Switching STudy of Kidney TRansplant PAtients with Tremor to LCP-TacrO (STRATO): an open-label, multicenter, prospective phase 3b study

Anthony Langone, Steven M Steinberg, Roberto Gedaly, Laurence K Chan, Tariq Shah, Kapil D Sethi, Vincenza Nigro, John C Morgan, STRATO Investigators, Richard N Formica, Antonios Arvelakis, Yousri M Barr, Daniel C Brennan, Laurence K Chan, Jose-Marie Albert El-Amm, Roberto Gedaly, Tomasz Kozlowski, Anthony Langone, Arthur Jeremy Matas, Tariq Shah, Steven M Steinberg, Patricia M West-Thielke, Kristin Kistler, Barbra Perry, Wenjiong Zhou, Anthony Langone, Steven M Steinberg, Roberto Gedaly, Laurence K Chan, Tariq Shah, Kapil D Sethi, Vincenza Nigro, John C Morgan, STRATO Investigators, Richard N Formica, Antonios Arvelakis, Yousri M Barr, Daniel C Brennan, Laurence K Chan, Jose-Marie Albert El-Amm, Roberto Gedaly, Tomasz Kozlowski, Anthony Langone, Arthur Jeremy Matas, Tariq Shah, Steven M Steinberg, Patricia M West-Thielke, Kristin Kistler, Barbra Perry, Wenjiong Zhou

Abstract

Tremor is a common side effect of tacrolimus correlated with peak-dose drug concentration. LCPT, a novel, once-daily, extended-release formulation of tacrolimus, has a reduced Cmax with comparable AUC exposure, requiring a ~30% dose reduction vs. immediate-release tacrolimus. In this phase 3b study, kidney transplant recipients (KTR) on a stable dose of tacrolimus and with a reported clinically significant tremor were offered a switch to LCPT. Tremor pre- and seven d post-conversion was evaluated by independent, blinded movement disorder neurologists using the Fahn-Tolosa-Marin (FTM) scale and by an accelerometry device; patients completed the QUEST (quality of life in essential tremor) and the Patient Global Impression of Change. There were 38 patients in the mITT population. A statistically and clinically significant improvement in tremor (FTM score, amplitude as measured by the accelerometry device and QOL [p-values < 0.05]) resulted post-conversion. Change in QUEST was significantly (p = 0.006) correlated (R = 0.44) with change in FTM; 78.9% of patients reported an improvement after switching to LCPT (p < 0.0005). To our knowledge this is the first trial in KTR that utilizes a sophisticated and reproducible measurement of tremor. Results suggest LCPT is associated with clinically meaningful improvement of hand tremor and may be an alternative management approach in lieu of further dose reduction of immediate-release tacrolimus for patients experiencing tremor.

Keywords: Envarsus; LCP-Tacro; MeltDose; Prograf; adverse events; extended-release; kidney transplantation; tacrolimus; tremor.

© 2015 The Authors. Clinical Transplantation Published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Study design. AE, adverse event; FTM, Fahn–Tolosa–Marin rating scale; CGI, clinician global impression of change; PGI, patient global impression of change; QUEST, quality of life in essential tremor scale.
Figure 2
Figure 2
Fahn–Tolosa–Marin (FTM) score reduction (improvement) after conversion to LCP‐Tacro in patients experiencing severe hand tremors.
Figure 3
Figure 3
Absolute and percent change (improvement) in Fahn–Tolosa–Marin (FTM) score and subscale scores at day 14.
Figure 4
Figure 4
Absolute change from baseline (improvement) in tremorometer amplitude indicators.
Figure 5
Figure 5
Absolute and percent change (improvement) in QUEST score and subscale scores at day 14.
Figure 6
Figure 6
CGI and PGI Scales show improvement after seven d of LCP‐Tacro treatment.

References

    1. Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR) . OPTN/SRTR 2012 Annual Data Report. Rockville, MD: Department of Health and Human Services, Health Resources and Services Administration, 2014.
    1. Webster AC, Taylor RRS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev. 2005(4): Art. No.: CD003961.
    1. Draft Guidance on Tacrolimus. Available at: [Last accessed 2 July 2014].
    1. Prograf Prescribing Information. Northbrook, IL: Astellas Pharma US, Inc., September 2013.
    1. Bulatova N, Yousef AM, Al‐Khayyat G, Qosa H. Adverse effects of tacrolimus in renal transplant patients from living donors. Curr Drug Saf 2011: 6: 3.
    1. Bechstein WO. Neurotoxicity of calcineurin inhibitors: impact and clinical management. Transpl Int 2000: 13: 313.
    1. Paul LC. Overview of side effects of immunosuppressive therapy. Transplant Proc 2001: 33: 2089.
    1. Martínez‐Sanchis S, Bernal MC, Montagud JV et al. Effects of immunosuppressive drugs on the cognitive functioning of renal transplant recipients: a pilot study. J Clin Exp Neuropsychol 2011: 33: 1016.
    1. Eidelman BH, Abu‐Elmagd K, Wilson J et al. Neurologic complications of FK 506. Transplant Proc 1991: 23: 3175.
    1. Abouljoud MS, Kumar MSA, Brayman KL, Emre S, Bynon JS, for the OLNSG . Neoral® rescue therapy in transplant patients with intolerance to tacrolimus. Clin Transplant 2002: 16: 168.
    1. Kugler C, Fischer S, Gottlieb J et al. Symptom experience after lung transplantation: impact on quality of life and adherence. Clin Transplant 2007: 21: 590.
    1. Kugler C, Geyer S, Gottlieb J, Simon A, Haverich A, Dracup K. Symptom experience after solid organ transplantation. J Psychosom Res 2009: 66: 101.
    1. de Barros CT, Cabrita J. Self‐report of symptom frequency and symptom distress in kidney transplant recipients. Pharmacoepidemiol Drug Saf 1999: 8: 395.
    1. Drent G, De Geest S, Dobbels F, Kleibeuker JH, Haagsma EB. Symptom experience, nonadherence and quality of life in adult liver transplant recipients. Neth J Med 2009: 67: 161.
    1. Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. Conversion from twice‐daily tacrolimus capsules to once‐daily extended‐release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients. Transplantation 2013: 96: 191.
    1. MeltDose® Technology by the US Patent and Trademark Office, US Patent No. 7,217,431.
    1. DuBay DA, Alloway RR, Alsina AE et al. A phase 2b, open‐label, multicenter, prospective, randomized study to compare the pharmacokinetics and safety of LCP‐Tacro™ tablets once‐a‐day to Prograf® capsules twice‐a‐day in de novo liver transplant patients. Liver Transpl 2009: 15(Suppl 7): S14.
    1. Alloway RR, Eckhoff DE, Washburn WK, Teperman LW. Conversion from twice‐daily tacrolimus capsules to once‐daily extended‐release tacrolimus (LCPT): phase II trial of stable liver transplant recipients. Liver Transpl 2014: 20: 564.
    1. Alloway R, Mulgaonkar S, Ueda K, Cohen D, Kaplan B. A phase 2 randomized study of the pharmacokinetics, safety and efficacy of LCP‐Tacro tablets once‐a‐day vs Prograf capsules twice‐a‐day in de novo kidney transplants. Am J Transplant 2011: 11(Suppl 2): 355.
    1. Alloway RR, Mulgaonkar S, Bowers VD et al. A phase 2b, open‐label, multi‐center, prospective, randomized study to compare the pharmacokinetics and safety of LCP‐Tacro™ tablets once‐a‐day to Prograf® capsules twice‐a‐day in de novo kidney transplant patients. Am J Transplant 2009: 9(Suppl 2): 414.
    1. Bunnapradist S, Ciechanowski K, West‐Thielke P et al. Conversion from twice‐daily tacrolimus to once‐daily extended release tacrolimus (LCPT): the phase III randomized MELT trial. Am J Transplant 2013: 13: 760.
    1. Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. Conversion from twice‐daily tacrolimus capsules to once‐daily extended‐release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients. Transplantation 2013: 96: 19.
    1. Stacy MA, Elble RJ, Ondo WG, Wu S‐C, Hulihan J. Assessment of interrater and intrarater reliability of the Fahn–Tolosa–Marin Tremor Rating Scale in essential tremor. Mov Disord 2007: 22: 833.
    1. Fahn S, Tolosa E, Marı′n C. Clinical rating scale for tremor In: Jankovic J, Tolosa E. eds. Parkinson's Disease and Movement Disorders. Baltimore: Williams & Wilkins, 1993: 225.
    1. Paul F, Müller J, Christe W, Steinmüller T, Poewe W, Wissel J. Postural hand tremor before and following liver transplantation and immunosuppression with cyclosporine or tacrolimus in patients without clinical signs of hepatic encephalopathy. Clin Transplant 2004: 18: 429.
    1. Tröster AI, Pahwa R, Fields JA, Tanner CM, Lyons KE. Quality of life in Essential Tremor Questionnaire (QUEST): development and initial validation. Parkinsonism Relat Disord 2005: 11: 367.
    1. Sandvik U, Hariz G‐M, Blomstedt P. Quality of life following DBS in the caudal zona incerta in patients with essential tremor. Acta Neurochir 2012: 154: 495.
    1. Ondo WG, Jandovic J, Connor GS et al. Topiramate in essential tremor: a doubleblind, placebo‐controlled trial. Neurology 2006: 66: 672.
    1. Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998: 13(Suppl 3): 2.

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