Microemulsion formulation of cyclosporin (Sandimmun Neoral®) vs Sandimmun®: comparative safety, tolerability and efficacy in severe active rheumatoid arthritis

D. E. Yocum22, S. Allard1, S. B. Cohen2, P. Emery3, R. M. Flipo4, J. Goobar5, S. Jayawardena6, C. Job-Deslandre7, R. W. Jubb8, K. Krüger9, A. Lopes Vaz10, B. Manger11, E. Mur12, H. Nygaard13, S. M. Weiner14, F. Rainer15, M. R. Sack16, M. H. Schiff17, T. J. Schnitzer18, L. B. Trigg19, I. Whatmough20, A.-G. Schmidt20 and on behalf of the OLR 302 Study Group

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


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To compare the safety, tolerability and efficacy of the new oral microemulsion formulation of cyclosporin A (CyA; Sandimmun Neoral®) and the original CyA formulation (Sandimmun®), in patients with severe active rheumatoid arthritis (RA), over a 12-month period.

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


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is an immune-mediated disease, with evidence of early T-cell involvement, and augmented turnover of interleukin-2 (IL-2) [14]. Cyclosporin A (CyA) is an effective immunosuppressive agent, which inhibits T cell and macrophage activation and proliferation. The agent suppresses the transcription of a number of early activation genes including those encoding for IL-1, IL-2 and interferon-{gamma} (IFN-{gamma}) [5, 6]. Consequently, there is a logical scientific rationale for the use of CyA in the treatment of RA.

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.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Study design
This was a two-phase, prospective, double-blind, parallel-group study involving 37 centres in nine countries. After a 4-week screening period, patients with severe active RA were randomized on a 1:1 basis to enter ‘phase 1’ of the study, comprising 24 weeks of treatment with either Neoral or SIM. The starting dose of each formulation was 2.5 mg/kg/day, equally divided between a morning and an evening dose. Neoral was provided as soft gelatin capsules, each containing 25, 50 or 100 mg CyA. SIM was provided as similar capsules containing the same amounts of CyA. Dose adjustments were made in accordance with guidelines based on efficacy and safety parameters [29, 30] and were identical for both treatment groups to enable direct comparisons to be made. Dose increases for lack of efficacy were permitted after 4 weeks. An assessment of lack of efficacy was based on both the patient and investigator global assessments indicating a poor or very poor patient condition which had worsened since day 0, or a <30% reduction in painful joint count compared with day 0, or a <30% reduction in swollen joint count compared with day 0. Dose reductions for safety were allowed at any time, based on elevated serum creatinine, elevated liver enzymes or bilirubin, hypertension or other clinical or biological abnormality causing clinical concern. The maximum permitted dose for each formulation was 5.0 mg/kg/day [32]. Patients were to visit the clinic at weeks 2, 4, 6, 8, 10, 12, 16, 20 and 24 to enable safety, tolerability and efficacy assessments to be made. In addition, samples for the determination of whole blood trough CyA concentrations were taken at these visits and at the end of week 52. More detailed pharmacokinetic assessments were made in a subgroup of patients at weeks 4 and 24.

Patients completing phase 1 of the study were eligible to enter the extension phase (phase 2; weeks 25–52), 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 25–52-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 25–52-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 0–78) [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 concentration–time 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.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient disposition
The sample size was exceeded, with a total of 335 patients screened and 299 patients randomized at day 0. Patient disposition and adherence to therapy are summarized in Table 1Go. A total of 25 patients were available for the subgroup pharmacokinetic assessment at week 24, 15 from the Neoral group and 10 from the SIM group.


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TABLE 1. Patient disposition

 

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 1Go and 2Go). 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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Fig. 1. Cumulative incidence of ACR 20 responders. [Number of patients is shown beneath the time axis; NN, Neoral (solid line); NS, SIM (broken line)].

 


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Fig. 2. Improvement from baseline in physical disability (HAQ) score.

 
There was a reduction from baseline in the Ritchie articular index in both treatment groups at all visits and at all treatment end-points. The difference in the change from baseline between groups was significant only at the week 16, 28 and 44 visits (P = 0.013, P = 0.040 and P = 0.006, respectively).

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 2Go.


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TABLE 2. Incidence of adverse eventsa occurring in at least 5% of the study population after administration of study medication, by organ system

 
Four malignancies were reported as serious adverse events during the study (three in the Neoral group and one in the SIM group). One patient in the Neoral group had carcinoma of the thyroid gland considered to be possibly related to study medication and which occurred 6 months after starting study medication. The second patient was diagnosed with squamous cell carcinoma of the vocal cords, considered to be unrelated to study medication. The third patient had basal cell carcinoma of the forehead; it was considered unlikely that this carcinoma was related to study medication. In the SIM group, a case of breast carcinoma was detected; the tumour was thought to have been present for at least 6 months prior to study entry and was considered to be unrelated to study medication.

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. 3Go). 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,BGo).



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Fig. 3. Changes in serum creatinine concentration from baseline (safety population). The top and bottom edges of the box are the upper and lower quartiles, the horizontal line within the box is the median (Neoral, solid line; SIM, broken line). Whiskers extend from the box as far as the data reach to a maximum of 1.5 times the interquartile range. Values beyond this are shown by a plot symbol [Neoral (•); SIM(x )]. (The number of patients is shown beneath the time axis; NN, Neoral; NS, SIM.)

 


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Fig. 4. (A) Systolic blood pressure (safety population). (B) Diastolic blood pressure (safety population). The top and bottom edges of the box are the upper and lower quartiles, the horizontal line within the box is the median (Neoral, solid line, SIM: broken line). Whiskers extend from the box as far as the data reach to a maximum of 1.5 times the interquartile range. Values beyond this are shown by a plot symbol [Neoral (•); SIM(x )]. (The number of patients is shown beneath the time axis; NN, Neoral; NS, SIM.)

 

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. 5Go). 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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Fig. 5. Mean daily dose of study medication since previous visit (safety population). The top and bottom edges of the box are the upper and lower quartiles, the horizontal line within the box is the median. Whiskers extend from the box as far as the data reach to a maximum of 1.5 times the interquartile range. Values beyond this are shown by a plot symbol [Neoral (•); SIM(x )]. (The number of patients is shown beneath the time axis; NN, Neoral; NS, SIM.)

 
By the week 52 visit, there was a total of 79 dose reductions (in 50 patients) due to elevated serum creatinine in the Neoral group and 60 dose reductions (in 42 patients) for the same reason in the SIM group. Six dose reductions (in six patients) in the Neoral group and 12 dose reductions (in 10 patients) in the SIM group were due to hypertension.

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 25–52, 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.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This double-blind, parallel-group study was conducted to compare the safety, tolerability and efficacy of Neoral and SIM in patients with severe active RA who were not currently receiving second-line treatment and who had not been treated previously with Neoral or SIM. The two treatment groups were similar with regard to their demographic characteristics, disease characteristics and use of concomitant medication (including NSAIDs, steroids and anti-hypertensive medications) at entry to the study. In the majority of patients, the disease was of extended duration, with a mean time since diagnosis of 133 months in the Neoral group and 130 months in the SIM group. Almost all of the patients had received SAARDs before entry into the study. The wash-out period of 6 weeks (including the 4-week screening period) may seem short. However, as the previous use of SAARDs was similar in the two groups, the length of the wash-out period is unlikely to have affected our results.

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 3Go. 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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TABLE 3. Summary of the main differences in efficacy results between the Neoral and SIM groups

 
Oral doses of both formulations increased slowly from week 4, indicating that the initial dose (Neoral: 2.48 mg/kg/day; SIM: 2.50 mg/kg/day) provided suboptimal efficacy in both groups. The proportion of patients requiring an increase in the initial dose was not statistically significantly different for the two groups. However, from week 6 there was a consistent trend of reduced requirement in the Neoral group for dose adjustments due to lack of efficacy, compared with SIM. Consequently, mean doses of Neoral were lower than those of SIM at all time points from week 6. This was an important observation, suggesting that long-term efficacy may be maintained using a lower dose of Neoral, compared with SIM. The reason for this is likely to be the greater bioavailability of CyA provided by the Neoral formulation, as indicated by the higher AUC and Cmax found in the Neoral arm of the pharmacokinetic assessment subgroup.

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.


    Acknowledgments
 
This work was supported by a grant from Novartis Pharma AG.


    Notes
 
22 Correspondence to: D. Yocum, Director—Arizona Arthritis Center, University of Arizona, Health Science Center, Room 6409, 1501 N. Campbell Avenue, Tucson, AZ 85724, USA. Back

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. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Waalen K, Førre Ø, Linker-Israeli M, Thoen J. Evidence of an activated T-cell system with augmented turnover of interleukin 2 in rheumatoid arthritis. Scand J Immunol 1987;25:367–73.[ISI][Medline]
  2. Harris ED Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 1990;322:1277–89.[ISI][Medline]
  3. Panayi GS, Lanchbury JS, Kingsley GH. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum 1992;35:729–35.[ISI][Medline]
  4. Salmon M, Gaston JSH. The role of T-lymphocytes in rheumatoid arthritis. Br Med Bull 1995;51:332–45.[Abstract]
  5. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporin A and FK506. Immunol Today 1992;13:136–42.[ISI][Medline]
  6. Baumann G. Molecular mechanism of immunosuppressive agents. Transplant Proc 1992;24(Suppl. 2):4–7.[ISI][Medline]
  7. Dougados M, Awada H, Amor B. Cyclosporin in rheumatoid arthritis: a double blind, placebo controlled study in 52 patients. Ann Rheum Dis 1988;47:127–33.[Abstract]
  8. Tugwell P, Bombardier C, Gent M et al. Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 1990;335:1051–5.[ISI][Medline]
  9. van Rijthoven AW, Dijkmans BB, Goei Thé HS et al. Comparison of cyclosporine and D-penicillamine for rheumatoid arthritis: a randomized, double blind, multicenter study. J Rheumatol 1991;18:815–20.[ISI][Medline]
  10. Krüger K, Schattenkirchner M. Cyclosporine A vs azathioprine in the treatment of RA: results of a controlled multicentre double-blind study. J Autoimmun 1992;5:xix (abstr.).
  11. Dougados M, Luchesne L, Awada H, Amor B. Assessment of efficacy and acceptability of low dose cyclosporin in patients with rheumatoid arthritis. Ann Rheum Dis 1989;48:550–6.[Abstract]
  12. Dijkmans BA, van Rijthoven AW, Goei Thé HS, Boers M, Cats A. Cyclosporine in rheumatoid arthritis. Semin Arthritis Rheum 1992;22:30–6.[ISI][Medline]
  13. Tugwell P. Cyclosporine in rheumatoid arthritis: documented efficacy and safety. Semin Arthritis Rheum 1992;21(Suppl. 3):30–8.[Medline]
  14. Førre Ø, The Norwegian Arthritis Study Group. Radiologic evidence of disease modification in rheumatoid arthritis patients treated with cyclosporine. Results of a 48-week multicenter study comparing low-dose cyclosporine with placebo. Arthritis Rheum 1994;37:1506–12.[ISI][Medline]
  15. Førre Ø. Cyclosporine in rheumatoid arthritis: an overview. Clin Rheumatol 1995;14(Suppl. 2):33–6.[ISI][Medline]
  16. Yocum DE, Torley H. Cyclosporine in rheumatoid arthritis. Rheum Dis Clin North Am 1995;21:835–44.[ISI][Medline]
  17. Landewé RB, Goei Thé HS, Van Rijthoven AWAM, Breedveld FC, Dijkmans BA. A randomized, double-blind, 24-week controlled study of low-dose cyclosporine versus chloroquine for early rheumatoid arthritis. Arthritis Rheum 1994;37:637–43.[ISI][Medline]
  18. Pasero G, Priolo F, Marubini E et al. Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 1996;39:1006–15.[ISI][Medline]
  19. Rodríguez F, Krayenbühl JC, Harrision WB et al. Renal biopsy findings and followup of renal function in rheumatoid arthritis patients treated with cyclosporin A: an update from the International Kidney Biopsy Registry. Arthritis Rheum 1996;39:1491–8.[Medline]
  20. von Graffenried B, Krupp P. Side effects of cyclosporin following kidney transplantation and in patients with autoimmune diseases. Internist Berl 1985;26:542–8.[Medline]
  21. Feutren G, Mihatsch MJ. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. N Engl J Med 1992;326:1654–60.[Abstract]
  22. Feutren G. Renal morphology after cyclosporin A therapy in rheumatoid arthritis patients. International Kidney Biopsy Registry of Cyclosporin (Sandimmun) in Autoimmune Diseases. Br J Rheumatol 1993;32(Suppl. 1):65–71.[ISI][Medline]
  23. Kovarik JM, Mueller EA, van Bree JB, Tetzloff W, Kutz K. Reduced inter- and intraindividual variability in cyclosporine pharmacokinetics from a microemulsion formulation. J Pharm Sci 1994;83:444–6.[ISI][Medline]
  24. Taesch S, Niese D. Safety and tolerability of a new oral formulation of cyclosporin A, Sandimmun Neoral, in renal transplant patients. Transplant Int 1994;7(Suppl. 1): S263–S6.[Medline]
  25. Niese D, and the International Sandimmun Neoral Study Group. A double-blind randomized study of Sandimmun Neoral versus Sandimmun in new renal transplant recipients: results after 12 months. Transplant Proc 1995;27:1849–56.[ISI][Medline]
  26. Kovarik JM, Mueller EA, van Bree JB et al. Cyclosporine pharmacokinetics and variability from a microemulsion formulation—a multicenter investigation in kidney transplant patients. Transplantation 1994;58:658–63.[ISI][Medline]
  27. van den Borne BEEM, Landewé RBM, Goei Thé HS, Mattie H, Breedveld FC, Dijkmans BAC. Relative bioavailability of a new oral form of cyclosporin A in patients with rheumatoid arthritis. Br J Clin Pharmacol 1995;39:172–5.[ISI][Medline]
  28. Leirisalo-Repo M, Anderson IF, Bjorneboe O, Kraag G, Schmidt A-G, for the OLR 301 study group. A randomized, double-blind study assessing the safety, tolerability and pharmacokinetic implications of a 1:1 dose conversion from stable Sandimmun® maintenance treatment to Sandimmun Neoral®, in RA patients. Rheumatol Eur 1996;26(Suppl. 1):49 abstract 106.
  29. Panayi GS, Tugwell P. An international consensus report: the use of cyclosporin A in rheumatoid arthritis. Br J Rheumatol 1993;32(Suppl. 1):1–3.
  30. Panayi GS, Tugwell P. The use of cyclosporin A in rheumatoid arthritis: conclusions of an international review. Br J Rheumatol 1994;33:967–9.[ISI][Medline]
  31. Panayi GS, Tugwell P. The use of cyclosporin A in rheumatoid arthritis: conclusions of an international review. Br J Rheumatol 1997;36:808–11.[ISI][Medline]
  32. Panayi G, Tugwell P. The use of cyclosporin A microemulsion in rheumatoid arthritis: conclusions of an international review. Br J Rheumatol 1997;36:808–11.[ISI][Medline]
  33. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35.[ISI][Medline]
  34. Ritchie DM, Boyle JA, McInnes JM et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Q J Med 1968;37:393–406.[Medline]
  35. Fries JF. The assessment of disability: from first to future principles. Br J Rheumatol 1983;22(Suppl.):48–58.[ISI][Medline]
Submitted 2 July 1998; revised version accepted 25 May 1999.



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