Multiple Sclerosis
Conditions
Keywords
Alemtuzumab, Palifermin, Reconstitution, Thymus
Brief summary
The purpose of this study is to test a novel strategy to prevent the clinical problem of secondary autoimmunity following alemtuzumab treatment of multiple sclerosis. The hypothesis is that autoimmunity after alemtuzumab can be prevented by giving a drug that promotes thymic T cell regeneration (Palifermin, Kepivance®).
Detailed description
This is a single-centre, double-blinded, randomised controlled trial of palifermin (Kepivance) vs. placebo in the prevention of autoimmunity following alemtuzumab treatment of multiple sclerosis. The dose of palifermin (kepivance)used in this trial will be informed by a dose-escalation study.
Interventions
DRUGPalifermin
Palifermin (Kepivance®) administered by intravenous bolus on days -5, -4. -3 prior to, and on days 8, 9 and 10 after each cycle of alemtuzumab, then again on 3 consecutive days at month 1 and month 3 after each cycle of alemtuzumab. Patients will be observed for adverse reactions for at least 1 to 2 hours following each bolus dose.
DRUGAlemtuzumab
Initial treatment alemtuzumab will be administered as a fixed total dose of 60 mg IV over 5 consecutive days (12mg/day). For re-treatment at Month 12, alemtuzumab will be administered as a fixed total dose of 36mg IV over 3 consecutive days (12mg/day).
Sponsors
Cambridge University Hospitals NHS Foundation Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Months to 50 Years
Healthy volunteers
No
Inclusion criteria
* Male or non-pregnant, non-lactating female patients * \> 18 years of age, and \<50 years of age inclusive * Diagnosis of MS using McDonald's 2010 criteria, including MRI abnormalities consistent with McDonald's 2010 criteria. * Onset of first MS symptoms within 10 years on the date the ICF is signed * EDSS score 0.0 to 5.0 (inclusive) at screening * At least 2 clinical episodes of MS in the 2 years prior to study entry, with at least 1 attack within 12 months, which may have occurred whilst on disease-modifying therapy, namely any beta interferon or glatiramer acetate. * Serum IL-7≤7pg/mL
Exclusion criteria
* Any progressive form of multiple sclerosis * Previous thymectomy * Previous treatment with alemtuzumab, natalizumab, mitoxantrone, cyclophosphomide, cladribine, rituximab or any other immunosuppressant or cytotoxic therapy (other than steroids and disease-modifying therapies listed above) * History of malignancy * Personal history of clinically significant autoimmune disease, other than multiple sclerosis (including but not limited to: thyroid disease, immune cytopenias, inflammatory bowel disease, diabetes, lupus, severe asthma) * Intolerance of pulsed corticosteroids, especially a history of steroid psychosis * Major systemic disease or other illness that would, in the opinion of the investigator, compromise patient safety or interfere with the interpretation of study results. * Seropositivity for human immunodeficiency virus (HIV) * Past or present hepatitis B infection (positive hepatitis B serology) * Pregnant women or male and female patients who do not agree to use effective contraception during the study. * Medical, psychiatric, cognitive or other conditions that, in the investigator's opinion, compromise the patient's ability to understand the patient information, to give informed consent, to comply with the trial protocol, or to complete the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| incidence of clinical autoimmunity | within 30 months of starting treatment with alemtuzumab | The primary endpoint is incidence of clinical autoimmunity within 30 months of starting treatment with alemtuzumab |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute numbers of naive T cells | within 30 months of starting treatment with alemtuzumab | Absolute numbers of naive T cells |
| Safety events | within 30 months of starting treatment with alemtuzumab | Safety outcomes - incidence and nature of adverse events |
Other
| Measure | Time frame | Description |
|---|---|---|
| T cell receptor (TCR) clonality | within 30 months of starting treatment with alemtuzumab | T cell receptor (TCR) clonality |
| Thymic function | within 30 months of starting treatment with alemtuzumab | Thymic function - determined by measuring TRECs |
| Thymic density | within 30 months of starting treatment with alemtuzumab | Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6. |
| Thymic volume | within 30 months of starting treatment with alemtuzumab | Thymic volume and density - as assessed by non-contrast enhanced, low dose CT scans of the chest performed at baseline and month 6. |
| Time at which autoimmunity develops | Within 30 months after alemtuzumab | — |
| Reconstitution of lymphocyte subsets | within 30 months of starting treatment with alemtuzumab | Percentage of naive, central memory, effector memory and effector memory RA cells within the CD4 and CD8 T cell populations |
Countries
United Kingdom
Outcome results
None listed