Neurodegeneration J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-322168 on 14 January 2020. Downloaded from ORIGINAL RESEARCH Effect of rovatirelin in patients with cerebellar ataxia: two randomised double- blind placebo- controlled phase 3 trials Masatoyo Nishizawa ,1 Osamu Onodera,2 Akihiro Hirakawa,3 Yoshitaka Shimizu,4 Masayuki Yamada,5 on behalf of the Rovatirelin Study Group ► Additional material is ABSTRact atrophy (MSA) show cerebellar symptoms and published online only. To view Objective To investigate the efficacy of rovatirelin, a extracerebellar symptoms. The presence of extra- please visit the journal online cerebellar symptoms also contributes to a patient’s (http:// dx. doi. org/ 10. 1136/ thyrotropin-releasing hormone analogue, for ataxias in jnnp- 2019- 322168). patients with spinocerebellar degeneration (SCD). disability and may interfere with evaluation of the Methods Two multicentre, randomised, double- blind, severity of cerebellar ataxia. Therefore, it is consid- 1Brain Research Institute, placebo- controlled phase 3 studies (KPS1301, KPS1305) ered more useful to evaluate the effect of a drug Niigata University, Niigata, enrolled patients with predominant cerebellar ataxia, on cerebellar ataxia in patients with predominant Japan 2Department of Neurology, including SCA6, SCA31 or cortical cerebellar atrophy. cerebellar symptoms. Brain Research Institute, Niigata KPS1301 enrolled patients with truncal ataxia and Thyrotropin- releasing hormone (TRH) is a University, Niigata, Japan KPS1305 enrolled patients with truncal and limb ataxia. hypothalamic hormone that promotes thyroid- 3 Department of Biostatistics and Each study included 4 weeks of pretreatment, a 28-week stimulating hormone and prolactin (PRL) release Bioinformatics, The University from the pituitary gland, and acts broadly on the of Tokyo, Graduate School of or 24-week treatment period and 4 weeks of follow-up . Medicine, Tokyo, Japan Patients were randomised (1:1:1) to rovatirelin (1.6 or central nervous system to activate several neurotrans- 4Strategic Alliance Department, 2.4 mg) or placebo in KPS1301, and randomised (1:1) mitters.4–7 TRH has been shown to improve ataxia Kissei Pharmaceutical Co., Ltd, to rovatirelin 2.4 mg or placebo in KPS1305. The primary in an ataxia mouse model with a CACNA1A muta- Tokyo, Japan endpoint was change in Scale for the Assessment and tion, the causative gene for SCA6.8 9 In a 2- week, 5Clinical Data Science Department, Kissei Rating of Ataxia (SARA) total scores. Pooled analysis was double- blind, placebo-controlled trial in 254 SCD copyright. Pharmaceutical Co., Ltd, Tokyo, performed in patients who met the SARA recruitment patients, the efficacy of a TRH analogue (TRH Japan criteria of KPS1305. tartrate) was demonstrated in patients with predom- Results From October 2013 to May 2014, KPS1301 inantly ataxic forms of SCD.10 Thus, the first TRH Correspondence to enrolled 411 patients; 374 were randomised to analogue was approved in Japan in 1985 for the Dr Masatoyo Nishizawa, rovatirelin 1.6 mg (n=125), rovatirelin 2.4 mg (n=126) or treatment of ataxia associated with SCD. However, Department of Neurology, Brain Research Institute, Niigata placebo (n=123). From November 2016 to August 2017, in the previous clinical trial, the diagnostic criteria University, Niigata 951-8585, KPS1305 enrolled 241 patients; 203 were randomised for SCD were not consistent with recent diagnostic Japan; nishizawamasatoyo@ to rovatirelin 2.4 mg (n=101) or placebo (n=102). The criteria. Further, over 60% of patients with the gmail. com primary endpoint showed no significant difference predominantly ataxic forms of SCD had olivopon- tocerebellar atrophy, and the drug effects were not Received 4 October 2019 between rovatirelin and placebo in these two studies. Revised 22 December 2019 In the pooled analysis (n=278), the difference between assessed using an ataxia rating scale alone. Finally, http://jnnp.bmj.com/ Accepted 25 December 2019 rovatirelin 2.4 mg (n=140) and placebo (n=138) the duration of the trial was only 2 weeks. There- Published Online First 14 was –0.61 (–1.64 vs –1.03; 95% CI –1.16 to –0.06; fore, well-designed double- blind trials were consid- January 2020 p=0.029) in the adjusted mean change in the SARA total ered necessary to demonstrate the efficacy of new score. drug candidates for cerebellar ataxia.11 12 Conclusions Rovatirelin is a potentially effective Rovatirelin is a new TRH analogue,13 which treatment option for SCD. showed higher affinity for human TRH recep- Trial registration number NCT01970098; tors and greater absorption and transition into on September 24, 2021 by guest. Protected NCT02889302 and stability in the brain than the existing TRH analogue, taltirelin.14 15 The effects of rovatirelin on the ataxic rolling Nagoya mice, which carry a mutation in the CACNA1A gene, were more potent INTRODUCTION and lasted longer than those of taltirelin (data on Spinocerebellar degeneration (SCD) is a neurode- file). To investigate the efficacy and safety of rovat- generative disease that is characterised by progres- irelin for the treatment of cerebellar ataxia, we © Author(s) (or their sive cerebellar ataxia.1 2 The main symptoms of employer(s)) 2020. Re- use performed two large- scale, randomised, double- permitted under CC BY-­NC. No SCD are gait ataxia, standing instability, limb ataxia 3 blind, phase 3 studies in patients with predominant commercial re-use . See rights and dysarthria. In addition, pyramidal tract, extra- cerebellar symptoms of SCD. and permissions. Published pyramidal or peripheral nervous symptoms can by BMJ. occur in patients with some types of SCDs.3 Hered- To cite: Nishizawa M, itary SCA6, SCA31 and sporadic cortical cerebellar METHODS Onodera O, Hirakawa A, et al. atrophy (CCA) mainly show cerebellar symptoms, Study design and participants J Neurol Neurosurg Psychiatry while hereditary SCA1, SCA2, SCA3 (Machado- Two similar multicentre, randomised, double- blind, 2020;91:254–262. Joseph disease) and sporadic multiple system placebo- controlled, phase 3 studies (KPS1301 254 Nishizawa M, et al. J Neurol Neurosurg Psychiatry 2020;91:254–262. doi:10.1136/jnnp-2019-322168 Neurodegeneration J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp-2019-322168 on 14 January 2020. Downloaded from and KPS1305) were conducted in Japanese patients with SCD. Efficacy and safety were evaluated during hospital visits every Patients were enrolled from 86 hospitals in Japan between 9 4 weeks. At weeks 0 through 24, SARA (Japanese version) was October 2013 and 30 May 2014 in KPS1301 and from 62 hospi- used to assess the degree of ataxia. Each patient was assessed tals in Japan between 15 November 2016 and 1 August 2017 in for SARA by the same investigator, who was a board- certified KPS1305. neurologist of the Japanese Society of Neurology. Because differ- Both studies included patients aged ≥20 years with only ences in SARA assessment between investigators cannot be elim- predominant cerebellar symptoms of SCD (CCA or geneti- inated in large- scale, multicentre trials, the investigators were cally confirmed SCA6 or SCA31). The diagnosis of CCA was trained using a video of the SARA assessment method to reduce mainly based on the idiopathic cerebellar ataxia diagnostic the variability in SARA assessments. Patient quality of life (QoL) criteria proposed by Yoshida et al.16 Briefly, patients with slowly was self- assessed using the Japanese version of the Short Form-8 progressive adult- onset cerebellar ataxia and with no first- degree (SF-8) questionnaire at weeks 0 through 24.20 or second- degree relatives with ataxia were enrolled, while patients with autoimmune- mediated, metabolic, alcoholic and Outcomes drug- induced ataxia were excluded. In addition, patients with The primary endpoint was change in the SARA total score from MSA were carefully excluded based on the second consensus baseline to the time point of final evaluation. The final eval- statement for the diagnosis of MSA.17 A detailed diagnostic flow uation was defined as the latest evaluation, excluding missing diagram of CCA is shown in online supplementary figure 1. data. Secondary efficacy endpoints were the SARA total score, The KPS1301 study included patients with truncal ataxia individual SARA scores and SF-8 scores at each evaluation time (Scale for the Assessment and Rating of Ataxia (SARA)18 19 total point. Safety endpoints included adverse events (AEs), vital score of ≥6 and SARA gait score of 2–6). The KPS1305 study signs, body weight, 12- lead ECG, clinical laboratory tests and included patients with both truncal and limb ataxia (SARA gait endocrinology tests (thyroid stimulating hormone (TSH), free score of 2–6, stance score of ≥2 and scores of ≥1 for the finger triiodothyronine (FT3), free thyroxine (FT4) and PRL). Investi- chase, nose- finger and fast alternating hand movements tests gators evaluated AEs for severity (mild, moderate or severe) and (patients with scores of ≥1 on unilateral tests were included if for causal relationships with the test agents. tests were not feasible on the right or left side for some reason other than the primary disease)). Exclusion criteria were: secondary ataxia (eg, cerebrovas- Statistical analyses cular disorder, brain tumour, multiple sclerosis, hypothyroidism, For the KPS1301 study, assuming a difference in the change drug- induced, paraneoplastic syndrome); suspected alcoholic in the SARA total score between the rovatirelin group and the ataxia; motor disorder due to musculoarticular disease; cogni- placebo group of −0.75, and a common SD of 2.0, a sample size copyright. tive impairment, depression or other mental diseases and a diag- of 113 randomly assigned patients was calculated as sufficient nosis of thyrotoxicosis. In the KPS1305 study, patients who had to provide 80% power with a two- sided 5% significance level. participated in a rovatirelin study ≥2 years ago were eligible to In the KPS1305 study, a sample size of 87 randomly assigned enrol; however, this group of patients was restricted to ≤30% of patients was calculated as sufficient to provide 80% power with the total number of patients enrolled in KPS1305.