ROCK-ALS: Protocol for a Randomized, Placebo-Controlled, Double-Blind Phase IIa Trial of Safety, Tolerability and Efficacy of the Rho Kinase (ROCK) Inhibitor Fasudil in Amyotrophic Lateral Sclerosis

Paul Lingor, Markus Weber, William Camu, Tim Friede, Reinhard Hilgers, Andreas Leha, Christoph Neuwirth, René Günther, Michael Benatar, Magdalena Kuzma-Kozakiewicz, Helen Bidner, Christiane Blankenstein, Roberto Frontini, Albert Ludolph, Jan C Koch, ROCK-ALS Investigators, Shahram Attarian, Mathias Bähr, Matthias Boentert, Nathalie Braun, Philippe Corcia, Isabell Cordts, Marcus Deschauer, Thorsten Grehl, Julian Grosskreutz, Andreas Hermann, Josua Kuttler, Teresa Lengenfeldt, Fabian Maass, Thomas Meyer, Susanne Petri, Yvonne Remane, Jens Schmidt, Joachim Schuster, Marie-Hélène Soriani, Jeffrey Statland, Jochen Weishaupt, Daniel Zeller, Eirini Zielke, Paul Lingor, Markus Weber, William Camu, Tim Friede, Reinhard Hilgers, Andreas Leha, Christoph Neuwirth, René Günther, Michael Benatar, Magdalena Kuzma-Kozakiewicz, Helen Bidner, Christiane Blankenstein, Roberto Frontini, Albert Ludolph, Jan C Koch, ROCK-ALS Investigators, Shahram Attarian, Mathias Bähr, Matthias Boentert, Nathalie Braun, Philippe Corcia, Isabell Cordts, Marcus Deschauer, Thorsten Grehl, Julian Grosskreutz, Andreas Hermann, Josua Kuttler, Teresa Lengenfeldt, Fabian Maass, Thomas Meyer, Susanne Petri, Yvonne Remane, Jens Schmidt, Joachim Schuster, Marie-Hélène Soriani, Jeffrey Statland, Jochen Weishaupt, Daniel Zeller, Eirini Zielke

Abstract

Objectives: Disease-modifying therapies for amyotrophic lateral sclerosis (ALS) are still not satisfactory. The Rho kinase (ROCK) inhibitor fasudil has demonstrated beneficial effects in cell culture and animal models of ALS. For many years, fasudil has been approved in Japan for the treatment of vasospasm in patients with subarachnoid hemorrhage with a favorable safety profile. Here we describe a clinical trial protocol to repurpose fasudil as a disease-modifying therapy for ALS patients. Methods: ROCK-ALS is a multicenter, double-blind, randomized, placebo-controlled phase IIa trial of fasudil in ALS patients (EudraCT: 2017-003676-31, NCT: 03792490). Safety and tolerability are the primary endpoints. Efficacy is a secondary endpoint and will be assessed by the change in ALSFRS-R, ALSAQ-5, slow vital capacity (SVC), ECAS, and the motor unit number index (MUNIX), as well as survival. Efficacy measures will be assessed before (baseline) and immediately after the infusion therapy as well as on days 90 and 180. Patients will receive a daily dose of either 30 or 60 mg fasudil, or placebo in two intravenous applications for a total of 20 days. Regular assessments of safety will be performed throughout the treatment period, and in the follow-up period until day 180. Additionally, we will collect biological fluids to assess target engagement and evaluate potential biomarkers for disease progression. A total of 120 patients with probable or definite ALS (revised El Escorial criteria) and within 6-18 months of the onset of weakness shall be included in 16 centers in Germany, Switzerland and France. Results and conclusions: The ROCK-ALS trial is a phase IIa trial to evaluate the ROCK-inhibitor fasudil in early-stage ALS-patients that started patient recruitment in 2019.

Keywords: ROCK inhibition; amyotrophic lateral sclerosis; clinical trial protocol; disease-modification; study design.

Figures

Figure 1
Figure 1
Scheme of trial (drawn to time scale). V, visit; bid, two times daily.

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