- Trials closed
Keratinocyte Growth Factor - promoting thymic reconstitution and preventing autoimmunity after alemtuzumab (Campath-1H) treatment of multiple sclerosis.
Multiple sclerosis is an autoimmune disease of the central nervous system in which focal lymphocytic infiltration leads to damage of myelin and axons. Initially, inflammation is transient and remyelination occurs, hence early in the disease patients typically experience episodes of neurological dysfunction from which they recover. With time neurodegeneration dominates the pathology, and patients enter a secondary progressive phase of the disease in which they slowly and relentlessly accumulate disability. Multiple sclerosis is the most common cause of disability in young adults in the western world. In the United Kingdom alone 100,000 people are affected, with 50 new cases being diagnosed each week. The cause of multiple sclerosis is not known, but it is believed to involve the interplay of genetic susceptibility with yet unknown environmental triggers.
By promoting thymic reconstitution and suppressing peripheral T-cell expansion, we hypothesise that palifermin will significantly reduce the risk of autoimmunity after alemtuzumab. If this trial is successful, the immediate beneficiaries will be patients with relapsing-remitting multiple sclerosis considering treatment with alemtuzumab: access to the profound efficacy of alemtuzumab will be maximised if its safety profile can be optimised. In addition, this work tests a general strategy for promoting thymic reconstitution in man so has wider implications; for example in reducing morbidity and mortality due to opportunistic infections caused by protracted T-cell lymphopenia following chemotherapy and transplant conditioning regimes.
Animal studies of the trial hypothesis are not possible, because there is no animal model of alemtuzumab-induced autoimmunity. A human-CD52 transgenic mouse exists, and alemtuzumab treatment leads to lymphocyte depletion and reconstitution similar to that observed in treated patients (Hu et al., 2009). However, for reasons which are not clear, these animals do not develop autoimmunity after alemtuzumab.
Our trial is designed to select patients with aggressive multiple sclerosis who would have qualified for treatment on the phase 3 studies, and therefore are the type of patients likely to be offered alemtuzumab once it is licensed for the treatment of MS. Our intervention, palifermin, is licensed for prophylaxis against severe mucositis induced by chemotherapy for haematological malignancies and is well tolerated. This is a randomised, double-blind study of palifermin (Kepivance®) given at the maximum tolerated dose (see Section 10.1) vs. placebo in the prevention of autoimmunity following alemtuzumab treatment of multiple sclerosis.
Main inclusion criteria
To be included in the trial the patient must have/be:
- Male or non-pregnant, non-lactating female patients.
- Aged between 18 and 50 years inclusive.
- Diagnosis of MS using McDonald’s criteria, including diagnostic MRI.
- Onset of first MS symptoms within 10 years.
- EDSS score 0.0 to 5.0 (inclusive) at screening.
- At least 2 clinical episodes of MS in the 2 years prior to signing of the ICF, with at least 1 attack within 12 months, which may have occurred whilst on disease-modifying therapy, namely any type of beta interferon therapy or glatiramer acetate (1 month washout period to be observed).
- Serum IL-21 ≤230pg/mL.
The details of patient selection are identical to those adopted in the phase 3 trials of alemtuzumab (CARE MS1 and MS2). This ensures that the results of this trial can be generalised to these patient groups.
Main exclusion criteria
The presence of any of the following will preclude patient inclusion:
- Any progressive form of multiple sclerosis.
- Previous thymectomy.
- Previous treatment with alemtuzumab, mitoxantrone, cyclophosphomide, cladribine, rituximab or any other immunosuppressant or cytotoxic therapy (other than steroids).
- 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. Reliable and effective contraceptive method(s) include intrauterine device (IUD), hormonal based contraception, surgical sterilisation, abstinence, or double barrier contraception i.e. condom and occlusive cap (diaphragm or cervical cap with spermicide).
- 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.