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Do we start too late? Insights from the real-world non-interventional BALANCE study on the present use of levodopa/carbidopa intestinal gel in advanced Parkinson's disease in Germany and Switzerland

      Highlights

      • In present clinical practice patients and physicians use LCIG late.
      • This practice is in contrast to the available randomized controlled trial.
      • Quality of life is lower and treatment-emergent adverse effects higher with this practice.
      • Nevertheless, some motor and non-motor outcomes may improve after 12 months with LCIG.
      • LCIG should not be delayed for too long, once the established indication criteria have been met.

      Abstract

      Introduction

      Advanced Parkinson's disease is characterized by motor and non-motor fluctuations to oral dopamine replacement therapy. The BALANCE study evaluated the clinical practice in Germany and Switzerland, when patients eligible for levodopa/carbidopa intestinal gel (LCIG) therapy decided to either switch to LCIG or to stay on optimized standard of care (SoC) oral therapy as a non-randomized regular clinical decision.

      Methods

      In this non-interventional, multicenter, prospective observational study, patients were recruited between 2015 and 2020. We obtained comprehensive baseline characteristics in both groups. As primary endpoint, we evaluated whether LCIG led to higher quality-of-life (QoL) improvement than SoC after 12 months. As secondary endpoints, we studied several motor and non-motor outcomes.

      Results

      About half of the 137 patients decided for LCIG treatment (n = 73, 53.5%). Those were aged >70 years more often, had more advanced disease stage, higher burden of motor and neuropsychiatric symptoms, and cognitive impairment including dementia compared to SoC. QoL change after 12 months did not differ between groups (P = 0.286). The LCIG group improved in secondary outcomes, including the UPDRS III in ON, UPDRS IV, Unified Dyskinesia Rating Scale, and Non-Motor Symptoms Scale. Clinical Global Impression-Improvement scale improved in 78.0% and 19.5% of patients receiving LCIG and SoC, respectively. Caregiver burden remained stable in LCIG but worsened with SoC.

      Conclusion

      In current practice, patients and physicians delayed LCIG treatment and started substantially beyond the established indication criteria. This practice bears the risk to produce inferior results compared to the results from existing high-level evidence.

      Keywords

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      References

        • de Bie R.M.A.
        • Clarke C.E.
        • Espay A.J.
        • Fox S.H.
        • Lang A.E.
        Initiation of pharmacological therapy in Parkinson's disease: when, why, and how.
        Lancet Neurol. 2020; 19: 452-461https://doi.org/10.1016/S1474-4422(20)30036-3
        • Weiss D.
        • Volkmann J.
        • Fasano A.
        • Kühn A.
        • Krack P.
        • Deuschl G.
        Changing gears - DBS for dopaminergic desensitization in Parkinson's disease?.
        Ann. Neurol. 2021; https://doi.org/10.1002/ana.26164
        • Calabresi P.
        • Di Filippo M.
        • Ghiglieri V.
        • Tambasco N.
        • Picconi B.
        Levodopa-induced dyskinesias in patients with Parkinson's disease: filling the bench-to-bedside gap.
        Lancet Neurol. 2010; 9: 1106-1117https://doi.org/10.1016/S1474-4422(10)70218-0
        • Olanow C.W.
        • Kieburtz K.
        • Odin P.
        • Espay A.J.
        • Standaert D.G.
        • Fernandez H.H.
        • Vanagunas A.
        • Othman A.A.
        • Widnell K.L.
        • Robieson W.Z.
        • Pritchett Y.
        • Chatamra K.
        • Benesh J.
        • Lenz R.A.
        • Antonini A.
        Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson's disease: a randomised, controlled, double-blind, double-dummy study.
        Lancet Neurol. 2014; 13: 141-149https://doi.org/10.1016/S1474-4422(13)70293-X
        • Volkmann J.
        • Albanese A.
        • Antonini A.
        • Chaudhuri K.R.
        • Clarke C.E.
        • de Bie R.M.A.
        • Deuschl G.
        • Eggert K.
        • Houeto J.-L.
        • Kulisevsky J.
        • Nyholm D.
        • Odin P.
        • Østergaard K.
        • Poewe W.
        • Pollak P.
        • Rabey J.M.
        • Rascol O.
        • Ruzicka E.
        • Samuel M.
        • Speelman H.
        • Sydow O.
        • Valldeoriola F.
        • van der Linden C.
        • Oertel W.
        Selecting deep brain stimulation or infusion therapies in advanced Parkinson's disease: an evidence-based review.
        J. Neurol. 2013; 260: 2701-2714https://doi.org/10.1007/s00415-012-6798-6
        • Dafsari H.S.
        • Martinez-Martin P.
        • Rizos A.
        • Trost M.
        • Dos Santos Ghilardi M.G.
        • Reddy P.
        • Sauerbier A.
        • Petry-Schmelzer J.N.
        • Kramberger M.
        • Borgemeester R.W.K.
        • Barbe M.T.
        • Ashkan K.
        • Silverdale M.
        • Evans J.
        • Odin P.
        • Fonoff E.T.
        • Fink G.R.
        • Henriksen T.
        • Ebersbach G.
        • Pirtošek Z.
        • Visser-Vandewalle V.
        • Antonini A.
        • Timmermann L.
        • Ray Chaudhuri K.
        EuroInf 2: subthalamic stimulation, apomorphine, and levodopa infusion in Parkinson's disease.
        Mov. Disord. 2019; 34: 353-365https://doi.org/10.1002/mds.27626
        • Nyholm D.
        • Odin P.
        • Johansson A.
        • Chatamra K.
        • Locke C.
        • Dutta S.
        • Othman A.A.
        Pharmacokinetics of levodopa, carbidopa, and 3-O-methyldopa following 16-hour jejunal infusion of levodopa-carbidopa intestinal gel in advanced Parkinson's disease patients.
        AAPS J. 2013; 15: 316-323https://doi.org/10.1208/s12248-012-9439-1
        • Fernandez H.H.
        • Standaert D.G.
        • Hauser R.A.
        • Lang A.E.
        • Fung V.S.C.
        • Klostermann F.
        • Lew M.F.
        • Odin P.
        • Steiger M.
        • Yakupov E.Z.
        • Chouinard S.
        • Suchowersky O.
        • Dubow J.
        • Hall C.M.
        • Chatamra K.
        • Robieson W.Z.
        • Benesh J.A.
        • Espay A.J.
        Levodopa-carbidopa intestinal gel in advanced Parkinson's disease: final 12-month, open-label results.
        Mov. Disord. 2015; 30: 500-509https://doi.org/10.1002/mds.26123
        • Krüger R.
        • Lingor P.
        • Doskas T.
        • Henselmans J.M.L.
        • Danielsen E.H.
        • de Fabregues O.
        • Stefani A.
        • Sensken S.-C.
        • Parra J.C.
        • Onuk K.
        • Yegin A.
        • Antonini A.
        An observational study of the effect of levodopa-carbidopa intestinal gel on activities of daily living and quality of life in advanced Parkinson's disease patients.
        Adv. Ther. 2017; 34: 1741-1752https://doi.org/10.1007/s12325-017-0571-2
        • Antonini A.
        • Poewe W.
        • Chaudhuri K.R.
        • Jech R.
        • Pickut B.
        • Pirtošek Z.
        • Szasz J.
        • Valldeoriola F.
        • Winkler C.
        • Bergmann L.
        • Yegin A.
        • Onuk K.
        • Barch D.
        • Odin P.
        Levodopa-carbidopa intestinal gel in advanced Parkinson's: final results of the GLORIA registry.
        Park. Relat. Disord. 2017; 45: 13-20https://doi.org/10.1016/j.parkreldis.2017.09.018
        • Eggert K.
        • Oertel W.
        • Reichmann H.
        Parkinson Syndrome – Diagnostik und Therapie. S2k-Leitlinie.
        Thieme Verlag, Stuttgart2012
        • Limousin P.
        • Foltynie T.
        Long-term outcomes of deep brain stimulation in Parkinson disease.
        Nat. Rev. Neurol. 2019; 15: 234-242https://doi.org/10.1038/s41582-019-0145-9
        • Jenkinson C.
        • Fitzpatrick R.
        • Peto V.
        • Greenhall R.
        • Hyman N.
        The Parkinson's Disease Questionnaire (PDQ-39): development and validation of a Parkinson's disease summary index score.
        Age Ageing. 1997; 26: 353-357https://doi.org/10.1093/ageing/26.5.353
        • Trenkwalder C.
        • Kohnen R.
        • Högl B.
        • Metta V.
        • Sixel-Döring F.
        • Frauscher B.
        • Hülsmann J.
        • Martinez-Martin P.
        • Chaudhuri K.R.
        Parkinson's disease sleep scale--validation of the revised version PDSS-2.
        Mov. Disord. 2011; 26: 644-652https://doi.org/10.1002/mds.23476
        • Johns M.W.
        A new method for measuring daytime sleepiness: the Epworth sleepiness scale.
        Sleep. 1991; 14: 540-545https://doi.org/10.1093/sleep/14.6.540
        • Goetz C.G.
        • Nutt J.G.
        • Stebbins G.T.
        The unified dyskinesia rating scale: presentation and clinimetric profile.
        Mov. Disord. 2008; 23: 2398-2403https://doi.org/10.1002/mds.22341
        • Guy W.
        Clinical Global Impressions, Ockville, MD: U.S. Department of Health, Education, and Welfare; Public Health Service, Alcohol; Drug Abuse, and Mental Health Administration.
        National Institute of Mental Health; Psychopharmacology Research Branch; Division of Extramural Research Programs, 1976: 218-222
        • Hagell P.
        • Nygren C.
        The 39 item Parkinson's disease questionnaire (PDQ-39) revisited: implications for evidence based medicine.
        J. Neurol. Neurosurg. Psychiatry. 2007; 78: 1191-1198https://doi.org/10.1136/jnnp.2006.111161
        • Braun M.
        • Scholz U.
        • Hornung R.
        • Martin M.
        Die subjektive Belastung pflegender Ehepartner von Demenzkranken. Hinweise zur Validität der deutschen Version des Zarit Burden Interviews.
        Z. Gerontol. Geriatr. 2010; 43: 111-119https://doi.org/10.1007/s00391-010-0097-6
        • Fahn S.
        • Elton R.L.
        Members of the UPDRS development committee, the unified Parkinson's disease rating scale.
        in: Recent Developments in Parkinson's Disease. vol. 2. Macmillan Healthcare Information, Florham Park, NJ1987: 293-304 (153-163)
        • Chaudhuri K.R.
        • Martinez-Martin P.
        • Brown R.G.
        • Sethi K.
        • Stocchi F.
        • Odin P.
        • Ondo W.
        • Abe K.
        • Macphee G.
        • Macmahon D.
        • Barone P.
        • Rabey M.
        • Forbes A.
        • Breen K.
        • Tluk S.
        • Naidu Y.
        • Olanow W.
        • Williams A.J.
        • Thomas S.
        • Rye D.
        • Tsuboi Y.
        • Hand A.
        • Schapira A.H.
        The metric properties of a novel non-motor symptoms scale for Parkinson's disease: results from an international pilot study.
        Mov. Disord. 2007; 22: 1901-1911https://doi.org/10.1002/mds.21596
        • Deuschl G.
        • Schade-Brittinger C.
        • Krack P.
        • Volkmann J.
        • Schäfer H.
        • Bötzel K.
        • Daniels C.
        • Deutschländer A.
        • Dillmann U.
        • Eisner W.
        • Gruber D.
        • Hamel W.
        • Herzog J.
        • Hilker R.
        • Klebe S.
        • Kloss M.
        • Koy J.
        • Krause M.
        • Kupsch A.
        • Lorenz D.
        • Lorenzl S.
        • Mehdorn H.M.
        • Moringlane J.R.
        • Oertel W.
        • Pinsker M.O.
        • Reichmann H.
        • Reuss A.
        • Schneider G.-H.
        • Schnitzler A.
        • Steude U.
        • Sturm V.
        • Timmermann L.
        • Tronnier V.
        • Trottenberg T.
        • Wojtecki L.
        • Wolf E.
        • Poewe W.
        • Voges J.
        A randomized trial of deep-brain stimulation for Parkinson's disease.
        N. Engl. J. Med. 2006; 355: 896-908https://doi.org/10.1056/NEJMoa060281
        • Krack P.
        • Batir A.
        • van Blercom N.
        • Chabardes S.
        • Fraix V.
        • Ardouin C.
        • Koudsie A.
        • Limousin P.D.
        • Benazzouz A.
        • LeBas J.F.
        • Benabid A.-L.
        • Pollak P.
        Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease.
        N. Engl. J. Med. 2003; 349: 1925-1934https://doi.org/10.1056/NEJMoa035275
        • Schuepbach W.M.M.
        • Rau J.
        • Knudsen K.
        • Volkmann J.
        • Krack P.
        • Timmermann L.
        • Hälbig T.D.
        • Hesekamp H.
        • Navarro S.M.
        • Meier N.
        • Falk D.
        • Mehdorn M.
        • Paschen S.
        • Maarouf M.
        • Barbe M.T.
        • Fink G.R.
        • Kupsch A.
        • Gruber D.
        • Schneider G.-H.
        • Seigneuret E.
        • Kistner A.
        • Chaynes P.
        • Ory-Magne F.
        • Brefel Courbon C.
        • Vesper J.
        • Schnitzler A.
        • Wojtecki L.
        • Houeto J.-L.
        • Bataille B.
        • Maltête D.
        • Damier P.
        • Raoul S.
        • Sixel-Doering F.
        • Hellwig D.
        • Gharabaghi A.
        • Krüger R.
        • Pinsker M.O.
        • Amtage F.
        • Régis J.-M.
        • Witjas T.
        • Thobois S.
        • Mertens P.
        • Kloss M.
        • Hartmann A.
        • Oertel W.H.
        • Post B.
        • Speelman H.
        • Agid Y.
        • Schade-Brittinger C.
        • Deuschl G.
        Neurostimulation for Parkinson's disease with early motor complications.
        N. Engl. J. Med. 2013; 368: 610-622https://doi.org/10.1056/NEJMoa1205158
        • Juhász A.
        • Aschermann Z.
        • Ács P.
        • Janszky J.
        • Kovács M.
        • Makkos A.
        • Harmat M.
        • Tényi D.
        • Karádi K.
        • Komoly S.
        • Takáts A.
        • Tóth A.
        • Nagy H.
        • Klivényi P.
        • Dibó G.
        • Dézsi L.
        • Zádori D.
        • Annus Á.
        • Vécsei L.
        • Varannai L.
        • Kovács N.
        Levodopa/carbidopa intestinal gel can improve both motor and non-motor experiences of daily living in Parkinson's disease: an open-label study.
        Park. Relat. Disord. 2017; 37: 79-86https://doi.org/10.1016/j.parkreldis.2017.02.001
        • Makkos A.
        • Kovács M.
        • Pintér D.
        • Janszky J.
        • Kovács N.
        Minimal clinically important difference for the historic parts of the Unified Dyskinesia Rating Scale.
        Park. Relat. Disord. 2019; 58: 79-82https://doi.org/10.1016/j.parkreldis.2018.08.018
        • Shulman L.M.
        • Gruber-Baldini A.L.
        • Anderson K.E.
        • Fishman P.S.
        • Reich S.G.
        • Weiner W.J.
        The clinically important difference on the unified Parkinson's disease rating scale.
        Arch. Neurol. 2010; 67: 64-70https://doi.org/10.1001/archneurol.2009.295
        • Lang A.E.
        • Rodriguez R.L.
        • Boyd J.T.
        • Chouinard S.
        • Zadikoff C.
        • Espay A.J.
        • Slevin J.T.
        • Fernandez H.H.
        • Lew M.F.
        • Stein D.A.
        • Odin P.
        • Fung V.S.C.
        • Klostermann F.
        • Fasano A.
        • Draganov P.V.
        • Schmulewitz N.
        • Robieson W.Z.
        • Eaton S.
        • Chatamra K.
        • Benesh J.A.
        • Dubow J.
        Integrated safety of levodopa-carbidopa intestinal gel from prospective clinical trials.
        Mov. Disord. 2016; 31: 538-546https://doi.org/10.1002/mds.26485