Arizona Arthritis Center, University of Arizona, Tucson, Arizona, USA,
1 Department of Rheumatology, West Middlesex University Hospital, Middlesex, UK,
2 Metroplex Clinical Research Center, Dallas, Texas, USA,
3 School of Medicine, Rheumatology and Rehabilitation Research Unit, University of Leeds, Leeds, UK,
4 Rhumatologie, Hôpital Roger Salengro, Lille, France,
5 Hospital for Rheumatic Diseases, Ostersund,
6 Medicinmottagningen, Bollnäs Iasarett Medicinklinikum, Bollnäs, Sweden,
7 Groupe Hospitalier Cochin, Paris, France,
8 Rheumatology Department, Selly Oak Hospital, Birmingham, UK,
9 Universitätskliniken links der Isar, Med Poliklinik, Munich, Germany,
10 Hospital S João, Unidade de Reumatologia, Porto, Portugal,
11 Rheumatologie, Universitätsklinik, Medizinische Klinik III, Erlangen, Germany,
12 Universtitätsklinik Innsbruck, Rheumaambulanz, Innsbruck, Austria,
13 The Rheumatism Hospital, Lillehammer, Norway,
14 Division of Rheumatology and Clinical Immunology, Department of Medicine, University Hospital, Freiburg, Germany
15 Medizinische Universitätsklinik, Graz, Austria,
16 Center for Clinical Research, Austin Diagnostic Clinic, Austin, Texas,
17 Denver Arthritis Clinic, Denver, Colorado,
18 Northwestern University, Office of Clinical Research and Training, Chicago, Illinois,
19 Little Rock Diagnostic Center, Little Rock, Arkansas, USA and
20 Novartis Pharma AG, Basel, Switzerland
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Abstract |
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Methods. In this double-blind, multicentre study, patients were randomized to treatment with Neoral or Sandimmun, starting with 2.5 mg/kg/day, with dose adjustments after 4 weeks. Primary efficacy criteria included patients assessment of disease activity. Pharmacokinetic and safety assessments were performed at regular intervals.
Results. Compared with Sandimmun, Neoral showed a consistent trend towards greater clinical efficacy from week 12 onwards, including a significant difference in patients assessment of disease activity at the study end-points. A significantly lower increase in dose from baseline was observed with Neoral at week 24. Pharmacokinetic assessments at week 24 showed increased absorption and decreased variability with Neoral. No differences in safety were found between treatment groups.
Conclusion. These observations indicate that Neoral is as safe and at least as effective as Sandimmun and have important implications for patient management given the increasing role for CyA in the treatment of severe, active RA.
KEY WORDS: Rheumatoid arthritis, Cyclosporin, Microemulsion formulation
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Introduction |
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Clinical trials conducted over the last 10 yr have demonstrated that CyA, administered as commercially available Sandimmun® (SIM) soft gelatin capsules, is effective in improving subjective and objective clinical parameters in patients with severe active and refractory RA in advanced stages of disease [716]. In addition, recent clinical trials in early RA have shown CyA to be well tolerated [17], to have a slowing effect on radiological progression and a preventive effect on the onset of erosions, compared with standard second-line therapy [18]. However, because the SIM formulation of CyA is an oil-in-water emulsion, the absorption of CyA is affected by food intake and fat content, by the dispersion of the agent in the gastrointestinal tract and by the secretion of bile. As a result, the use of SIM is limited by a degree of variability in CyA bioavailability, both between patients and within an individual patient over time. This is of particular concern given the potential renal side-effects of CyA [1922].
The experience gained with SIM has facilitated the development of a new oral formulation of CyA called Sandimmun Neoral® (Neoral), which is based on microemulsion technology [22]. Neoral is designed to increase the bioavailability and reduce the pharmacokinetic variability of CyA and thus to simplify its clinical use. The principal features that enable Neoral to achieve these aims are the fast release of CyA at the site of absorption, improved dissolution of CyA in the gastrointestinal tract and dispersion independent of food and the flow of bile.
It has been shown previously that the inter- and intra-patient variability of all pharmacokinetic parameters is reduced compared with SIM [23]. In addition, clinical studies conducted in de novo and stable renal transplant recipients for up to 1 yr have shown that Neoral is as safe and well tolerated as commercial SIM when used at a 1:1 dosage ratio, providing dosing and monitoring guidelines for SIM are adhered to [2426]. Furthermore, SIM to Neoral conversion studies in RA patients have confirmed the improved bioavailability and reduced pharmacokinetic variability of CyA when administered as Neoral; no safety problems were observed post-conversion and efficacy was maintained compared with SIM [27, 28]. However, monitoring and dosing guidelines established for SIM in RA must be followed to ensure maintenance of safety, tolerability and efficacy [2931].
The purpose of this trial was to compare the safety, tolerability and efficacy of SIM and Neoral in patients with severe, active RA who were not currently receiving second-line treatment and had not been treated previously with CyA. Patients with severe, rather than early, RA were chosen because most studies using SIM in this indication have involved this group of patients. The study also aimed to compare the effective dosage of the two formulations expressed as mg/kg/day, after 16 and 24 weeks, in accordance with the titration scheme.
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Patients and methods |
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Patients completing phase 1 of the study were eligible to enter the extension phase (phase 2; weeks 2552), during which the treatment to which patients were randomized in phase 1 was continued. During this phase, dose adjustments for safety or efficacy reasons were permitted at any time. Additional safety, efficacy and tolerability evaluations were made at the end of weeks 28, 36, 44 and 52.
Patient eligibility
Patients over 18 yr of age with severe active RA were eligible to enter the screening period at week -4 (i.e. 4 weeks before the start of study phase 1). Active disease was confirmed by the presence of at least three of the following four criteria: (i) six or more tender joints; (ii) three or more swollen joints; (iii) early morning joint stiffness (of average duration 45 min) during previous week; or (iv) erythrocyte sedimentation rate (ESR) <28 mm at 1 h (Westergren) or C-reactive protein (CRP) <20 mg/l. Severe disease was defined as a requirement for slow-acting anti-rheumatic drug (SAARD) therapy, which had proven inappropriate or ineffective after 3 months. Additional eligibility criteria for patients entering the 2552-week phase were the completion of the initial 24-week treatment period with all evaluations and ability to continue with study medication. Written informed consent was a prerequisite for the inclusion of all patients. Patients were excluded if they had previously been treated with SIM at any time, were suffering from liver or haematopoietic disease or uncontrolled hypertension, if serum creatinine was above the upper limit of the normal range, if they were receiving systemic corticosteroids exceeding 10 mg prednisone (or equivalent) per day, or if they had received SAARDs within the previous 2 weeks. Other exclusion criteria included concomitant therapy with nephrotoxic drugs or drugs affecting CyA pharmacokinetics, chronic infection, history of malignancy, recent myocardial infarction (within 6 months), pregnancy or lactation, or history of drug abuse. Additional exclusion criteria for patients considered for inclusion in the 2552-week phase were the discontinuation of therapy during the initial 24-week period and protocol violations during the initial 24 weeks requiring the discontinuation of study medication. Patients without changes in their concomitant RA medications between week -4 and day 0 were randomized at day 0 to enter the treatment period at day +1.
Study criteria
Efficacy outcome parameters in this study reflect current recommendations for clinical trials in RA [33]. The primary efficacy criteria were number of swollen joints (out of a total score of 66), number of painful/tender joints (out of a total score of 68) and patient's overall assessment of disease activity, using a five-point verbal rating scale from very poor to very good. Secondary efficacy criteria were: (i) Ritchie articular index (score 078) [34]; (ii) physician's overall assessment of disease activity; (iii) patient's assessment of pain, using a 10-cm visual analogue scale (VAS); (iv) central laboratory determination of CRP, local assessment of ESR; and (v) physical disability assessment, derived from a Health Assessment Questionnaire (HAQ) completed at day 0 and at week 24 or at the time of premature discontinuation [35]. All efficacy criteria were assessed on the basis of the intention-to-treat (ITT) population.
Blood samples for the determination of whole blood CyA trough concentrations were collected at the local clinic and stored (- 20°C) before being assayed at a central laboratory, using a commercially available SIM radioimmunoassay kit (Incstar®), based on a monoclonal antibody to CyA. The results of trough CyA determinations did not become known to investigators during the study. For the subgroup pharmacokinetic assessments, blood samples were collected immediately before and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 4, 6, 9 and 12 h after the morning dose of CyA was taken. The samples were assayed as above. The full results from the subgroup pharmacokinetic assessments will be detailed elsewhere, but herein we will report steady-state maximum blood CyA concentrations (Cmax) and area under the concentrationtime curve from 0 to 12 h (AUC) data from the week 24 visit.
Safety assessment was based on the incidence and severity of adverse events, physical examination, vital signs and laboratory tests. The main safety parameters were blood pressure and serum creatinine.
Statistical methods
The two treatment groups were compared descriptively using summary statistics and comparisons between treatment groups were made using appropriate statistical significance tests. Demographic characteristics at baseline were compared. For the safety analysis, a single population was defined, comprising all randomized patients who had received at least one dose of study medication and had at least one safety evaluation after the administration of study medication. For the efficacy analysis, the ITT population comprised all randomized patients who had received at least one dose of study medication, and had a baseline evaluation and at least one efficacy evaluation after the administration of study medication. The intention was to recruit at least 250 patients (125 per treatment group). The number of patients was based on practical, rather than power considerations.
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Results |
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Key demographic data at entry
The two treatment groups were similar with respect to demographic characteristics, disease characteristics and use of concomitant medications at study entry (safety population). The mean age of patients entering phase 1 of the study was 53.4 yr in the Neoral group and 54.0 yr in the SIM group. For patients entering the extension phase, the corresponding mean ages were 53.0 and 52.5 yr, respectively. Female patients predominated in phase 1 (Neoral, 109/143: 76%; SIM, 121/155: 78%), as expected in this indication, and continued to predominate in the extension phase (Neoral, 53/78: 68%; SIM, 57/78: 73%). All but 27 patients were White. In the majority of patients the disease was of long duration; the mean time since diagnosis was 133 months in the Neoral group and 130 months in the SIM group. Approximately 40% of patients in both treatment groups had undergone articular surgery (Neoral, 60/143: 42%; SIM, 62/155: 40%) and approximately half the patients had previously been hospitalized for RA (Neoral, 61/143: 43%; SIM, 77/155: 50%). In the Neoral group, 123/143 (86%) patients tested positive for rheumatoid factor at week -4, compared with 137/155 (88%) patients in the SIM group. Every patient in the SIM group and all but three in the Neoral group had received SAARDs before entry to the study; the most common of these agents was methotrexate, taken by 105 (73%) of Neoral patients and 115 (74%) of SIM patients. None of the patients had previously received CyA. Oral corticosteroids were being taken at baseline by 105 patients (73%) in the Neoral group and 113 patients (73%) in the SIM group, and non-steroidal anti-inflammatory drugs (NSAIDs) were taken by 107 (75%) patients in the Neoral group and 121 (78%) in the SIM group. Twenty-one patients (15%) in the Neoral group and 33 patients (21%) in the SIM group were taking anti-hypertensive medication at baseline. There were no differences between the treatment groups in terms of any other type of concomitant medication.
Efficacy analysis
Both treatment groups showed clinically significant improvement, with a consistent trend towards improved clinical efficacy with Neoral compared with SIM from week 12 onwards (Figs 1 and 2
). The reduction in swollen and painful or tender joints that had occurred by week 24 was maintained during the extension phase of the study in both treatment groups. At the week 24 and 52 end-points, the mean changes in swollen joint counts from baseline were -4.98 and -5.51, respectively, for Neoral and -4.37 and -4.22, respectively, for SIM. This difference in swollen joint count was observed consistently at all visits, but was statistically significant in favour of Neoral only at the week 20 and week 36 evaluations (P = 0.031 and P = 0.006, respectively). At the week 24 and 52 end-points, the mean changes in painful/tender joint counts from baseline were -8.35 and -8.20, respectively, for Neoral and -6.61 and -6.45, respectively, for SIM. Again, the trend in favour of Neoral was observed consistently, with differences between the treatment groups reaching statistical significance at weeks 12, 16, 20 and 28 (P = 0.050, P < 0.001, P = 0.038 and P = 0.044, respectively).
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The physicians overall assessment of disease activity differed significantly between treatment groups only at the week 20 visit (P = 0.027). At all other visits and at the treatment end-points, the physicians assessed disease activity as being similar in both Neoral and SIM groups. However, the cumulative incidence of patients classed as responders to therapy American College of Rheumatology [(ACR) 20% criterion] was consistently higher in the Neoral group, compared with the SIM group, throughout the study (Fig. 1).
With regard to the primary efficacy parameter of patient's overall assessment of disease activity, significantly more Neoral patients than SIM patients had improved at the week 20, 24 and 52 visits (P = 0.026, P = 0.025 and P = 0.025, respectively) and at the week 24 and week 52 end-points (P = 0.038 and P = 0.039, respectively). This evidence of patient improvement was supported by the significantly greater reduction in physical disability at the week 52 end-point (P = 0.007) in Neoral patients compared with SIM patients, as measured by the health assessment total score (Fig. 2).
The mean ESR change from baseline was significantly lower for Neoral patients than for SIM patients at the week 12, 20, 24, 28 and 36 visits (P = 0.034, P = 0.019, P = 0.014, P = 0.011 and P = 0.025, respectively), and for the week 24 and week 52 end-points (P = 0.041 and P = 0.040, respectively). CRP was reduced from baseline to a significantly greater degree in the Neoral group than the SIM group at weeks 16, 20 and 52 (P = 0.038, P = 0.010 and P = 0.037, respectively). A significant difference in the change from baseline between the groups with regard to pain, as assessed by a VAS, was recorded only at week 44 (P = 0.039). Again, this significant difference favoured Neoral.
Safety analysis
The adverse event profiles of both treatments were not statistically significant, with 124 (87%) patients in the Neoral group and 125 (81%) patients in the SIM group having reported adverse events that were considered to be at least possibly related to study medication by the week 52 visit. Serious adverse events during treatment were recorded for 25 (18%) Neoral patients, compared with 28 (18%) SIM patients. Adverse events were associated with the discontinuation of study medication in 35 (25%) Neoral patients, compared with 55 (36%) SIM patients (P = 0.044). At the week 52 visit, 33 patients (23%) in the Neoral group and 48 patients (31%) in the SIM group had withdrawn from the study due to the occurrence of an event defined as adverse by the investigators.
Overall, the incidence and pattern of adverse events reflected the known side-effect profile of CyA. The most common events were those associated with the gastrointestinal system (nausea, diarrhoea and abdominal pain) and the central/peripheral nervous system (headache, tremor and paraesthesia). The incidence of adverse events occurring in at least 5% of the study population is presented by organ system in Table 2.
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Seven other serious adverse events were considered to be probably, possibly or definitely related to study medication: in the Neoral group, one case each of severe hypertension, cardiac failure, chest infection and dysmenorrhoea occurred; in the SIM group, there were individual cases of uncontrolled hypertension, abscess of the femoral shaft (osteonecrosis), and diverticulitis (coexistent disease; SIM).
No clinically relevant differences were found between the treatment groups with regard to changes in laboratory parameters or vital signs. Serum creatinine levels did not differ significantly between the groups at baseline (Neoral: 76 µmol/l; SIM: 75 µmol/l). There was a slight increase in the mean serum creatinine during the study, but there was no significant difference between treatment groups (Fig. 3). At the week 52 visit, 18 out of 54 (33%) evaluable patients in the Neoral group and 15 out of 54 (28%) evaluable patients in the SIM group had a clinically notable increase (
30%) in creatinine, relative to their pre-treatment value (difference between groups not significant). Of these 54 evaluable patients in each group, five (9.3%) receiving Neoral and three (5.6%) receiving SIM had an increase in serum creatinine of
50% relative to pre-treatment. Systolic and diastolic blood pressure remained stable throughout the study period in both treatment groups (Fig. 4A,B
).
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Study medication dosage
The mean CyA dose at randomization was 2.50 mg/kg/day (SIM group) and 2.48 mg/kg/day (Neoral group). There was a slow dose increase in both treatment groups from week 4 onwards. However, the trend towards dose increases was less pronounced for Neoral compared with SIM, with mean doses of Neoral remaining consistently lower than mean doses of SIM from week 6 onwards (Fig. 5). Overall, dose adjustments were made in 117 (82%) of the patients in the Neoral group and in 129 (83%) of the patients in the SIM group; a marginally lower proportion of patients in the Neoral group [105 (73%)] than in the SIM group [118 (76%)] required dose increases and a higher proportion of patients in the Neoral group than in the SIM group had their dose reduced [88 (62%) vs 77 (50%), respectively]. The mean Neoral and SIM doses were 2.92 and 3.27 mg/kg/day, respectively, at the week 24 study period (i.e. from the week 20 visit to 1 day before the week 24 visit); and 2.59 mg/kg/day and 2.99 mg/kg/day, respectively, at the week 52 study period (i.e. from the week 44 visit to the week 52 visit). The change in dose, from baseline, differed significantly between treatment groups at week 24 (P = 0.027), but did not differ significantly between groups at week 52 (P = 0.077).
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The mean trough blood CyA concentrations (ITT population) were not statistically significantly different in the Neoral and SIM groups at week 2 (94.6 ± 66.4 ng/ml and 103.1 ± 60.8 ng/ml, respectively; P = 0.216) and remained similar at all visits (P > 0.05), except week 20 (Neoral: 123.5 ± 79.7 ng/ml; SIM: 161.7 ± 101.8 ng/ml; P = 0.030), week 28 (Neoral: 94.3 ± 45.2 ng/ml; SIM: 124.8 ± 70.6 ng/ml; P = 0.046) and week 52 (Neoral: 79.3 ± 43.3 ng/ml; SIM: 105.2 ± 46.7 ng/ml; P = 0.045). The mean trough blood CyA concentrations (ITT population) were significantly lower for the Neoral than for the SIM group at both the week 24 and week 52 end-points. At the week 24 end-point, the mean trough blood CyA concentration in the Neoral group was 109.7 ± 77.3 ng/ml, compared with 146.3 ± 107.3 ng/ml in the SIM group (P = 0.002). At the week 52 end-point, the trough CyA concentration in the Neoral group was 94.7 ± 64.2 ng/ml and in the SIM group was 122.6 ± 86.3 ng/ml (P = 0.003). During weeks 2552, mean trough blood CyA concentrations decreased in both groups and remained consistently lower for Neoral than for SIM.
In the subgroup pharmacokinetic analysis, dose-normalized mean Cmax at the week 24 visit were 8.61 and 4.96 ng/ml/mg in the Neoral and SIM groups, respectively. The difference (74%) was statistically significant (P < 0.010). A difference was also seen in dose-normalized mean AUC, being higher in the Neoral group by 16% (32.3 vs 27.8 ng.h/ml/mg). This increase in absorption for Neoral was accompanied by a decrease in the median intra-patient variability, as measured by the coefficient of variance for these pharmacokinetic parameters (Cmax: Neoral 17.6%; SIM 19.1%; AUC: Neoral 15.3%; SIM 21.0%), although these differences were not significant.
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Discussion |
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Both treatment groups showed a clinically significant improvement in disease activity, but there was a consistent trend towards improved clinical efficacy with Neoral, compared with SIM, from week 12 onwards. Notably, there was no clinically or statistically significant trend in favour of SIM for any efficacy parameter at any time point. A summary of the main differences in efficacy between the two formulations is shown in Table 3. Throughout the study, a higher percentage of patients on Neoral, compared with SIM, had a clinically relevant response, according to the 20% ACR criterion. Most notably, physical disability, as assessed by the HAQ score, improved to a greater extent with Neoral, compared with SIM (week 24, P = 0.034; week 52, P = 0.006; ITT population). Overall safety, tolerability and patient compliance did not differ significantly between the two treatment groups. Baseline values for serum creatinine concentration, one of the main safety parameters, were not statistically significantly different in the Neoral and SIM groups. As might have been expected with CyA therapy, the mean serum creatinine rose slightly throughout the study, but no clinically relevant differences were observed between treatment groups. Diastolic and systolic blood pressure (another two safety variables) remained stable in both groups throughout the study.
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In conclusion, this double-blind 52-week study confirms that Neoral is at least as effective, safe and well tolerated as SIM in patients suffering from severe active RA, when used within the dose range and in accordance with dose-modification guidelines established for SIM. The improved bioavailability of the microemulsion formulation is reflected in a reduced requirement for dose increases over time. This supports a Neoral starting dose of 2.5 mg/kg/day, towards the lower end of the recommended initial dose range for SIM [29, 30], which is likely to require relatively limited upward titration to maintain clinical efficacy. Furthermore, the variation in bioavailability may be decreased with Neoral, which is of importance given the safety issues associated with CyA treatment.
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Acknowledgments |
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Notes |
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Additional members of the Neoral/RA OLR 302 Study Group include: D. Becker-Capeller, P. Bertin, C. M. Black, M. I. D. Cawley, B. Combe, M. Dougados, E. Fjeld, N. Gerber, I. M. Gilboe, E. Gromnica-Ihle, G. Hein, K. Helmke, D. W. James, J. P. Kaltwasser, T. K. Kvien, P. E. McGill, G. Myklebust, A. Nicholls, H.-H. Peter, D. M. Reid, P. J. Smith and H. Zeidler.
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References |
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