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Effect of Alfacalcidol on multiple sclerosis-related fatigue: A randomized, double-blind placebo-controlled study Anat Achiron, Uri Givon, David Magalashvili, Mark Dolev, Sigal Liraz Zaltzman, Alon Kalron, Yael Stern, Zeev Mazor, David Ladkani and Yoram Barak Mult Scler published online 24 October 2014 DOI: 10.1177/1352458514554053 The online version of this article can be found at: http://msj.sagepub.com/content/early/2014/10/20/1352458514554053
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On behalf of: European Committee for Treatment and Research in Multiple Sclerosis
Americas Committee for Treatment and Research in Multiple Sclerosis
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Latin American Committee on Treatment and Research of Multiple Sclerosis
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554053
research-article2014
MSJ0010.1177/1352458514554053Multiple Sclerosis JournalA Achiron, U Givon
MULTIPLE SCLEROSIS MSJ JOURNAL
Original Research Paper
Effect of Alfacalcidol on multiple sclerosisrelated fatigue: A randomized, double-blind placebo-controlled study
Multiple Sclerosis Journal 1–9 DOI: 10.1177/ 1352458514554053 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Anat Achiron, Uri Givon, David Magalashvili, Mark Dolev, Sigal Liraz Zaltzman, Alon Kalron, Yael Stern, Zeev Mazor, David Ladkani and Yoram Barak
Abstract Context: Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS); however, there is no medication that has been approved specifically to treat MS-related fatigue. Objective: We aimed to evaluate the effect of vitamin D analogue, Alfacalcidol, on MS-related fatigue. Design, settings, participants: This was a randomized, double-blind, parallel group, placebo-controlled trial in patients with clinically definite MS by McDonald criteria conducted in a single university-affiliated medical center in Israel. Randomly selected patients from the Sheba MS Registry computerized database (N=600) were assessed using the self-report Fatigue Severity Scale (FSS). Patients with clinically meaningful fatigue (N=259) were further assessed for trial eligibility, and MS patients with significant fatigue (N=158; 61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) were included in the study and randomized to receive treatment or placebo. Intervention: Alfacalcidol (1 mcg/d, N=80) or placebo (N=78) was administered for six consecutive months. Main outcome measure: The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the Fatigue Impact Scale (FIS) score; the cut-off point for improvement was defined as 30% decrease. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated regardless of whether or not they dropped out. Results: Alfacalcidol decreased the mean relative FIS score as compared with placebo (–41.6% vs. –27.4%, p=0.007, respectively). This advantage was further emphasized when the modified FIS (MFIS) relative change was calculated. Quality of Life (QoL) improved in Alfacalcidol-treated patients as compared with placebo in the RAYS psychological (p=0.033) and social (p=0.043) sub-scales. The Alfacalcidol-treated group had reduced number of relapses (p=0.006) and higher proportion of relapse-free patients (p=0.007). Reduction of relapses by Alfacalcidol became significant at 4 months of treatment, was sustained at 6 months and decayed 2 months after drug discontinuation. Alfacalcidol treatment was safe and no serious adverse events were recorded. Conclusion: Alfacalcidol is a safe and effective treatment strategy to decrease fatigue and improve QoL in patients with MS.
Keywords: Multiple sclerosis, fatigue, Quality of Life, Alfacalcidol, clinical trial Date received: 20 May 2014; revised: 24 August 2014; accepted: 7 September 2014
Introduction Fatigue is one of the most common and disabling symptoms of multiple sclerosis (MS) occurring in 30%–80% of patients.1 According to the MS Council
for Clinical Practice Guidelines, fatigue is “a subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities”.2 MS-related fatigue
Correspondence to: Anat Achiron Multiple Sclerosis Center, Sheba Medical Center, Tel-Hashomer, 52621, Israel.
[email protected]. gov.il Anat Achiron Uri Givon David Magalashvili Mark Dolev Sigal Liraz Zaltzman Alon Kalron Yael Stern Yoram Barak Multiple Sclerosis Center, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel-Aviv University, Israel Zeev Mazor David Ladkani Teva Pharmaceutical Industries, Israel
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Multiple Sclerosis Journal occurs on a daily basis and is characterized by worsening as the day progresses, and aggravation by heat and humidity. It is not directly correlated with either depression or with the degree of neurological disability, and may occur first thing in the morning even if the patient has had a restful full night’s sleep. There is no medication that has been approved specifically to treat MS-related fatigue. Amantadine was the first medication used to treat fatigue, although its mechanism of action is not clear and most studies have not supported the benefit. Modafinil has been recently studied, demonstrating inconsistent results,3,4 and several nonpharmaceutical interventions have been proposed including, amongst others, aquatic exercise training and internet-based programs.5,6 In the present study we aimed to evaluate the effect of Alfacalcidol (1 a-hydroxy vitamin D3), a synthetic analogue of vitamin D, on MS-related fatigue. Alfacalcidol is hydroxylated in the liver to calcitriol (1,25 dihydroxyvitamin D) and has a stable pharmacokinetic profile as it avoids serum peaks that may lead to elevated calcium levels and associated adverse effects. Alfacalcidol was demonstrated to improve and recover muscle strength7,8 and to decrease the number of falls in the elderly.9 Moreover, Alfacalcidol has immunological effects culminating in reversible blockade of the progression of relapsing murine experimental autoimmune encephalomyelitis,10 and we have previously shown its safety over a 6-month treatment period in a small group of patients with MS.11 In a recent study,12 we have elucidated the role of 1-alpha, 25-dihydroxyvitamin D3 (VitD3) in MS, showing low expression of NR4A gene family members and 1-alpha, 25-dihydroxyvitamin D3 receptor (VDR) genes in peripheral blood mononuclear cells of subjects evaluated during the pre-disease state of MS, in patients with clinically isolated syndrome during the very early presentation of neurological symptomatology and in patients with relapsing–remitting MS (RRMS). Both NR4A1 and NR4A3 are known to be involved in T-cell receptor-induced apoptosis and are regulated by VDR. We demonstrated that this undesired low apoptotic level in MS patients could be repaired by VitD3, confirming its role as a possible therapeutic intervention. Taken together, these diseaserelated beneficial effects prompted us to evaluate the effect of Alfacalcidol to reduce MS-related fatigue in a randomized placebo-controlled study design. Patients and methods Study design This was a randomized, double-blind, placebo-controlled, sample enrichment single-site study conducted
at the Multiple Sclerosis Center at the Sheba Medical Center, Tel-Hashomer, Israel to evaluate the effect of Alfacalcidol on MS-related fatigue. The study was approved by the Sheba Medical Center Independent Ethics Committee and participants signed written informed consent following a detailed explanation. The study was designed as a two-stage process in order to enrich the studied population in subjects whose fatigue is significant. The study design is presented in Figure 1. First, fatigue was assessed by the self-reported Fatigue Severity Scale (FSS)13 in patients with clinically definite MS by McDonald criteria,14 randomly selected from the Sheba MS Registry computerized database (N=600). Patients responding to the 9th item of the FSS i.e. ‘Fatigue interferes with my work, family, or social life’ with a score of 3 or higher on a 1–7 rating (first stage, N=259), were further assessed (second stage) for eligibility according to the following criteria: (1) Fatigue Impact Scale (FIS) score15 of 40 points or more; (2) age18–55 years; and (3) neurological disability by the Expanded Disability Status Scale (EDSS) at screening of up to 5.5. Patients were excluded if they had a relapse within 30 days prior to the study, if their blood calcium level was higher than 10.5 mg/dl, if there was a history of hypersensitivity or intolerance to Alfacalcidol or related substances, or if they endured a life threatening and/or unstable clinical condition and/or alcohol or drug abuse. Accordingly, 101 MS patients, 61 females, mean age 39.2 ± 8.2 years, disease duration 7.2 ± 4.6 years, EDSS 2.2 ± 2.5 were excluded after the second waiver, and 158 MS patients with significant fatigue were included in the study and randomized to receive treatment or placebo. Treatment Eligible patients were randomized to receive orally a soft gelatin capsule containing 1 mcg Alfacalcidol or placebo, daily, for 6 consecutive months (supplied by Teva Pharmaceuticals Ltd., Israel). The placebo soft gelatin capsules were filled with arachis oil and were identical in appearance to Alfacalcidol capsules. Randomization included a clear allocation concealment process performed on balanced blocks of four patients each, and was conducted independently of the trial team delivering the medications and recruiting the patients. The various placebo and treatment blocks were issued with a medication number and assigned to consecutive patients in a sequential order. Sheba Medical Center Pharmacy Department distributed the study medications and held the trial codes. All study personnel, patients, and sponsor personnel
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A Achiron, U Givon et al.
Assessed for eligibility (n=600) Stage 1, Fatigue recognition
Excluded (n=341) Not meeting inclusion criteria (n=241) Declined to participate (n=100)
Enrollment
Assessed for eligibility (n=259) Stage 2, Severe fatigue
Excluded (n=101) Not meeting inclusion criteria (n=101)
Randomized (n=158)
Allocated to placebo (n=78)
Allocation
Discontinued intervention (n=7) 3 Had adverse events 3 Requested withdrawal 1 Was noncompliant
Discontinued intervention (n=8)
ITT data analysis performed for all randomized subjects
Completed 2m follow-up (n=71)
Allocated to intervention (n=80) Alfacalcidol 1 µg/d
3 Had adverse events 3 Requested withdrawal 2 Were noncompliant
Completed 2m follow-up (n=72)
Figure 1. Study CONSORT flow diagram.
involved in the conduct of the study, were unaware of treatment assignments throughout the study. Treating neurologists were responsible for all aspects of patient care, including the evaluation and management of adverse events and acute relapses. Examining neurologists performed neurologic examinations and the EDSS score during the study visits and were instructed not to discuss with patients various disease aspects, side-effects or laboratory results in order to reduce the possibility of being unblinded. If a relapse was suspected, the patient was referred to the examining neurologist, who evaluated the patient within 3 days after the onset or worsening of the neurological symptoms. Relapse was defined as new or worsening neurologic symptoms not associated with fever or infection that lasted for at least 24 hours and accompanied by new
objective neurologic signs. At the discretion of the treating neurologist, relapses were treated with intravenous methylprednisolone at a dose of 1000 mg per day for five consecutive days.
Outcome measures Patients were examined once monthly for six consecutive months during treatment; neurological examination was scored by the EDSS. Fatigue was evaluated by the FIS, a reliable and validated 40-items questionnaire that is sensitive to treatment effects on fatigue. It comprises three sub-scales: physical, cognitive and social. Each question is scored from 0–4, allowing a total score of 160, with higher scores indicating greater fatigue.15
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Multiple Sclerosis Journal In addition, modified FIS (MFIS) scores16 based on items derived from interviews with MS patients concerning how fatigue impacts their lives were calculated. Similarly to the FIS, MFIS provides an assessment of the effects of fatigue in terms of physical, cognitive, and psychosocial functioning. The full-length MFIS consists of 21 items. Each question is scored from 0–4, allowing a maximal score of 84, with higher scores indicate greater fatigue. Quality of life (QoL) was evaluated in all patients by the RAYS questionnaire,17 a disease-specific instrument that provides precise and detailed information concerning the impact of MS on a variety of daily activities. The RAYS consists of three dimensions: physical, psychological, and social–familial, each containing 15 self-reported items scored from 1 (best) to 4 (worse), focusing on the preceding week. The RAYS score ranges between 45 and 180, and the questionnaire was validated in MS patients and demonstrated high internal validity with SF-36. All questionnaires were performed at baseline and after 6 months of treatment. Study endpoints The primary endpoint of the study was the change between Alfacalcidol and placebo-treated patients in the FIS score; the cut-off point for improvement was defined as 30% decrease. A sample size of 72 in each group was calculated to have 80% power to detect a difference of 14.0 in the mean FIS score between groups, assuming that the common standard deviation is 30.0 and using a two group t-test with a 0.050 twosided significance level. With an assumed dropout rate of 5%, the number of patients needed was estimated to be 152. The secondary endpoints were the change between Alfacalcidol and placebo-treated patients in the (1) RAYS QoL score (2) neurological disability by the EDSS and (3) the number of acute relapses during the study. Safety Special attention was given to detecting adverse effects. Investigators were instructed to record a comprehensive description of the adverse experience, duration, severity, action taken, relationship to the study drug and outcome of the event. Statistical analysis Demographic and disease-related clinical variables as well as fatigue duration are presented as mean ± SD. The paired t-test or signed rank test for two
means (paired observations) were applied for analyzing within-group changes from baseline in quantitative parameters. The two-sample t-test or non-parametric Wilcoxon–Mann–Whitney rank sum test for independent samples were applied for analyzing the differences in quantitative parameters as well as changes from baseline between the study groups. Chi-square test or Fisher’s Exact test were applied for testing differences in categorical parameters between the study groups. Logistic regression was applied for analyzing dichotomous outcome (FIS improvement of at least 30%) by predictive variables (treatment group), and with adjustment to the following confounders: baseline measures, age, gender, disease duration, number of relapses, EDSS and MS treatment. Analysis of variance (ANCOVA) was applied for analyzing the differences in quantitative parameters between the treatment groups with adjustment to confounders. Specifically, ANCOVA analysis was performed to predict FIS relative change by treatment group (Alfacalcidol/ placebo) adjusted for age, EDSS and MS treatment. Data are presented as mean + SD. All analyses followed the intention-to-treat principle and were performed for all participants based on the group they were randomly allocated, regardless of whether or not they dropped out. All tests applied were twotailed, and a p-value of 5% or less was considered statistically significant. The data was analyzed using the SAS® version 9.1 (SAS Institute, Cary North Carolina). Results Sample enrichment In the first stage of the study 600 MS patients living in the community and followed regularly at our center were approached randomly. The FSS response rate was 83.3% (500/600) and 51.8% (259/500) of respondents had reported that they were suffering from fatigue and qualified the stage 1 criterion for fatigue recognition. Of these 259 MS patients with fatigue, 158 patients (61%, 118 females, mean age 41.1 ± 9.2 years and mean disease duration of 6.2 ± 5.5 years) satisfied the additional set criteria for the intervention phase of the study having been defined as suffering from significant fatigue. The great majority of these patients (91.7%) had a relapsing– remitting disease course, mean FIS score was 77.0 ± 25.9 and mean EDSS was 2.9 ± 2.6. Fatigue was reported to occur for most of the day in 30.9% of patients, persisted in 69% for more than 1 year, and in 59.8% of patients fatigue was reported not to be associated with effort. Following randomization
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A Achiron, U Givon et al. Table 1. Baseline characteristics of patients.
Age, years Female, n (%) Age at disease onset, years EDSS IMD treated, n (%) Fatigue duration, years FIS MFIS
Placebo N=78
Alfacalcidol N=80
p-value
40.8 ± 8.7 59 (75.6) 31.2 ± 10.0 2.8 ± 1.6 54 (69) 4.1 ± 3.8 80.0 ± 27.9 43.7 ± 15.2
41.3 ± 9.8 59 (73.8) 33.0 ± 9.6 2.5 ± 1.6 53 (66) 3.7 ± 3.7 74.0 ± 23.7 40.7 ± 12.9
0.733 0.785 0.259 0.241 0.653 0.412 0.145 0.183
EDSS: Expanded Disability Status Scale; IMD: immunomodulatory drugs; FIS: Fatigue Index Scale; MFIS: modified FIS. Data are presented as mean ± SD.
Table 2. Outcome parameters.
% FIS relative change % MFIS relative change FIS decrease by 1SD (%) % RAYS relative change: Physical Psychological Social EDSS change % Relapse free
Placebo N=78
Alfacalcidol N=80
p-value
–27.4 –25.1 40
–41.6 –40.5 60
–7.2 –3.5 –14.6 0.06 67.1
–13.9 –27.2 –31.5 0.31 89.5
0.007 0.005 0.018 0.687 0.033 0.043 0.096 0.007
(N=80 Alfacalcidol treatment, N=78 placebo) no statistically significant between-group differences were observed in baseline characteristics (Table 1). The proportion of patients treated with disease-immunomodulating drugs (IMDs) at baseline was similar in the Alfacalcidol (66%) and in the placebo (69%) groups (p=0.65).
Fatigue Baseline FIS score was 74.0 ± 23.7 in the Alfacalcidoltreated group and 80.0 ± 27.8 in the placebo group (p=NS). At study completion (6 months) the mean relative reduction from baseline was greater in the Alfacalcidol treatment arm compared with the placebo treatment arm (–41.6% vs. –27.4%; p=0.007), respectively (Table 2). These results held true after correction for the predefined confounders. Similarly, the mean relative reduction in the MFIS from baseline to study completion was greater in the Alfacalcidol treatment arm compared with the placebo treatment arm (–40.5% vs. –25.1%; p=0.005), respectively. When examining the improvement in at least 1 SD,
the same trends were observed between the groups. Some 60% of the Alfacalcidol-treated patients showed improvement in FIS vs. 40% in the placebo group (p=0.018).
EDSS No statistically significant differences in EDSS were observed during the study (Table 2). Relapses In the year prior to the study 52 relapses occurred in 62.8% of patients in the Alfacalcidol treatment group, and 48 relapses involved 57.5% of patients in the placebo group. During the study, the number of relapses was significantly lower in the Alfacalcidoltreated group compared with the placebo arm [8 (10.5%) vs. 25 (33%) respectively, p=0.006]. Four patients (all in the placebo arm) had suffered from more than one relapse during the study. Thus, the proportion of patients free of relapses was significantly higher in the Alfacalcidol treatment arm
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Multiple Sclerosis Journal
Relapses (%)
40 30 20
p