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23 March 2010
Oral cladribine, given as one of two cumulative doses (either 3.5mg or 5.25mg/kg) in short courses, was more effective at preventing relapse than placebo in the 96 week CLARITY trial of patients (n=1326) with relapsing-remitting multiple sclerosis (RRMS). Cladribine was associated with lymphocytopenia and infections, such as herpes zoster.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
An oral formulation of cladribine is in licensing currently and, if it receives marketing authorisation, it and fingolimod could be the first oral disease-modifying drugs for multiple sclerosis (MS). NICE has recently started appraising the evidence for cladribine for this indication but the date of publication for this single technology appraisal is not yet known. The publication of this study along with those for oral fingolimod has attracted much interest from patients and clinicians. Therefore local decision making bodies may wish to plan ahead with stakeholders for the introduction of these therapies.
What is the background to this?
MS is characterised by periods of relapse and remission but some patients have a single episode and others a progressive form of the disease. The exact prevalence is unknown, but it has been estimated that 85,000 people in the UK currently have MS, with 2500 new cases diagnosed each year. RRMS accounts for approximately 40% of all MS cases, which equates to roughly 34,000 people in the UK. Information on the management of MS can be found on the NICE website. The clinical guideline is due for review and a single technology appraisal on the use of cladribine in RMMS is planned.
Amendment February 2011– The European licence application for cladribine was withdrawn by the manufacturer on 17th February 2011 after the Committee for Medicinal Products for Human Use (CHMP) had adopted a negative opinion, recommending refusal of the Market Authorisation. Fingolimod was given a Positive Opinion in January 2011.
Cladribine is an immunomodulator which selectively targets lymphocyte subtypes. It was submitted to the European Medicines Agency in 2009 and as it is an oral preparation there is likely to be much patient interest if it should receive a licence. Another oral therapy, fingolimod, is also in development and data from two trials of that medicine in development are the subject of a recent NPC On the Horizon Rapid Review.
What does this study claim?
Short courses of oral cladribine at cumulative doses of 3.5mg/kg and 5.25mg/kg reduced the annualised relapse rate (ARR) compared to placebo at 96 weeks. The ARR was 0.14 (95% confidence interval [CI] 0.12 to 0.17), 0.15 (0.12 to 0.17) and 0.33 (0.29 to 0.38), respectively (P<0.001 for both doses vs. placebo).
A key secondary efficacy outcome was the time to sustained progression of disability confirmed after a three-month period within the 96 weeks. The risk was lower for the cladribine groups: hazard ratio 0.67 (95% CI 0.48 to 0.93) for the 3.5mg/kg group and 0.69 (0.49 to 0.96) for the higher dose, P=0.02 and P=0.03, respectively, vs. placebo.
Cladribine was administered in short course with the aim of providing a period of haematopoietic recovery before subsequent doses; however, treatment was associated with persistent lymphocytopenia (mostly graded as mild to moderate). Activation of latent herpes zoster occurred in 20 patients who received cladribine.
How does this relate to other studies?
Two trials of oral fingolimod in RRMS were published at the same time as the CLARITY study and have been covered in a recent blog. Only one fingolimod trial was against an active comparator (interferon) and that showed benefit. Although both agents have been shown to have benefits on the relapse rate more data are required both against active treatment and on preventing progression of disability. A phase II trial of cladribine in addition to interferon beta in patients who have experienced at least one relapse on interferon is on-going. Cladribine is also in a trial for patients with clinically isolated syndrome who have had their first clinical demyelinating event.
Understandably there is no head-to-head study of fingolimod versus cladribine, and we do not know where these agents will be placed in relation to each other in the management of patients with MS.
Fampridine (known as dalfampridine in the States) is an oral therapy which has recently been approved in the US for improving walking in patients with MS.
An NPC blog has discussed a trial of alemtuzumab▼increases in RRMS. Although alemtuzumab was more effective than interferon beta-1a at reducing the annualised risk of relapse and sustained disability, treatment in the alemtuzumab groups was stopped early due to the development of immune thrombocytopenic purpura in three patients, one of whom died.
So what?
Whilst an oral preparation will be more acceptable and convenient for patients a complicated administration schedule, as in the CLARITY trial, may hinder compliance. The long term benefits (for example on disability), data on efficacy compared with active treatment, and further data on the safety profile require assessment. A two-year extension to CLARITY is in progress and it is hoped that this will tell us more about long-term and rare adverse events.
Design: Phase III, randomised double-blind, placebo-controlled trial with concealed allocation.
Patients: 1,326 patients (mean age 38.5 years) with RRMS were included. They had a history of at least one relapse in the previous 12 months and a score of not more than 5.5 on the Expanded Disability Status Scale (EDSS). Exclusions included failure of two or more previous disease-modifying drugs, previous immunosuppressive therapy; or cytokine-based treatment, intravenous immune globulin or plasmapheresis within three months of study entry. 30% of patients had received therapy with a disease modifying drug, but these had to be stopped for at least three months before study entry.
Although the groups were well balanced in other respects, patients in the low dose cladribine group had had MS for less time than patients in other groups: mean of 7.9 years (standard deviation [+/-SD] 7.2, P=0.005 for the overall comparison between groups) in the low dose group, 9.3 (7.6) in the high dose group and 8.9 (7.4) in the placebo group.
Intervention and comparison: Oral cladribine, in a cumulative dose of either 3.5mg/kg (n=433) or 5.25mg/kg (n=456), or placebo (n=437) were taken once daily in short courses for 96 weeks. Patients received treatment on a total of 8 to 20 days per year. After 24 weeks, subcutaneous interferon beta-1a could be administered as rescue therapy.
Outcomes and results: The primary end point was rate of relapse at 96 weeks. Secondary outcomes included time to sustained progression of disability, proportion of patients who were relapse-free and proportion of patients who received interferon. 89.3% of patients completed the trial. In the intention-to-treat population, the annualised relapse rate at 96 weeks was 0.14 (95% CI 0.12 to 0.17) in the 3.5mg/kg group, 0.15 (0.12 to 0.17) in the 5.25mg/kg patients and 0.33 (0.29 to 0.38) in the placebo group (P<0.001 for both doses vs. placebo). This reduces the frequency of relapses by 0.18 to 0.19 per patient per year.
In the secondary outcomes, there were more patients without relapse in the cladribine groups (79.7% and 78.9% in the low and high dose cladribine groups, respectively vs. 60.9% for placebo patients, P<0.001 for both groups vs. placebo). Few patients received interferon as rescue medication, so the confidence intervals around the results are very wide (2.5% of the 3.5mg/kg group received interferon [P=0.01] and 2.0% of the 5.25mg/kg group [P=0.003] compared to 6.2% of the placebo group). This gives an odds ratio of 0.40 (95% CI 0.19 to 0.81) for the low dose group and 0.31 (0.14 to 0.66) for the higher dose, compared to placebo. Cladribine was slightly better for the secondary outcome of time to sustained progression of disability: hazard ratio 0.67 (95% CI 0.48 to 0.93) for the 3.5mg/kg group and 0.69 (0.49 to 0.96) for the higher dose, P=0.02 and P=0.03, respectively, vs. placebo.
Adverse events led to discontinuation of treatment in 3.5% and 7.9% of the lower and higher cladribine doses, respectively and 2.1% of the placebo patients. Lymphocytopenia was more common in patients who received cladribine: 21.6% of the 3.5mg patients and 31.5% of the higher dose, compared to 1.8% of placebo patients. Dermatomal herpes zoster was seen in 20 cladribine patients, 12 of whom were in the high dose group.
Serious adverse events included infection or infestation (2.3% and 2.9% of patients on the lower and higher cladribine doses, respectively vs.1.6% of placebo patients). No neoplasms were reported in patients taking placebo, but occurred in 1.4% and 0.9% of patients receiving low and high dose cladribine, respectively.. Two patients in the high dose and one in the low dose cladribine groups developed severe neutropenia. Two patients in each group died, including one patient in the high dose group who experienced severe thrombocytopenia and pancytopenia and an exacerbation of latent tuberculosis.
Sponsorship: Merck Serono
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