Browsing by Author "Gudesblatt, Mark"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Effect of Deutetrabenazine on Chorea Among Patients With Huntington Disease A Randomized Clinical Trial
    (2016-07) Frank, Samuel; Testa, Claudia M.; Stamler, David; Kayson, Elise; Davis, Charles; Edmondson, Mary C.; Kinel, Shari; Leavitt, Blair; Oakes, David; O'Neill, Christine; Vaughan, Christina; Goldstein, Jody; Herzog, Margaret; Snively, Victoria; Whaley, Jacquelyn; Wong, Cynthia; Suter, Greg; Jankovic, Joseph; Jimenez-Shahed, Joohi; Hunter, Christine; Claassen, Daniel O.; Roman, Olivia C.; Sung, Victor; Smith, Jenna; Janicki, Sarah; Clouse, Ronda; Saint-Hilaire, Marie; Hohler, Anna; Turpin, Denyse; James, Raymond C.; Rodriguez, Ramon; Rizer, Kyle; Anderson, Karen E.; Heller, Hope; Carlson, Alexis; Criswell, Susan; Racette, Brad A.; Revilla, Fredy J.; Nucifora, Frederick, Jr.; Margolis, Russell L.; Ong, MaryJane; Mendis, Tilak; Mendis, Neila; Singer, Carlos; Quesada, Monica; Paulsen, Jane S.; Brashers-Krug, Thomas; Miller, Amanda; Kerr, Jane; Dubinsky, Richard M.; Gray, Carolyn; Factor, Stewart A.; Sperin, Elaine; Molho, Eric; Eglow, Mary; Evans, Sharon; Kumar, Rajeev; Reeves, Christina; Samii, Ali; Chouinard, Sylvain; Beland, Monica; Scott, Burton L.; Hickey, Patrick T.; Esmail, Sherali; Fung, Wai Lun Alan; Gibbons, Clare; Qi, Lina; Colcher, Amy; Hackmyer, Cory; McGarry, Andrew; Klos, Kevin; Gudesblatt, Mark; Fafard, Lori; Graffitti, Laura; Schneider, Daniel P.; Dhall, Rohit; Wojcieszek, Joanne M.; LaFaver, Kathrin; Duker, Andrew; Neefus, Erin; Wilson-Perez, Hilary; Shprecher, David; Wall, Paola; Blindauer, Karen A.; Wheeler, Lynn; Boyd, James T.; Houston, Emily; Farbman, Eric S.; Agarwal, Pinky; Eberly, Shirley W.; Watts, Arthur; Tariot, Pierre N.; Feigin, Andrew; Evans, Scott; Beck, Chris; Orme, Constance; Edicola, Jon; Christopher, Emily; Department of Neurology, IU School of Medicine
    Importance Deutetrabenazine is a novel molecule containing deuterium, which attenuates CYP2D6 metabolism and increases active metabolite half-lives and may therefore lead to stable systemic exposure while preserving key pharmacological activity. Objective To evaluate efficacy and safety of deutetrabenazine treatment to control chorea associated with Huntington disease. Design, Setting, and Participants Ninety ambulatory adults diagnosed with manifest Huntington disease and a baseline total maximal chorea score of 8 or higher (range, 0-28; lower score indicates less chorea) were enrolled from August 2013 to August 2014 and randomized to receive deutetrabenazine (n = 45) or placebo (n = 45) in a double-blind fashion at 34 Huntington Study Group sites. Interventions Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout. Main Outcomes and Measures Primary end point was the total maximal chorea score change from baseline (the average of values from the screening and day-0 visits) to maintenance therapy (the average of values from the week 9 and 12 visits) obtained by in-person visits. This study was designed to detect a 2.7-unit treatment difference in scores. The secondary end points, assessed hierarchically, were the proportion of patients who achieved treatment success on the Patient Global Impression of Change (PGIC) and on the Clinical Global Impression of Change (CGIC), the change in 36-Item Short Form– physical functioning subscale score (SF-36), and the change in the Berg Balance Test. Results Ninety patients with Huntington disease (mean age, 53.7 years; 40 women [44.4%]) were enrolled. In the deutetrabenazine group, the mean total maximal chorea scores improved from 12.1 (95% CI, 11.2-12.9) to 7.7 (95% CI, 6.5-8.9), whereas in the placebo group, scores improved from 13.2 (95% CI, 12.2-14.3) to 11.3 (95% CI, 10.0-12.5); the mean between-group difference was –2.5 units (95% CI, –3.7 to –1.3) (P < .001). Treatment success, as measured by the PGIC, occurred in 23 patients (51%) in the deutetrabenazine group vs 9 (20%) in the placebo group (P = .002). As measured by the CGIC, treatment success occurred in 19 patients (42%) in the deutetrabenazine group vs 6 (13%) in the placebo group (P = .002). In the deutetrabenazine group, the mean SF-36 physical functioning subscale scores decreased from 47.5 (95% CI, 44.3-50.8) to 47.4 (44.3-50.5), whereas in the placebo group, scores decreased from 43.2 (95% CI, 40.2-46.3) to 39.9 (95% CI, 36.2-43.6), for a treatment benefit of 4.3 (95% CI, 0.4 to 8.3) (P = .03). There was no difference between groups (mean difference of 1.0 unit; 95% CI, –0.3 to 2.3; P = .14), for improvement in the Berg Balance Test, which improved by 2.2 units (95% CI, 1.3-3.1) in the deutetrabenazine group and by 1.3 units (95% CI, 0.4-2.2) in the placebo group. Adverse event rates were similar for deutetrabenazine and placebo, including depression, anxiety, and akathisia. Conclusions and Relevance Among patients with chorea associated with Huntington disease, the use of deutetrabenazine compared with placebo resulted in improved motor signs at 12 weeks. Further research is needed to assess the clinical importance of the effect size and to determine longer-term efficacy and safety.
  • Thumbnail Image
    Item
    Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study
    (Oxford University Press, 2024) Westenberger, Ana; Skrahina, Volha; Usnich, Tatiana; Beetz, Christian; Vollstedt, Eva-Juliane; Laabs, Björn-Hergen; Paul, Jefri J.; Curado, Filipa; Skobalj, Snezana; Gaber, Hanaa; Olmedillas, Maria; Bogdanovic, Xenia; Ameziane, Najim; Schell, Nathalie; Aasly, Jan Olav; Afshari, Mitra; Agarwal, Pinky; Aldred, Jason; Alonso-Frech, Fernando; Anderson, Roderick; Araújo, Rui; Arkadir, David; Avenali, Micol; Balal, Mehmet; Benizri, Sandra; Bette, Sagari; Bhatia, Perminder; Bonello, Michael; Braga-Neto, Pedro; Brauneis, Sarah; Costa Cardoso, Francisco Eduardo; Cavallieri, Francesco; Classen, Joseph; Cohen, Lisa; Coletta, Della; Crosiers, David; Cullufi, Paskal; Dashtipour, Khashayar; Demirkiran, Meltem; de Carvalho Aguiar, Patricia; De Rosa, Anna; Djaldetti, Ruth; Dogu, Okan; Dos Santos Ghilardi, Maria Gabriela; Eggers, Carsten; Elibol, Bulent; Ellenbogen, Aaron; Ertan, Sibel; Fabiani, Giorgio; Falkenburger, Björn H.; Farrow, Simon; Fay-Karmon, Tsviya; Ferencz, Gerald J.; Fonoff, Erich Talamoni; Fragoso, Yara Dadalti; Genç, Gençer; Gorospe, Arantza; Grandas, Francisco; Gruber, Doreen; Gudesblatt, Mark; Gurevich, Tanya; Hagenah, Johann; Hanagasi, Hasmet A.; Hassin-Baer, Sharon; Hauser, Robert A.; Hernández-Vara, Jorge; Herting, Birgit; Hinson, Vanessa K.; Hogg, Elliot; Hu, Michele T.; Hummelgen, Eduardo; Hussey, Kelly; Infante, Jon; Isaacson, Stuart H.; Jauma, Serge; Koleva-Alazeh, Natalia; Kuhlenbäumer, Gregor; Kühn, Andrea; Litvan, Irene; López-Manzanares, Lydia; Luxmore, McKenzie; Manandhar, Sujeena; Marcaud, Veronique; Markopoulou, Katerina; Marras, Connie; McKenzie, Mark; Matarazzo, Michele; Merello, Marcelo; Mollenhauer, Brit; Morgan, John C.; Mullin, Stephen; Musacchio, Thomas; Myers, Bennett; Negrotti, Anna; Nieves, Anette; Nitsan, Zeev; Oskooilar, Nader; Öztop-Çakmak, Özgür; Pal, Gian; Pavese, Nicola; Percesepe, Antonio; Piccoli, Tommaso; Pinto de Souza, Carolina; Prell, Tino; Pulera, Mark; Raw, Jason; Reetz, Kathrin; Reiner, Johnathan; Rosenberg, David; Ruiz-Lopez, Marta; Ruiz Martinez, Javier; Sammler, Esther; Santos-Lobato, Bruno Lopes; Saunders-Pullman, Rachel; Schlesinger, Ilana; Schofield, Christine M.; Schumacher-Schuh, Artur F.; Scott, Burton; Sesar, Ángel; Shafer, Stuart J.; Sheridan, Ray; Silverdale, Monty; Sophia, Rani; Spitz, Mariana; Stathis, Pantelis; Stocchi, Fabrizio; Tagliati, Michele; Tai, Yen F.; Terwecoren, Annelies; Thonke, Sven; Tönges, Lars; Toschi, Giulia; Tumas, Vitor; Urban, Peter Paul; Vacca, Laura; Vandenberghe, Wim; Valente, Enza Maria; Valzania, Franco; Vela-Desojo, Lydia; Weill, Caroline; Weise, David; Wojcieszek, Joanne; Wolz, Martin; Yahalom, Gilad; Yalcin-Cakmakli, Gul; Zittel, Simone; Zlotnik, Yair; Kandaswamy, Krishna K.; Balck, Alexander; Hanssen, Henrike; Borsche, Max; Lange, Lara M.; Csoti, Ilona; Lohmann, Katja; Kasten, Meike; Brüggemann, Norbert; Rolfs, Arndt; Klein, Christine; Bauer, Peter; Neurology, School of Medicine
    Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.