A number of landmark clinical studies in the field of MS have been published, shaping how the disease is treated.
Multiple sclerosis (MS) is a debilitating autoimmune disease characterized by fatigue, impaired coordination, and muscle spasm and weakness. More than 400,000 people in the United States and 2.5 million people around the world have MS, according to the Multiple Sclerosis Foundation.
Studies show that individuals with MS use health care services significantly more than those without the disease. For example, a newly diagnosed MS patient visits a physician an average of 8 times annually, about 3 times as often as someone without MS.1 Additionally, MS can present significant non-medical costs through lost productivity and caregiver burden.
Over the years, a number of landmark clinical studies in the field of MS have been published, shaping how the disease is treated. Here are 4 that every pharmacist should know about. We will cover 4 more studies in Part 2.
1. PRISMS (1998)2,3
By the late 1990s, the results of preliminary studies of interferon beta in MS had shown promising signs for treating relapsing-remitting multiple sclerosis (RRMS). However, its efficacy and optimum dosing were not yet universally accepted. As a result, the PRISMS study looked to address questions raised by previous trials and further explore the clinical effects of Rebif (interferon beta-1a) in RRMS.
The study was designed as a double-blind, randomized, placebo-controlled trial in patients who had clinically definite or laboratory-supported definite MS of at least 1 year’s duration. Five hundred and sixty patients were randomly assigned to receive subcutaneous Rebif 22 μg, 44 μg or a placebo 3 times a week for 2 years. Neurological examinations were done every 3 months. The primary endpoint was the relapse count over the course of the study.
Study results showed the relapse rate was significantly lower at both 1 and 2 years with both doses of Rebif compared with the placebo (27% risk reduction with the 22 μg group; 33% reduction with the 44 μg group; and P < 0.005 for both groups). Additionally, the time to first relapse was prolonged by 3 and 5 months in the 22 μg and 44 μg groups, respectively. Rebif was also found to significantly delay progression in disability and reduce the number of active lesions on a MRI compared with the placebo. In general, Rebif was well-tolerated in terms of its adverse event rate.
In a 2-year extension phase, patients previously receiving a placebo were re-randomized to active treatment at either dose. The data showed that a further 2 years of treatment was associated with continued efficacy and a good safety profile. Follow-up visits up to 8 years demonstrated a long-term benefit, with the greatest efficacy in those originally randomized to the 44 μg dose compared with those receiving the lower dose or whose treatment had been delayed 2 years.
Conclusion: Rebif is an effective and safe treatment for RRMS, with up to 8 years of data reported.
2. PreCISe (2009)4
Copaxone (glatiramer acetate) is a disease-modifying immunomodulator that was originally FDA approved to reduce the frequency of relapses in patients with RRMS. At the time, there was limited data on Copaxone for the treatment of clinically isolated syndrome (CIS), an MS disease course characterized by a first episode of neurological symptoms caused by inflammatory demyelination. Although these individuals typically do not present with enough evidence to definitively diagnosis MS, investigators hypothesized that early treatment with Copaxone could potentially reduce long-term neuronal damage.
To further explore the efficacy of early treatment with Copaxone in delaying the onset of clinically definite multiple sclerosis (CDMS) researchers conducted a randomized, double-blind, placebo-controlled study in 16 countries worldwide. Four hundred and eighty-one patients between 18 and 45 presenting with a CIS with unifocal manifestation and 2 or more T2-weighted brain lesions were randomly assigned to receive either subcutaneous Copaxone 20 mg per day or a placebo for up to 36 months. The primary endpoint was time to CDMS, based on a second clinical attack.
The study results showed that Copaxone reduced the risk of developing CDMS by 45% compared with the placebo (P = 0.0005). Additionally, the time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for the placebo to 722 days for Copaxone. When looking at the number of new T2 lesions, Copaxone demonstrated a statistically significant reduction of 58% (P < 0.0001). A subgroup analysis revealed better response in women, younger patients, and those with one or more GdE lesions at entry. The adverse events reported in this trial were consistent with the known safety profile of Copaxone.
Based on the study results, the FDA expanded Copaxone’s indication to include the treatment of patients who experienced a first clinical episode and MRI features consistent with MS.
Conclusion: In patients presenting with CIS, early treatment with Copaxone is effective in delaying conversion to CDMS.
3. GALA (2013)5
Copaxone was first FDA-approved in 1996 as a 20-mg daily subcutaneous injection. Seventeen years later, researchers published the results of the GALA study, which aimed to assess the efficacy of a higher Copaxone dose administered 3 times weekly.
The study was designed as a randomized, double-blind, parallel-group trial conducted at 142 sites in 17 countries. On thousand four hundred and four patients with RRMS with at least 1 documented relapse in the 12 months before screening or at least 2 documented relapses in the 24 months prior were included in the study. Patients with progressive forms of MS and previous treatment with Copaxone were excluded from study entry. Patients were randomized 2:1 to receive either subcutaneous Copaxone 40 mg 3 times weekly or a placebo for 12 months. The primary endpoint was the annualized relapse rate.
Upon analyzing the data, researchers found that the Copaxone group was associated with a 34% risk reduction of confirm relapses compared with the placebo (0.331 vs 0.505; P < 0.0001). Additionally, those who received Copaxone 3 times weekly demonstrated a significant reduction in the number of lesions on MRI readings, from 35% to 45%. The percent change in normalized brain volume at month 12 from the baseline was not statistically different between the 2 treatment arms. Adverse events reported with the Copaxone group were consistent with the known safety profile of the existing 20-mg formulation.
Results from the study led the FDA to approve Copaxone 40 mg 3 times a week in the year following the study's publication.
Conclusion: Copaxone 40 mg 3 times weekly is an effective and safe treatment for RRMS.
4. TOPIC (2014)6
In 2012, the FDA approved Aubagio (teriflunomide), an immunomodulatory, once-daily, oral treatment for patients with relapsing forms of MS. Two years later, researchers published TOPIC, the first study to demonstrate the benefit of an oral disease-modifying therapy in patients with early MS.
The study was a double-blind, placebo-controlled, parallel-group trial of 618 patients 18 to 55 years old with CIS, defined as a neurological event consistent with demyelination, starting within 90 days of randomization, and 2 or more T2-weighted MRI lesions. Participants were randomly assigned 1:1:1 to receive once-daily oral Aubagio 14 mg, Aubagio 7 mg, or a placebo for up to 108 weeks. The primary endpoint was time to relapse, which defined conversion to CDMS.
Compared with the placebo, Aubagio reduced the risk of relapse defining CDMS at the 14-mg dose by 42.6%
(p = 0.0087) and at the 7-mg dose by 37.2% (P = 0.0271). Aubagio also reduced the risk of relapse or a new MRI lesion compared with the placebo by 34.9% at the 14-mg dose (P = 0.0003) and 31.4% at the 7-mg dose (P = 0.0020). Moreover, Aubagio 14 mg reduced the number of gadolinium-enhancing T1 lesions per scan, and the volume of these lesions compared with the placebo, while the 7-mg dose reduced the volume but not the number.
Adverse events occurring in 10% or more of patients in either Aubagio group and with an incidence that was at least 2% higher than that of the placebo, include diarrhea, hair thinning, increased alanine aminotransferase, paresthesia, and upper respiratory tract infection.
Conclusion: Aubagio significantly reduces the risk of relapse indicating conversion to CDMS.
The Clinical Focus condition center at NeurologyLive, Pharmacy Times' new sister site, provides even more extensive coverage from the multiple sclerosis space, as well as updates from the field’s most prominent conferences.
1. Owens G. Economic Burden of Multiple Sclerosis and the Role of Managed Care Organizations in Multiple Sclerosis Management. Am J Manag Care. 2016;22:(6 Suppl)s:151-8.
2. PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon Beta-1a in relapsing/remitting multiple sclerosis. Lancet. 1998;352(9139):1498—504.
3. Cohen BA, Rivera VM. PRISMS: the story of a pivotal clinical trial series in multiple sclerosis. Curr Med Res Opin. 2010 Apr;26(4):827-38. doi: 10.1185/03007991003604018.
4. Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374(9700):1503-11. doi: 10.1016/S0140-6736(09)61259-9.
5. Khan O, Rieckmann P, Boyko A, Selmaj K, Zivadonov R, GALA Study Group. Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis. Ann Neurol. 2013;73(6):705-13. doi: 10.1002/ana.23938.
6. Miller AE, Wolinsky JS, Kappos L, et al. Oral teriflunomide for patients with a first clinical episode suggestive of multiple sclerosis (TOPIC): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(10):977-86. doi: 10.1016/S1474-4422(14)70191-7.