyto-Chex BCT tubes for flow Cytometry, ACD 
tubes for isolation of PBMC’s and SST tube to collect serum. and shipped to the PI’s laboratory 
at UT Southwestern by FedEx express overnight.  Samples collected at UT Southwestern will 
be picked up in the clinic. 
 
8 Data Analysis 
The sample size of 40 patients was chosen to obtain a result that would be seen as meaningful 
by neurologists.  Disease activity is expected to be extremely low on natalizumab and 
subsequently on alemtuzumab.  Thus, it will be impossible to power a superiority or non-
inferiority study. 
All outcome measures will be assessed in the 12 months prior to natalizumab, on 
natalizumab, and on alemtuzumab.  We will control secondary endpoints for multiple 
comparisons by testing sequentially the proportion of relapse-free patients, EDSS change, and 
T2-hyperintense lesion volume change. 
The analysis of the acquired standardized imaging data will include a qualitative 
assessment of structural features suggestive of progressive multi-focal leukoencephalopathy 
(PML), T2-weighted lesion volumes, T1-weighted lesion volumes, a determination of new or 
enlarging T2 foci, the presence of acute blood brain barrier compromise and number of 
identified contrast enhanced lesions, and an assessment of brain volumetric changes by SIENA 
between the baseline and year 2 MRI study. 
We will analyse the proportion of patients who are relapse-free with a proportional 
hazards model.  We will analyse changes from baseline in EDSS at the pre-defined time points 
with a mixed model for repeated measures.  We will make treatment comparisons of all 
available 3 month assessments with a non-parametric test for repeated measures.  We will 
analyze changes in T2-hyperintense lesion volume, and RNFL thickness with a ranked 
ANCOVA model.  We will analyse proportions of patients with new or enlarging T2-hyperintense 
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9 Reference List 
1. 
Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, 
Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW. 2006. 
Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N.Engl.J.Med. 354: 
911-23 
2. 
Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, 
Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW. 2006. A 
randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. 
N.Engl.J.Med. 354: 899-910 
3. 
Stuve O, Marra CM, Bar-Or A, Niino M, Cravens PD, Cepok S, Frohman EM, Phillips JT, 
Arendt G, Jerome KR, Cook L, Grand'Maison F, Hemmer B, Monson NL, Racke MK. 
2006. Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated 
patients with multiple sclerosis. Arch.Neurol. 63: 1383-7 
4. 
Stuve O, Marra CM, Jerome KR, Cook L, Cravens PD, Cepok S, Frohman EM, Phillips 
JT, Arendt G, Hemmer B, Monson NL, Racke MK. 2006. Immune surveillance in multiple 
sclerosis patients treated with natalizumab. Ann.Neurol. 59: 743-7 
5. 
Stuve O, Cravens PD, Frohman EM, Phillips JT, Remington GM, von GG, Cepok S, 
Singh MP, Cohen Tervaert JW, De BM, MacManus D, Miller DH, Radu EW, Cameron 
EM, Monson NL, Zhang S, Kim R, Hemmer B, Racke MK. 2009. Immunologic, clinical, 
and radiologic status 14 months after cessation of natalizumab therapy. Neurology 72: 
396-401 
6. 
Kowarik MC, Pellkofer HL, Cepok S, Korn T, Kumpfel T, Buck D, Hohlfeld R, Berthele A, 
Hemmer B. 2011. Differential effects of fingolimod (FTY720) on immune cells in the CSF 
and blood of patients with MS. Neurology 76: 1214-21 
7. 
del Pilar MM, Cravens PD, Winger R, Frohman EM, Racke MK, Eagar TN, Zamvil SS, 
Weber MS, Hemmer B, Karandikar NJ, Kleinschmidt-Demasters BK, Stuve O. 2008. 
Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular 
spaces due to natalizumab. Arch.Neurol. 65: 1596-603 
8. 
Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee 
S, Plavina T, Scanlon JV, Sandrock A, Bozic C. 2012. Risk of natalizumab-associated 
progressive multifocal leukoencephalopathy. N Engl J Med 366: 1870-80 
9. 
Berger JR, Fox RJ. 2016. Reassessing the risk of natalizumab-associated PML. J 
Neurovirol  
10. 
Berger JR, Fox RJ. 2016. Erratum to: Reassessing the risk of natalizumab-associated 
PML. J Neurovirol  
11. 
O'Connor PW, Goodman A, Kappos L, Lublin FD, Miller DH, Polman C, Rudick RA, 
Aschenbach W, Lucas N. 2011. Disease activity return during natalizumab treatment 
interruption in patients with multiple sclerosis. Neurology 76: 1858-65 
12. 
Krumbholz M, Meinl I, Kumpfel T, Hohlfeld R, Meinl E. 2008. Natalizumab 
disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 
71: 1350-4 
13. 
Kivisakk P, Healy BC, Viglietta V, Quintana FJ, Hootstein MA, Weiner HL, Khoury SJ. 
2009. Natalizumab treatment is associated with peripheral sequestration of 
proinflammatory T cells. Neurology 72: 1922-30 
14. 
Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, 
Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake 
SL, Margolin DH, Panzara MA, Compston DA. 2012. Alemtuzumab versus interferon 
beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a 
randomised controlled phase 3 trial. Lancet 380: 1819-28 


Sequential natalizumab – alemtuzumab therapy trial 
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15. 
Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, 
Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin 
DH, Oyuela P, Panzara MA, Compston DA. 2012. Alemtuzumab for patients with 
relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled 
phase 3 trial. Lancet 380: 1829-39 
16. 
Hale G, Rye PD, Warford A, Lauder I, Brito-Babapulle A. 1993. The 
glycosylphosphatidylinositol-anchored lymphocyte antigen CDw52 is associated with the 
epididymal maturation of human spermatozoa. J Reprod Immunol 23: 189-205 
17. 
Xia MQ, Tone M, Packman L, Hale G, Waldmann H. 1991. Characterization of the 
CAMPATH-1 (CDw52) antigen: biochemical analysis and cDNA cloning reveal an 
unusually small peptide backbone. Eur J Immunol 21: 1677-84 
18. 
Rowan WC, Hale G, Tite JP, Brett SJ. 1995. Cross-linking of the CAMPATH-1 antigen 
(CD52) triggers activation of normal human T lymphocytes. Int Immunol 7: 69-77 
19. 
Hederer RA, Guntermann C, Miller N, Nagy P, Szollosi J, Damjanovich S, Hale G, 
Alexander DR. 2000. The CD45 tyrosine phosphatase regulates Campath-1H (CD52)-
induced TCR-dependent signal transduction in human T cells. Int Immunol 12: 505-16 
20. 
Stauch D, Dernier A, Sarmiento Marchese E, Kunert K, Volk HD, Pratschke J, Kotsch K. 
2009. Targeting of natural killer cells by rabbit antithymocyte globulin and campath-1H: 
similar effects independent of specificity. PLoS One 4: e4709 
21. 
Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G, 
Waldmann H, Compston DA. 2006. The window of therapeutic opportunity in multiple 
sclerosis: evidence from monoclonal antibody therapy. J Neurol 253: 98-108 
22. 
Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran S, Margolin DH, Norris K, Tandon 
PK. 2008. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N.Engl.J.Med. 
359: 1786-801 
23. 
Hu Y, Turner MJ, Shields J, Gale MS, Hutto E, Roberts BL, Siders WM, Kaplan JM. 
2009. Investigation of the mechanism of action of alemtuzumab in a human CD52 
transgenic mouse model. Immunology 128: 260-70 
24. 
Bologna L, Gotti E, Manganini M, Rambaldi A, Intermesoli T, Introna M, Golay J. 2011. 
Mechanism of action of type II, glycoengineered, anti-CD20 monoclonal antibody GA101 
in B-chronic lymphocytic leukemia whole blood assays in comparison with rituximab and 
alemtuzumab. J Immunol 186: 3762-9 
25. 
Hill-Cawthorne GA, Button T, Tuohy O, Jones JL, May K, Somerfield J, Green A, 
Giovannoni G, Compston DA, Fahey MT, Coles AJ. 2012. Long term lymphocyte 
reconstitution after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg 
Psychiatry 83: 298-304 
26. 
Cossburn MD, Harding K, Ingram G, El-Shanawany T, Heaps A, Pickersgill TP, Jolles S, 
Robertson NP. 2013. Clinical relevance of differential lymphocyte recovery after 
alemtuzumab therapy for multiple sclerosis. Neurology 80: 55-61 
27. 
Coles AJ, Fox E, Vladic A, Gazda SK, Brinar V, Selmaj KW, Skoromets A, Stolyarov I, 
Bass A, Sullivan H, Margolin DH, Lake SL, Moran S, Palmer J, Smith MS, Compston 
DA. 2012. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of 
CAMMS223 clinical trial. Neurology 78: 1069-78 
 
 
 


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Appendix 1. Lemtrada REMS Program Prescriber Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2. Expanded Disability Status Scale (EDSS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3. Components of the CSSRS will be performed at months 0, 3, 6, 9, 
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COLUMBIA-SUICIDE SEVERITY RATING SCALE  
Screen Version - Recent  
SUICIDE IDEATION DEFINITIONS AND PROMPTS 
Past 
month 
Ask questions that are bolded and underlined.   
YES NO 
Ask Questions 1 and 2   
1)  Wish to be Dead:  
Person endorses thoughts about a wish to be dead or not alive anymore, or 
wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep and 
not wake up?  
 
 
2)  Suicidal Thoughts:  
General non-specific thoughts of wanting to end one’s life/commit suicide, 
“I’ve thought about killing myself” without general thoughts of ways to kill 
oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself?  
 
 
If YES to 2, ask questions 3, 4, 5, and 6.  If NO to 2, go directly to question 6. 


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SUICIDE IDEATION DEFINITIONS AND PROMPTS 
Past 
month 
Ask questions that are bolded and underlined.   
YES NO 
3)  Suicidal Thoughts with Method (without Specific Plan or Intent to 
Act):  
Person endorses thoughts of suicide and has thought of a least one method 
during the assessment period. This is different than a specific plan with time, 
place or method details worked out. “I thought about taking an overdose but 
I never made a specific plan as to when where or how I would actually do 
it….and I would never go through with it.”  
Have you been thinking about how you might do this?  
 
 
4)  Suicidal Intent (without Specific Plan):  
Active suicidal thoughts of killing oneself and patient reports having some 
intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.”  
Have you had these thoughts and had some intention of acting on 
them?  
 
 
5)  Suicide Intent with Specific Plan:  
Thoughts of killing oneself with details of plan fully or partially worked out 
and person has some intent to carry it out.  
Have you started to work out or worked out the details of how to kill 
yourself? Do you intend to carry out this plan?  
 
 
 
6)  Suicide Behavior Question:  
YES NO 


S e q u e nti al n at ali z u m a b –  al e mt u z u m a b t h er a p y tri al  
C o nfi d e nti al V er si o n 1. 0  
8 0  
 
S T U 1 1 2 0 1 6 -0 6 0, St u v e, F or m A, M o d _ 1 0, 0 6 -1 4 -1 9 ( 1)  
 
 8 0  
 
H a v e y o u e v er d o n e a n yt hi n g, st art e d t o d o a n yt hi n g, or pr e p ar e d t o 
H a v e y o u e v er d o n e a n yt hi n g, st art e d t o d o a n yt hi n g, or pr e p ar e d t o 
d o a n yt hi n g t o e n d y o ur lif e ?
d o a n yt hi n g t o e n d y o ur lif e ?  
E x a m pl es: C oll e ct e d pills, o bt ai n e d a g u n, g a v e a w a y v al u a bl es, wr ot e a will 
or s ui ci d e n ot e, t o o k o ut pills b ut di d n’t s w all o w  a n y, h el d a g u n b ut c h a n g e d 
y o ur mi n d or it w as gr a b b e d fr o m y o ur h a n d, w e nt t o t h e r o of b ut di d n’t 
j u m p; or a ct u all y t o o k pills, tri e d t o s h o ot y o urs elf, c ut y o urs elf, tri e d t o h a n g 
y o urs elf, et c.  
If Y E S, a s k: H o w 
H o w l o n g a g o di d y o u d o a n y of t h e s e ?
l o n g a g o di d y o u d o a n y of t h e s e ?  
   O v er a y e ar a g o     B et w e e n t hr e e m o nt h s a n d a y e ar a g o    Wit hi n t h e 
l ast t hr e e m o nt hs  
 
 
 
 
 
 


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COLUMBIA-SUICIDE SEVERITY RATING SCALE  
Screening Version – Since Last Visit 
SUICIDE IDEATION DEFINITIONS AND PROMPTS 
Since Last 
Visit 
Ask questions that are bold and underlined  
YES 
NO 
Ask Questions 1 and 2 
1) Wish to be Dead:  
Person endorses thoughts about a wish to be dead or not alive anymore, 
or wish to fall asleep and not wake up. 
Have you wished you were dead or wished you could go to sleep 
and not w ake up? 
 
 
2) Suicidal Thoughts:  
General non-specific thoughts of wanting to end one’s life/die by suicide, 
“I’ve thought about killing myself” without general thoughts of ways to kill 
oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself?  
 
 
If YES to 2, ask questions 3, 4, 5, and 6.  If NO to 2, go directly to question 6 
3) Suicidal Thoughts with Method (without Specific Plan or Intent to 
Act):  
Person endorses thoughts of suicide and has thought of a least one 
method during the assessment period. This is different than a specific plan 
with time, place or method details worked out. “I thought about taking an 
overdose but I never made a specific plan as to when where or how I 
would actually do it….and I would never go through with it.”  
Have you been thinking about how you might do this?  
 
 


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SUICIDE IDEATION DEFINITIONS AND PROMPTS 
Since Last 
Visit 
Ask questions that are bold and underlined  
YES 
NO 
4) Suicidal Intent (without Specific Plan):  
Active suicidal thoughts of killing oneself and patient reports having some 
intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.”  
Have you had these thoughts and had some intention of acting on 
them?  
 
 
5) Suicide Intent with Specific Plan:  
Thoughts of killing oneself with details of plan fully or partially worked out 
and person has some intent to carry it out.  
Have you started to work out or worked out the details of how to 
kill yourself and do you intend to carry out this plan?  
 
 
6) Suicide Behavior 
 
Have you done anything, started to do anything, or prepared to do 
anything to end your life? 
 
Examples: Collected pills, obtained a gun, gave away valuables, wrote a 
will or suicide note, took out pills but didn’t swallow any, held a gun but 
changed your mind or it was grabbed from your hand, went to the roof but 
didn’t jump; or actually took pills, tried to shoot yourself, cut yourself, tried 
to hang yourself, etc. 
 
 
 
 


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COLUMBIA-SUICIDE SEVERITY RATING SCALE (C-SSRS)  
Posner, Brent, Lucas, Gould, Stanley, Brown, Fisher, Zelazny, Burke, Oquendo, & Mann 
© 2008 The Research Foundation for Mental Hygiene, Inc. 
RISK ASSESSMENT 
Instructions: Check all risk and protective factors that apply. To be completed following the patient interview, 
review of medical record(s) and/or consultation with family members and/or other professionals. 
 
Past 3 
Months 
Suicidal and Self-Injurious 
Behavior 
Lifetime 
Clinical Status (Recent) 
 
Actual suicide attempt
 
  
 Lifetime 
 
 
Hopelessness 
 
Interrupted attempt
 
  
 Lifetime 
 
 
Major depressive episode 
 
Aborted or Self-Interrupted attempt
 
  
 Lifetime 
 
 
Mixed affective episode (e.g. Bipolar) 
 
Other preparatory acts to kill self
 
  
 Lifetime 
 
 
Command hallucinations to hurt self 
 
Self-injurious behavior without 
suicidal intent           
 
 
Highly impulsive behavior 
Suicidal Ideation 
Check Most Severe in Past Month 
 
Substance abuse or dependence 
 
Wish to be dead 
 
Agitation or severe anxiety 
 
Suicidal thoughts 
 
Perceived burden on family or others 
 
Suicidal thoughts with method  
(but without specific plan or intent to act) 
 
Chronic physical pain or other acute medical  
problem (HIV/AIDS, COPD, cancer, etc.) 


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Suicidal intent (without specific plan) 
 
Homicidal ideation  
 
Suicidal intent with specific plan 
 
Aggressive behavior towards others 
Activating Events (Recent) 
 
Method for suicide available (gun, pills, etc.) 
 
 
Recent loss(es) or other significant negative 
event(s) (legal, financial, relationship, etc.) 
 
Refuses or feels unable to agree to safety plan 
Describe: 
 
Sexual abuse (lifetime) 
 
Family history of suicide (lifetime) 
 
 
Pending incarceration or homelessness 
Protective Factors (Recent) 
 
 
Current or pending isolation or feeling alone 
 
Identifies reasons for living 
Treatment History 
 
Responsibility to family or others; living with 
family 
 
 
Previous psychiatric diagnoses and treatments 
 
Supportive social network or family 
 
 
Hopeless or dissatisfied with treatment  
 
Fear of death or dying due to pain and suffering 
 
 
Non-compliant with treatment  
 
Belief that suicide is immoral; high spirituality 
 
 
Not receiving treatment 
 
Engaged in work or school 
Other Risk Factors 
Other Protective Factors 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Describe any suicidal, self-injurious or aggressive behavior (include dates) 
 
 
 
 


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COLUMBIA-SUICIDE SEVERITY RATING SCALE 
Psychiatric Inpatient Setting – Discharge Screener 
Ask questions that are bold and underlined 
Discharge 
Ask Questions 1 and 2 
YES 
NO 
3) Wish to be Dead:  
Person endorses thoughts about a wish to be dead or not alive anymore, or 
wish to fall asleep and not wake up. 
While you were here in the hospital, have you wished you were dead 
or wished you could go to sleep and not wake up? 
 
 
4) Suicidal Thoughts:  
General non-specific thoughts of wanting to end one’s life/die by suicide, “I’ve 
thought about killing myself” without general thoughts of ways to kill 
oneself/associated methods, intent, or plan.  
While you were here in the hospital, have you actually had thoughts 
about killing yourself?  
 
 
If YES to 2, ask questions 3, 4, 5, and 6.  If NO to 2, go directly to question 6 
3) Suicidal Thoughts with Method (without Specific Plan or Intent to 
Act):  
Person endorses thoughts of suicide and has thought of a least one method 
during the assessment period. This is different than a specific plan with time, 
place or method details worked out. “I thought about taking an overdose but I 
never made a specific plan as to when where or how I would actually do 
it….and I would never go through with it.”  
Have you been thinking about how you might kill yourself?  
 
 


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Ask questions that are bold and underlined 
Discharge 
Ask Questions 1 and 2 
YES 
NO 
4) Suicidal Intent (without Specific Plan):  
Active suicidal thoughts of killing oneself and patient reports having some 
intent to act on such thoughts, as opposed to “I have the thoughts but I 
definitely will not do anything about them.”  
Have you had these thoughts and had some intention of acting on 
them or do you have some intention of acting on them after you 
leave the hospital?  
 
 
5) Suicide Intent with Specific Plan:  
Thoughts of killing oneself with details of plan fully or partially worked out and 
person has some intent to carry it out.  
Have you started to work out or worked out the details of how to kill 
yourself either for w hile you were here in the hospital or for after 
you leave the hospital? Do you intend to carry out this plan?  
 
 
6) Suicide Behavior 
 
While you were here in the hospital, have you done anything, started 
to do anything, or prepared to do anything to end your life? 
 
Examples: Took pills, cut yourself, tried to hang yourself, took out pills but 
didn’t swallow any because you changed your mind or someone took them 
from you, collected pills, secured a means of obtaining a gun, gave away 
valuables, wrote a will or suicide note, etc. 
 
 
 
 
 


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COLUMBIA-SUICIDE SEVERITY RATING SCALE 
Daily/ Shift Screen 
Ask questions that are bold and underlined 
Since Last 
Asked 
Ask Question 2* 
YES 
NO 
5) Suicidal Thoughts:  
 
Since you were last asked, have you actually had thoughts about 
killing yourself?  
 
 
If YES to 2, ask questions 3, 4, 5, and 6.  If NO to 2, go directly to question 6 
3) Suicidal Thoughts with Method (without Specific Plan or Intent to 
Act):  
 
Have you been thinking about how you might do this?  
 
 
4) Suicidal Intent (without Specific Plan):  
 
Have you had these thoughts and had some intention of acting on 
them?  
 
 
5) Suicide Intent with Specific Plan:  
 
Have you started to work out or worked out the details of how to kill 
yourself? Do you intend to carry out this plan?  
 
 


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Ask questions that are bold and underlined 
Since Last 
Asked 
Ask Question 2* 
YES 
NO 
6) Suicide Behavior 
 
Have you done anything, started to do anything, or prepared to do 
anything to end your life? 
 
Examples: Collected pills, obtained a gun, gave away valuables, wrote a will or 
suicide note, took out pills but didn’t swallow any, held a gun but changed 
your mind or it was grabbed from your hand, went to the roof but didn’t jump; 
or actually took pills, tried to shoot yourself, cut yourself, tried to hang 
yourself, etc. 
If YES, what did you 
do?____________________________________________ 
______________________________________________________
_________ 
 
 
 
* Note – for frequent assessment purposes, Question 1 has been omitted  
 
 


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COLUMBIA-SUICIDE SEVERITY RATING SCALE 
Screener/ Recent – Self-Report 
 
In The Past Month 
Answer Questions 1 and 2 
YES 
NO 
1) Have you wished you were dead or wished you could go to 
sleep and not wake up? 
 
 
2) Have you actually had any thoughts about killing yourself?  
 
 
If YES to 2, answer questions 3, 4, 5, and 6.  If NO to 2, go directly to question 6 
3) Have you thought about how you might do this?  
 
 
4) Have you had any intention of acting on these thoughts of 
killing yourself, as opposed to you have the thoughts but you 
definitely would not act on them?  
 
 
5) Have you started to work out or worked out the details of how 
to kill yourself?  
Do you intend to carry out this plan?  
 
 
 
In the Past 3 
Months 
6) Have you done anything, started to do anything, or prepared to 
do anything to end your life? 
 
 
 


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In The Past Month 
Examples: Collected pills, obtained a gun, gave away valuables, wrote a 
will or suicide note, took out pills but didn’t swallow any, held a gun but 
changed your mind or it was grabbed from your hand, went to the roof 
but didn’t jump; or actually took pills, tried to shoot yourself, cut 
yourself, tried to hang yourself, etc. 
 
In your entire lifetime, how many times have you done any of 
these things? 
 
 
 
COLUMBIA-SUICIDE SEVERITY RATING SCALE 
Screener/ Since Last Contact – Self-Report 
 
Since Last 
Contact 
Answer Questions 1 and 2 
YES 
NO 
3) Have you wished you were dead or wished you could go to 
sleep and not wake up? 
 
 
4) Have you actually had any thoughts about killing yourself?  
 
 
If YES to 2, answer questions 3, 4, 5, and 6.  If NO to 2, go directly to question 6 
3) Have you thought about how you might do this?  
 
 
4) Have you had any intention of acting on these thoughts of 
killing yourself, as opposed to you have the thoughts but you 
definitely would not act on them?  
 
 


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Since Last 
Contact 
5) Have you started to work out or worked out the details of how 
to kill yourself?  
Do you intend to carry out this plan?  
 
 
6) Have you done anything, started to do anything, or prepared to 
do anything to end your life? 
 
Examples: Collected pills, obtained a gun, gave away valuables, wrote a 
will or suicide note, took out pills but didn’t swallow any, held a gun but 
changed your mind or it was grabbed from your hand, went to the roof 
but didn’t jump; or actually took pills, tried to shoot yourself, cut 
yourself, tried to hang yourself, etc. 
 
If YES, How many times have you done any of these things? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4. Professional Quality of Life Scale (ProQOL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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