Treatment of diffuse systemic sclerosis with hyperimmune caprine serum (AIMSPRO): a phase II double-blind placebo-controlled trial

N P Quillinan, D McIntosh, J Vernes, S Haq, C P Denton, N P Quillinan, D McIntosh, J Vernes, S Haq, C P Denton

Abstract

Objective: The primary objective of the study was to explore safety and tolerability of hyperimmune caprine serum (AIMSPRO) in established diffuse cutaneous systemic sclerosis (SSc). Secondary objectives included assessment of potential efficacy and biological activity and exploration of candidate biomarkers.

Methods: This was a double-blind parallel group randomised placebo-controlled clinical trial. After informed consent 20 patients with established diffuse cutaneous SSc of greater than 3 years duration not receiving immunosuppressive therapy were randomised to receive either active (n=10) or placebo formulation (n=10) by subcutaneous twice weekly injection over 26 weeks. Clinical assessments were evaluated over 26 weeks.

Results: There were no safety concerns during this study. Frequency of adverse events was not different between active and placebo groups. Mean modified Rodnan Skin Score (mRSS) fell by 1.4±4.7 units with active treatment but increased by 2.1±6.4 units on placebo when baseline values were compared with 26 weeks and responder analysis showed clinically meaningful improvement in mRSS at 26 weeks in 5 (50%) of actively treated patients compared with 1 (10%) in the control group (p=0.062). PIIINP (µg/L) showed a comparatively larger increase in the treatment group compared with the placebo group, (p=0.0118).

Conclusions: These results confirm tolerability and safety of this novel biological agent in established diffuse SSc. The value of a placebo treated control group in small clinical trials evaluating skin disease in SSc is confirmed. Potential improvement in mRSS and changes in PIIINP in cases receiving active therapy suggest that this intervention may be of clinical benefit and warrants further evaluation.

Trial registration: ClinicalTrials.gov NCT00769028.

Keywords: Autoimmune Diseases; DMARDs (biologic); Systemic Sclerosis; Treatment.

Figures

Figure 1
Figure 1
Improvement in modified Rodnan Skin Score (mRSS) and in neuropathic pain visual analogue scale (VAS) from baseline to week 26 in active treatment arm. (A) There was an increase in mean mRSS in the placebo treated subjects and improvement in those receiving active therapy. This did not reach statistical significance but changes were driven by the larger number of cases on active treatment that showed clinically meaningful improvement in mRSS during the trial (>4 skin score units and 20% of baseline mRSS). The lines marked in bold show cases with significant improvement on active treatment or placebo. Responder frequency analysis showed a strong trend in favour of active treatment (p=0.062). (B) Neuropathic pain VAS showed a significant difference between groups at week 26 with an improvement in the treatment group and no significant change in the placebo group.
Figure 2
Figure 2
Graphical representation of change from baseline to week 26 for candidate serum biomarkers. There were no statistically significant changes in von Willebrand factor (vWF; A) or sIL-2R (panel B) between baseline and end of study. However, PIIINP (C) showed significant increase in the active treatment arm compared with the placebo group. This novel observation may reflect increased connective tissue remodelling in late-stage SSc cases receiving active treatment as it occurs in the context of improvement in average skin score.

References

    1. Shand L, Lunt M, Nihtyanova S, et al. Relationship between change in skin score and disease outcome in diffuse cutaneous systemic sclerosis: application of a latent linear trajectory model. Arthritis Rheum 2007;56:2422–31
    1. LeRoy EC, Black C, Fleischmajer R, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol 1988;15:202–5
    1. Nihtyanova SI, Tang EC, Coghlan JG, et al. Improved survival in systemic sclerosis is associated with better ascertainment of internal organ disease: a retrospective cohort study. QJM 2010;103:109–15
    1. Denton CP. Therapeutic targets in systemic sclerosis. Arthritis Res Ther 2007;9(Suppl 2):S6.
    1. Postlethwaite AE, Wong WK, Clements P, et al. A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I. oral type I collagen does not improve skin in all patients, but may improve skin in late-phase disease. Arthritis Rheum 2008;58:1810–22
    1. Quillinan NP, Denton CP. Disease modifying treatment in Systemic Sclerosis: current status. Curr Opin Rheumatol 2009;21:636–41
    1. Kowal-Bielecka O, Landewe R, Avouac J, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 2009;68:620–8
    1. Moore CEG, Hannan R, McIntosh D. In vivo, human peripheral nerve strength duration time constant changes with Aimspro implicate altered sodium channel function as a putative mechanism of action. J Neurol Sci 2005;238:S238
    1. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980;23:581–90
    1. Khanna D, Furst DE, Hays RD, et al. Minimally important difference in diffuse systemic sclerosis: results from the D-penicillamine study. Ann Rheum Dis 2006;65:1325–9
    1. Steen VD, Medsger TA., Jr The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum 1997;40:1984–91
    1. Serednicka K, Smyth AE, Black CM, et al. Using a self-reported functional score to assess disease progression in systemic sclerosis. Rheumatology 2007;46:1107–10
    1. Chung L, Denton CP, Distler O, et al. Clinical trial design in scleroderma. Clin Exp Rheumatol 2012;30:S97–102
    1. Lydersen S, Langaas M, Bakke Ø. The exact unconditional z-pooled test for equality of two binomial probabilities: optimal choice of the berger and Boos Confidence coefficient. J Stat Comput Simulation 82:1311–16
    1. Levy Y, Amital H, Langevitz P, et al. Intravenous immunoglobulin modulates cutaneous involvement and reduces skin fibrosis in systemic sclerosis: an open-label study. Arthritis Rheum 2004;50:1005–7
    1. Denton CP, Engelhart M, Tvede N, et al. An open-label pilot study of infliximab therapy in diffuse cutaneous systemic sclerosis. Ann Rheum Dis 2009;68:1433–9
    1. Denton CP, Merkel PA, Furst DE, et al. Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192. Arthritis Rheum 2007;56:323–33
    1. Merkel PA, Silliman NP, Clements PJ, et al. Patterns and predictors of change in outcome measures in clinical trials in scleroderma: an individual patient meta-analysis of 629 subjects with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2012;64:3420–9
    1. Gliddon AE, Doré CJ, Black CM, et al. Prevention of vascular damage in scleroderma and autoimmune Raynaud's phenomenon: a multicenter, randomized, double-blind, placebo-controlled trial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 2007;56:3837–46
    1. Lee YJ, Shin KC, Kang SW, et al. Type III procollagen N-terminal propeptide, soluble interleukin-2 receptor, and von Willebrand factor in systemic sclerosis. Clin Exp Rheumatol 2001;19:69–74
    1. Khanna D, Saggar R, Mayes MD,et al. A one-year, phase I/IIa, open-label pilot trial of imatinib mesylate in the treatment of systemic sclerosis-associated active interstitial lung disease. Arthritis Rheum 2011;63:3540–6

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться