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HOME > J Mov Disord > Volume 18(1); 2025 > Article
Original Article
Efficacy and Safety of Taltirelin Hydrate in Patients With Ataxia Due to Spinocerebellar Degeneration
Jin Whan Cho1orcid, Jee-Young Lee2orcid, Han-Joon Kim3orcid, Joong-Seok Kim4orcid, Kun-Woo Park5orcid, Seong-Min Choi6orcid, Chul Hyoung Lyoo7orcid, Seong-Beom Koh8corresp_iconorcid
Journal of Movement Disorders 2025;18(1):35-44.
DOI: https://doi.org/10.14802/jmd.24127
Published online: October 21, 2024

1Department of Neurology, Samsung Seoul Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea

2Department of Neurology, SMG-SNU Boramae Medical Center, Seoul, Korea

3Department of Neurology, Seoul National University College of Medicine, Seoul, Korea

4Department of Neurology, College of Medicine, The Catholic University of Korea, Seoul, Korea

5Department of Neurology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea

6Department of Neurology, Chonnam National University Hospital, Chonnam National University Medical School, Gwangju, Korea

7Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

8Department of Neurology, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea

Corresponding author: Seong-Beom Koh, MD, PhD Department of Neurology, Korea University Guro Hospital, Korea University College of Medicine, 148 Gurodong-ro, Guro-gu, Seoul 08308, Korea / Tel: +82-2-2626-3169 / Fax: +82-2-2626-1257 / E-mail: parkinson@korea.ac.kr
• Received: May 28, 2024   • Revised: July 23, 2024   • Accepted: October 18, 2024

Copyright © 2025 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • Objective
    We conducted this study to assess the efficacy and safety of taltirelin hydrate (TH) in patients with ataxia due to spinocerebellar degeneration (SCD).
  • Methods
    Patients were randomly assigned to either the taltirelin group (5 mg orally, twice daily) or the control group. The primary endpoint was the change in the Korean version of the Scale for the Assessment and Rating of Ataxia (K-SARA) score at 24 weeks. The secondary endpoints included changes in the K-SARA score at 4 and 12 weeks as well as the Clinical Global Impression Scale, the five-level version of the EuroQol five-dimensional questionnaire, the Tinetti balance test, and gait analysis at 4, 12, and 24 weeks.
  • Results
    A total of 149 patients (hereditary:nonhereditary=86:63) were enrolled. There were significant differences in the change in the K-SARA score at 24 weeks from baseline between the taltirelin group and the control group (-0.51±2.79 versus 0.36±2.62, respectively; p=0.0321). For the K-SARA items, the taltirelin group had significantly lower “Stance” and “Speech disturbance” subscores than the control group (-0.04±0.89 versus 0.23±0.79 and -0.07±0.74 versus 0.18±0.67; p=0.0270 and 0.0130, respectively). However, there were no significant differences in changes in other secondary efficacy outcome measures at 24 weeks from baseline between the two treatment arms (p>0.05).
  • Conclusion
    Clinicians might consider the use of TH in the treatment of patients with ataxia due to SCD.
Spinocerebellar degeneration (SCD) is a heterogeneous group of neurodegenerative diseases that affect the cerebellum, brainstem, spinal cord, and basal ganglia to varying extents [1]. Patients with SCD present with diverse symptoms, such as limb and truncal ataxia, dysarthria, dysphagia, extrapyramidal signs (dystonia, rigidity, and bradykinesia), pyramidal signs, and autonomic disorders. Of these, ataxia is the core symptom that may arise from degeneration of the cerebellum or its connecting pathways; thus, it is referred to as cerebellar ataxia [2]. Diverse factors, with both hereditary and nonhereditary etiologies, including vascular, infectious, inflammatory, paraneoplastic, neoplastic, toxic, and degenerative etiologies, are involved in the pathogenesis of spinocerebellar ataxia (SCA) [3].
There are no established optimal pharmacological treatments for patients with ataxia due to SCD. The beneficial effects of riluzole and valproic acid have been suggested, but their clinical efficacies has not yet been verified [4,5]. Only supportive treatment modalities, such as balance and coordination training, strengthening exercises, and gait training, are used to maintain function in these patients [6].
To date, considerable efforts have been devoted to developing effective treatment agents, such as thyrotropin-releasing hormone (TRH) analogs, for SCD [7,8]. In this context, taltirelin hydrate (TH) deserves special attention in patients with SCD. Compared with TRH, TH has 10–100 times more potent central nervous system (CNS) stimulant activity and an 8-fold longer duration. More importantly, TH has been studied in the treatment of SCD [9], and its anti-ataxic effects have been described in the literature [8]. Notably, TH is a disease-modifying drug that arrests the course of the disease and improves ataxia in patients with SCD [10,11]; its preclinical profile has been described in detail [8].
Given this background, this study was conducted to assess the efficacy and safety of TH in patients with ataxia due to SCD.
Study design
This 24-week, multicenter, prospective, randomized, double-blind, placebo-controlled, phase IV study was conducted at eight institutions in Korea between March 2019 and February 2021.
Patients
Patients aged 20 years and older who were diagnosed with hereditary or nonhereditary cerebellar ataxia were enrolled in this study. All of them provided written informed consent. The current study was approved by the Institutional Review Board (IRB) of respective institutions involved in it and is registered with the ClinicalTrials. gov (NCT04107740).
The inclusion criteria for the current study were as follows: 1) Korean adult men or women aged 20 years or older and 2) patients with a diagnosis of (hereditary or nonhereditary) ataxia due to SCD according to the essential diagnostic criteria, as determined by the investigators.
The exclusion criteria for the current study were as follows: 1) patients who were confined to a bed or chair at screening, 2) patients with ataxia caused by stroke, alcohol, drugs, or paraneoplastic syndrome, 3) patients with other neurodegenerative disorders, such as Parkinson’s disease or multiple system atrophy without a diagnosis of SCA2, SCA3, or SCA17, 4) patients with a history of malignancies, renal or hepatic failure, schizophrenia or major depressive disorder, thyroid diseases, acute myocardial infarction, or unstable angina within two years of the screening visit, 5) patients with clinically notable laboratory abnormalities, such as those with hepatic dysfunction (aspartate transaminase/alanine transaminase level >3 upper limit of normal [ULN], total serum bilirubin level >1.5 ULN, and serum creatinine level >1.5 mg/dL) and those with thyroid dysfunction (free T4 outside the normal range), 6) patients with a concurrent presence of lesions other than SCA on brain magnetic resonance imaging or computed tomography scans, 7) patients with cognitive dysfunction, as evidenced by a Korean Mini-Mental State Examination (K-MMSE) score ≥20, 8) women who are pregnant or breastfeeding, and 9) patients who are deemed ineligible for study participation according to the investigator’s judgment.
In a previous clinical trial, the mean Korean version of the Scale for the Assessment and Rating of Ataxia (K-SARA) scores were -1.00±1.75 at 3 months and -1.02±2.15 at 12 months in the riluzole group and 0.50±2.28 at 3 months and 1.67±2.63 at 12 months in the placebo group [4]. Using a conservative approach, the mean K-SARA score at 6 months was set at -1.00 in the taltirelin group and 0.50 in the placebo group. Moreover, the greatest possible standard deviation (σ=2.63) was applied as the pooled standard deviation for the current study. Given a two-sided statistical significance of 0.05, statistical power of 90% and anticipated drop-out rate of 20%, it was determined that 166 patients (83 per group) should be enrolled in this study.
Randomization and masking
After providing written informed consent for study participation, the patients received the necessary examinations and tests in accordance with the study protocol. Then, they were evaluated based on inclusion/exclusion criteria. Once their eligibility for study participation was confirmed, they were randomly assigned to either the taltirelin group or the control group at a 1:1 ratio according to a biostatistician-generated randomization list consisting of a randomization code (RC) and a randomization number (RN). Each patient was assigned to either the taltirelin group or the control group based on the RN.
To achieve a homogeneous distribution of the patients between the study centers, the stratified block randomization method was used. Thus, the patients were stratified at each center, and a certain block size was used for randomization. The RC was generated via SAS (SAS Institute Inc., Cary, NC, USA) Proc Plan, for which the size of the block and number of seeds were arbitrarily selected by the randomization personnel.
The RNs were consecutively distributed to the patients in the order of their enrollment and then used as subject identification codes throughout the study. In cases of withdrawal of informed consent or discontinuation of study participation, the RNs were not reused, as they were already assigned to patients.
Procedures
The patients in both the taltirelin group and the control group were given 5 mg TH orally and placebo, respectively, after a meal two times a day in the morning and evening during a 24-week period.
The study treatment dosages were determined as appropriate and were approved by the Korean Ministry of Food and Drug Safety. No dose escalation was attempted for any patient in the two treatment arms; the patients received study treatments on a fixed-dose basis.
Outcomes
The baseline characteristics of the patients included age, sex, genetic inheritance of ataxia (hereditary or nonhereditary), disease duration, and K-MMSE score.
The patients were evaluated on their K-SARA and Clinical Global Impression Scale-Severity (CGI-S) scores at 0, 4, 12, and 24 weeks, whereas they were evaluated on their Clinical Global Impression Scale-Improvement (CGI-I) and Clinical Global Impression Scale-Efficacy Index (CGI-E) scores at 4, 12, and 24 weeks [12,13]. Further, they were evaluated on their Korean version of Scales of Outcome in Parkinson’s Disease Autonomic (K-SCOPA-AUT) scores, five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L) scores, Korean version of the Tinetti balance and gait scores and spatiotemporal gait parameters via a gait analysis system (GAITRite system; CIR Systems Inc., Franklin, NJ, USA) at 0 and 24 weeks [14-16].
For the efficacy assessment, a full analysis was performed. The full analysis set (FAS) comprised the subjects with available efficacy outcome data who received study treatments at least once after randomization.
In the present study, changes in the K-SARA score at 24 weeks from baseline served as the primary efficacy outcome measure. Additionally, changes in the K-SARA scores at 12 weeks as well as the CGI-S score, K-SCOPA-AUT score, EQ-5D-5L score, Tinetti balance and gait score, and spatiotemporal gait parameters at 24 weeks from baseline served as a secondary efficacy outcome measure. Finally, changes in CGI-I and CGI-E scores at 24 weeks from 4 weeks also served as a secondary efficacy outcome measure.
Based on the patients’ genetic profiles, a subgroup analysis was also performed to assess the efficacy of the study treatments in improving K-SARA scores depending on genetic inheritance of the ataxia or SCA subtypes at 24 weeks from baseline in both treatment arms. The SCA subtypes include SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, and SCA17 [17]. Another subgroup analysis was performed to assess the efficacy of the study treatments in improving subscores for each K-SARA item at 24 weeks from baseline for all patients irrespective of their subtype.
For the safety assessment, any adverse events (AEs) were categorized by the system organ class and then coded by preferred terms using the Medical Dictionary for Regulatory Activities version 19 [18]. Incidences of AEs served as safety outcome measures.
Statistical analysis
All the data are expressed as the means±standard deviations or frequencies of patients with percentages, where appropriate. Prior to the statistical calculations, a Grubbs’ t-tests was employed to detect significant outliers in the patients’ data. In each treatment arm, changes in the outcome measures at 24 weeks from baseline were analyzed via the Wilcoxon signed-rank test. Moreover, differences in efficacy and safety outcome measures between the two groups were analyzed via independent-samples t-tests or Wilcoxon rank sum tests, if applicable. Missing data were imputed using the last observation carried forward method. Statistical analysis was performed via Statistical Analysis Software version 9.4 (SAS Institute Inc., Cary, NC, USA). A p value less than 0.05 was considered statistically significant.
Patients’ baseline characteristics
A total of 149 patients with ataxia due to SCD were ultimately enrolled in the study. Of them, 75 were assigned to the taltirelin group, whereas 74 were assigned to the control group. The dispositions of the patients are shown in Figure 1.
The baseline characteristics of the patients in the FAS are presented in Table 1. There was a significant difference in the mean age between the taltirelin group and the control group (56.60±10.55 versus 52.51±12.17 years, respectively; p=0.0265). However, there were no significant differences in the male-to-female ratio, indications, disease duration, or K-MMSE scores between the two treatment arms (p>0.05) (Table 1).
Efficacy outcomes in the full analysis
The efficacy outcomes are summarized in Table 2. The time-dependent changes in the K-SARA scores at 0, 4, 12, and 24 weeks are shown as spaghetti plots (Supplementary Figure 1 in the online-only Data Supplement). Moreover, the distribution of the baseline K-SARA scores is shown in Figure 2. This analysis revealed no outliers in the patients’ data (Figure 2).
The full analysis revealed significant differences in the changes in the K-SARA scores at 24 weeks from baseline between the taltirelin group and the control group (-0.51±2.79 versus 0.36±2.62, respectively; p=0.0321) (Figure 3).
There were no significant differences in changes in other secondary efficacy outcome measures at 24 weeks from baseline between the two treatment arms (p>0.05) (Table 2).
Among the K-SARA items, the taltirelin group had significantly lower subscores on both “Stance” and “Speech disturbance” than the control group (-0.04±0.89 versus 0.23±0.79 and -0.07±0.74 versus 0.18±0.67; p=0.0270 and 0.0130, respectively) (Supplementary Table 1 in the online-only Data Supplement). The patients with hereditary ataxia in the taltirelin group had significantly lower “Speech disturbance” subscores than did those in the control group (-0.17±0.67 versus 0.13±0.63; p=0.0233) (Supplementary Table 1 in the online-only Data Supplement).
Efficacy outcomes in the subgroup analysis
The degree of change in the K-SARA score at 24 weeks from baseline was significantly lower among the patients with hereditary ataxia in the taltirelin group (n=41) than among those in the control group (n=45) (-1.28±2.91 versus 0.03±2.41, respectively; p=0.0099) (Figure 3). Despite a lack of statistical significance, the patients with nonhereditary ataxia in the taltirelin group (n=34) also had lower K-SARA scores than those in the control group did (n=29) (0.41±2.35 versus 0.86±2.88, respectively; p=0.6581) (Figure 3). Finally, the degree of change in the K-SARA score at 24 weeks from baseline was significantly lower in the patients with SCA3 in the taltirelin group (n=7) than in those in the control group (n=12) (-2.36±2.30 versus 0.29±1.98, respectively; p=0.0220) (Figure 4).
Safety outcomes
There were no significant differences in the incidence of AEs between the two treatment arms (p=0.3828) (Table 3). Moreover, there were no cases of AEs with a causal relationship with the study treatments.
There were significant differences in the changes in the K-SARA score at 24 weeks from baseline between the taltirelin group and the control group, indicating that TH was effective in significantly improving the K-SARA score (p=0.0321). Although there were no significant changes in the K-SARA scores at 24 weeks from baseline in either treatment arm, there were significant changes at 24 weeks from baseline in patients with hereditary ataxia. Moreover, whereas this trial was a 6-month followup study, a relatively lower degree of decrease in the K-SARA score suggests that TH might affect the progression of the disease. Further studies are warranted to assess the long-term protective effects of TH against ataxia due to SCD. There were also significant improvements in the K-SARA score at 24 weeks from baseline in the patients with hereditary ataxia in the taltirelin group. Diverse genetic mutations are involved in the etiology of hereditary ataxia. Both the complexity of hereditary ataxia and the lack of disease-modifying drugs limit therapeutic options for patients with hereditary ataxia [19]. In this context, the efficacy of taltirelin in the context of hereditary ataxia is noteworthy.
The current study also showed that patients with SCA3 in the taltirelin group had significantly lower K-SARA scores than did those in the control group (p=0.0220). To date, randomized controlled trials have been conducted to assess the efficacy and safety of several drugs, including lithium, varenicline, and riluzole, in patients with different types of neurodegenerative ataxias [20-22], including Zesiewicz et al.’s [21] randomized controlled trial to assess the efficacy of varenicline in patients with SCA3. Nevertheless, no new treatments have been approved for the treatment of hereditary ataxias. SCA3 is a devastating neurodegenerative condition that mainly affects the deep cerebellar and pontine nuclei, basal ganglia, and spinal cord [23]. Despite the variability in its prevalence depending on the location of the SCA, SCA3 is considered the most common type of autosomal dominant hereditary ataxia worldwide. The prevalence of SCA3 is estimated to be 20%–50% of affected families [24,25]. In this context, the efficacy of TH in the context of SCA3 treatment might be promising. However, this topic warrants additional large-scale studies.
Of the K-SARA items, the taltirelin group had significantly lower subscores on both “Stance” and “Speech disturbance” than did the control group. The patients with hereditary ataxia in the taltirelin group had significantly lower “Speech disturbance” subscores than did those in the control group (-0.17±0.67 versus 0.13±0.63; p=0.0233). Healthy individuals can stand naturally with their feet spread <12 cm apart and can stand stably with their feet together or in tandem for >30 seconds. However, an impaired stance in the absence of motor weakness or gross involuntary movement is indicative of cerebellar or sensory ataxia [26]. Notably, the patients in the taltirelin group had significant improvements in their “Stance” scores than those in the control group; this is a promising finding because speech plays a key role in verbal communication.
The current study revealed no significant differences in the incidence of AEs between the two treatment arms; there were also no cases of AEs with a causal relationship with the study treatments. These results indicate that TH is a safe treatment agent for patients with ataxia due to SCD.
TH is a synthetic analog of TRH [27,28]. Since the first report that the intravenous administration of TH improved ataxia in 1983, it has been used to treat neurodegenerative ataxia [29]. TH has a broad spectrum of CNS effects, including antiatactic activity, analeptic activity, arousal action, reversal of reserpine-induced hypothermia, and antidepressant activity [30]. Little is known about the mechanism underlying the actions of TH in various neurological diseases, although it acts as a homeostatic modulator by responding to many elements of the immune system and affecting them in a manner that maintains or restores homeostasis [31]; moreover, its efficacy in improving the symptoms of ataxia in patients with SCD has been well described in the literature [11,32]. This finding is in alignment with the results of this study.
The current study has several limitations. First, although it was conducted based on the sample size estimation, relatively few patients with each subtype of SCD were enrolled, depending on the type of genetic aberration; presumably, this might have been unavoidable because this clinical trial was conducted with a cohort of patients with rare diseases. It would, therefore, be difficult to perform a detailed analysis according to various genetic causes of hereditary ataxia. Second, as the current study included only Korean patients, the results may not adequately represent the genetic diversity of patients worldwide. Nevertheless, the current multicenter, randomized, controlled trial is noteworthy in that it showed meaningful results because treatment for ataxia due to SCD poses a challenge for clinicians. Third, the heterogeneity of the patients in this study remains a critical problem; the rate of disease progression depends on the cause of SCD, patient’s genetic background and disease duration; this is a limitation arising from the fact that this clinical trial was conducted with patients with rare diseases; further multinational studies are warranted. Fourth, the patients had average K-SARA scores of 12.50±5.03 (range, 0–27.5) points. Consequently, in future studies, it would be rational to stratify patients based on the cutoff value of their K-SARA scores. Fifth, K-SARA scores were analyzed in this study. However, assessing the efficacy of study treatments via additional patient-reported outcome measures (PROMs) is essential; patients’ reports of their daily activities and symptoms play a crucial role in assessing treatment outcomes and, therefore, optimizing care [33]. PROMs may offer deeper insights into the natural history and course of ataxia [34,35]. In this context, they can serve as essential factors that are closely associated with the conduct and interpretation of clinical trials [36]. Sixth, it is mandatory to consider the clinical importance of analyzing the actual treatment effect with confidence intervals when interpreting the results of the current study [37]. The current study failed to analyze this difference; it simply provided information about statistical significance solely based on p values. Further studies are warranted to determine the minimal clinically important differences in a cohort of Korean patients with ataxia due to SCD.
In summary, TH significantly improved both “Stance” and “Speech disturbance” in patients with hereditary ataxia, especially those with the SCA3 subtype.
Based on the findings of the current study, clinicians might consider the use of TH in the treatment of patients with ataxia due to SCD.
T he online-only Data Supplement is available with this article at https://doi.org/10.14802/jmd.24127.

Supplementary Table 1.

Changes in the K-SARA subscores at 24 weeks from baseline
jmd-24127-Supplementary-Table-1.pdf

Supplementary Figure 1.

Spaghetti plot of time-dependent changes in the K-SARA scores at 0, 4, 12, and 24 weeks. K-SARA, Korean version of the Scale for the Assessment and Rating of Ataxia.
jmd-24127-Supplementary-Figure-1.pdf

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This study was funded by HLB Pharmaceutical Co., LTD. (Seoul, Korea) (HLB-004).

Author contributions

Conceptualization: all authors. Data curation: all authors. Formal analysis: all authors. Funding acquisition: all authors. Investigation: all authors. Methodology: all authors. Project administration: all authors. Resources: all authors. Software: all authors. Supervision: all authors. Validation: all authors. Visualization: all authors. Writing—original draft: all authors. Writing—review & editing: Seong-Beom Koh.

None
Figure 1.
Dispositions of the patients in the study. FAS, full analysis set.
jmd-24127f1.jpg
Figure 2.
Distribution of the baseline K-SARA scores. K-SARA, Korean version of the Scale for the Assessment and Rating of Ataxia.
jmd-24127f2.jpg
Figure 3.
Overall changes in the K-SARA scores at 24 weeks from baseline. *p value<0.05. K-SARA, Korean version of the Scale for the Assessment and Rating of Ataxia.
jmd-24127f3.jpg
Figure 4.
Overall changes in the K-SARA scores at 24 weeks from baseline. *p value<0.05. K-SARA, Korean version of the Scale for the Assessment and Rating of Ataxia.
jmd-24127f4.jpg
jmd-24127f5.jpg
Table 1.
Baseline characteristics of the patients
Variables Values
p value
Taltirelin group (n=75) Control group (n=74)
Age (yr) 56.60±10.55 52.51±12.17 0.0265*
Sex 0.9385
 Men 40 (53.33) 39 (52.70)
 Women 35 (46.67) 35 (47.30)
Genetic inheritance of ataxia 0.6927
 Hereditary ataxia 41 (54.67) 45 (60.81)
  SCA 37 (49.33) 42 (56.76)
  Other types of hereditary ataxia 4 (5.33) 3 (4.05)
   Spastic ataxia of Charlevoix-Saguenay 0 (0.00) 1 (1.35)
   Hereditary spastic ataxia 1 (1.33) 0 (0.00)
   DRPLA gene 1 (1.33) 0 (0.00)
   Chromosome analysis 1 (1.33) 0 (0.00)
   Unknown 1 (1.33) 2 (2.70)
 Non-hereditary ataxia 34 (45.33) 29 (39.19)
  ILOCA 34 (45.33) 29 (39.19)
Disease duration (yr) 2.33 (0.07–16.47) 3.23 (0.00–22.50) 0.4165
K-MMSE scores 28.03±1.69 27.93±2.07 0.7894

Values are presented as mean±standard deviation, number (%), or median with the range unless otherwise indicated.

* p value<0.05.

SCA, spinocerebellar ataxia; ILOCA, idiopathic late onset cerebellar ataxia; K-MMSE, Korean Mini-Mental State Examination.

Table 2.
Efficacy outcome measures of taltirelin
Outcome measures Taltirelin group (n=75) Control group (n=74) p value
Primary efficacy outcome measure
 Changes in K-SARA scores at 24 weeks from baseline -0.51±2.79 0.36±2.62 0.0321*
Secondary efficacy outcome measures
 Changes in K-SARA scores at 12 weeks from baseline -0.47±3.05 0.05±2.66 0.1151
 Changes in CGI-S scores at 24 weeks from baseline 0.08±0.56 0.03±0.47 0.4925
 Changes in CGI-I scores at 24 weeks from 4 weeks 0.15±0.65 0.31±0.57 0.1170
 Changes in CGI-E scores at 24 weeks from 4 weeks -0.08±0.65 -0.16±0.57 0.3440
 Changes in K-SCOPA-AUT scores at 24 weeks from baseline -2.27±6.09 -0.45±5.34 0.2349
 Changes in EQ-5D-5L scores at 24 weeks from baseline
  EQ-5D-5L descriptive system 0.00±0.16 -0.02±0.13 0.3159
  EQ VAS 1.92±21.72 -3.88±18.32 0.1539
 Changes in Tinetti balance and gait scores at 24 weeks from baseline 0.03±4.02 -0.34±3.25 0.5874
 Spatio-temporal parameters of gait
 Spatial parameters
  Changes in step length at 24 weeks from baseline (cm)
   Left -1.25±8.93 -0.95±7.22 >0.9999
   Right -1.52±8.09 -1.00±6.00 0.9320
  Changes in CoV of step length at 24 weeks from baseline (%)
   Left 0.51±7.43 3.44±13.29 0.2066
   Right 1.86±14.76 -3.07±11.17 0.5682
  Changes in stride length at 24 weeks from baseline (cm)
   Left -2.96±17.19 -1.65±12.23 0.9008
   Right -2.89±15.96 -2.37±12.11 0.8286
  Changes in CoV of stride length at 24 weeks from baseline (%)
   Left 3.51±16.33 -0.68±5.78 0.6273
   Right 1.29±9.67 -0.19±5.30 0.4704
  Changes in base of support at 24 weeks from baseline (cm)
   Left 0.34±4.41 0.29±3.87 0.8388
   Right 0.41±4.40 0.43±3.65 0.9895
  Changes in CoV of base of support at 24 weeks from baseline (%)
   Left -4.72±15.87 -2.12±12.16 0.9112
   Right -3.44±13.87 -2.50±10.98 0.7930
 Temporal parameters
  Changes in walking velocity at 24 weeks from baseline (cm/s) -1.14±14.74 -3.15±13.28 0.5651
  Changes in cadence at 24 weeks from baseline (step/min) 1.49±11.81 -4.41±16.06 0.2761
  Changes in proportion in gait cycle of swing time at 24 weeks from baseline (%GC)
   Left -1.37±7.11 -1.48±7.34 0.2077
   Right -0.62±6.27 -1.42±5.07 0.3792
  Changes in proportion in gait cycle of stance time at 24 weeks from baseline (%GC)
   Left 1.36±7.10 3.00±6.20 0.1023
   Right -0.06±7.48 1.41±5.05 0.2997
  Changes in proportion in gait cycle of single support time at 24 weeks from baseline (%GC)
   Left -0.89±6.53 -1.41±5.03 0.4584
   Right -1.36±7.16 -1.69±7.43 0.1380
  Changes in proportion in gait cycle of double support time at 24 weeks from baseline (%GC)
   Left -0.36±10.25 5.77±14.20 0.1346
   Right 0.69±7.91 4.02±8.93 0.1850

Values are presented as mean±standard deviation.

* p value<0.05.

K-SARA, Korean version of Scale for the Assessment and Rating of Ataxia; CGI-S, Clinical Global Impression Scale-Severity; CGI-I, Clinical Global Impression Scale-Improvement; CGI-E, Clinical Global Impression Scale-Efficacy Index; K-SCOPA-AUT, Korean version of Scales of Outcome in Parkinson’s Disease Autonomic; EQ-5D-5L, five-level version of the EuroQol five-dimensional questionnaire; EQ, European quality; VAS, visual analogue scale; CoV, coefficient of variation; GC, gait cycle.

Table 3.
Safety outcomes-adverse events
SOC/PT Safety set taltirelin group (n=77)
Safety set control group (n=80)
p value
n (%) E n (%) E
AE 0.3828
 Total incidences 22 (28.57) 33 18 (22.50) 22
 Injury, poisoning and procedural complications 7 (9.09) 8 2 (2.50) 3
  Rib fracture 2 (2.60) 3 0 (0.00) 0
  Limb injury 0 (0.00) 0 1 (1.25) 1
  Fall 1 (1.30) 1 0 (0.00) 0
  Ligament sprain 1 (1.30) 1 0 (0.00) 0
  Hand fracture 0 (0.00) 0 1 (1.25) 1
  Procedural pain 1 (1.30) 1 0 (0.00) 0
  Skin laceration 0 (0.00) 0 1 (1.25) 1
  Spinal column injury 1 (1.30) 1 0 (0.00) 0
  Head injury 1 (1.30) 1 0 (0.00) 0
 Psychiatric disorders 2 (2.60) 2 4 (5.00) 4
  Insomnia 2 (2.60) 2 3 (3.75) 3
  Rapid eye movement sleep behaviour disorder 0 (0.00) 0 1 (1.25) 1
 Skin and subcutaneous tissue disorders 2 (2.60) 2 4 (5.00) 4
  Pruritus 1 (1.30) 1 1 (1.25) 1
  Keloid scar 0 (0.00) 0 1 (1.25) 1
  Rash 0 (0.00) 0 1 (1.25) 1
  Urticaria 0 (0.00) 0 1 (1.25) 1
  Psoriasis 1 (1.30) 1 0 (0.00) 0
 Gastrointestinal disorders 4 (5.19) 4 2 (2.50) 2
  Abdominal pain upper 1 (1.30) 1 1 (1.25) 1
  Gastric ulcer 1 (1.30) 1 0 (0.00) 0
  Nausea 1 (1.30) 1 0 (0.00) 0
  Dyspepsia 1 (1.30) 1 0 (0.00) 0
  Dry mouth 0 (0.00) 0 1 (1.25) 1
 Nervous system disorders 5 (6.49) 5 1 (1.25) 1
  Dizziness 3 (3.90) 3 0 (0.00) 0
  Somnolence 1 (1.30) 1 0 (0.00) 0
  Seizure 1 (1.30) 1 0 (0.00) 0
  Headache 0 (0.00) 0 1 (1.25) 1
 Investigations 2 (2.60) 2 2 (2.50) 2
  Blood creatine phosphokinase increased 0 (0.00) 0 2 (2.50) 2
  Thyroxine free increased 1 (1.30) 1 0 (0.00) 0
  Liver function test abnormal 1 (1.30) 1 0 (0.00) 0
 Musculoskeletal and connective tissue disorders 2 (2.60) 2 1 (1.25) 1
  Back pain 0 (0.00) 0 1 (1.25) 1
  Muscular weakness 1 (1.30) 1 0 (0.00) 0
  Arthralgia 1 (1.30) 1 0 (0.00) 0
 Infections and infestations 2 (2.60) 2 0 (0.00) 0
  Nasopharyngitis 1 (1.30) 1 0 (0.00) 0
  Otitis externa 1 (1.30) 1 0 (0.00) 0
 Metabolism and nutrition disorders 1 (1.30) 1 1 (1.25) 1
  Decreased appetite 0 (0.00) 0 1 (1.25) 1
  Hyperlipidaemia 1 (1.30) 1 0 (0.00) 0
 General disorders and administration site conditions 1 (1.30) 1 1 (1.25) 1
  Gait disturbance 1 (1.30) 1 0 (0.00) 0
  Feeling hot 0 (0.00) 0 1 (1.25) 1
 Reproductive system and breast disorders 1 (1.30) 1 0 (0.00) 0
  Menstruation irregular 1 (1.30) 1 0 (0.00) 0
 Renal and urinary disorders 1 (1.30) 1 0 (0.00) 0
  Haematuria 1 (1.30) 1 0 (0.00) 0
 Hepatobiliary disorders 0 (0.00) 0 1 (1.25) 1
  Hepatotoxicity 0 (0.00) 0 1 (1.25) 1
 Congenital, familial and genetic disorders 1 (1.30) 1 0 (0.00) 0
  Congenital cystic kidney disease 1 (1.30) 1 0 (0.00) 0
 Ear and labyrinth disorders 1 (1.30) 1 0 (0.00) 0
  Vertigo 1 (1.30) 1 0 (0.00) 0
 Vascular disorders 0 (0.00) 0 1 (1.25) 1
  Hypertension 0 (0.00) 0 1 (1.25) 1
 Surgical and medical procedures 0 (0.00) 0 1 (1.25) 1
  Removal of internal fixation 0 (0.00) 0 1 (1.25) 1

SOC, system organ class; PT, preferred term; E, number of events; AE, adverse event.

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      JEE YOUNG LEE

      이 임상시험의 전 과정에서 고생해주신 교신저자 선생님과 여러 공저자 선생님들 노고에 감사드리며, 어려운 임상시험이었지만 덕분에 많이 배울 수 있었습니다. 2025년 1월호 논문으로 출판을 진심으로 축하드려요!

      January 30, 2025

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      Efficacy and Safety of Taltirelin Hydrate in Patients With Ataxia Due to Spinocerebellar Degeneration
      Image Image Image Image Image
      Figure 1. Dispositions of the patients in the study. FAS, full analysis set.
      Figure 2. Distribution of the baseline K-SARA scores. K-SARA, Korean version of the Scale for the Assessment and Rating of Ataxia.
      Figure 3. Overall changes in the K-SARA scores at 24 weeks from baseline. *p value<0.05. K-SARA, Korean version of the Scale for the Assessment and Rating of Ataxia.
      Figure 4. Overall changes in the K-SARA scores at 24 weeks from baseline. *p value<0.05. K-SARA, Korean version of the Scale for the Assessment and Rating of Ataxia.
      Graphical abstract
      Efficacy and Safety of Taltirelin Hydrate in Patients With Ataxia Due to Spinocerebellar Degeneration
      Variables Values
      p value
      Taltirelin group (n=75) Control group (n=74)
      Age (yr) 56.60±10.55 52.51±12.17 0.0265*
      Sex 0.9385
       Men 40 (53.33) 39 (52.70)
       Women 35 (46.67) 35 (47.30)
      Genetic inheritance of ataxia 0.6927
       Hereditary ataxia 41 (54.67) 45 (60.81)
        SCA 37 (49.33) 42 (56.76)
        Other types of hereditary ataxia 4 (5.33) 3 (4.05)
         Spastic ataxia of Charlevoix-Saguenay 0 (0.00) 1 (1.35)
         Hereditary spastic ataxia 1 (1.33) 0 (0.00)
         DRPLA gene 1 (1.33) 0 (0.00)
         Chromosome analysis 1 (1.33) 0 (0.00)
         Unknown 1 (1.33) 2 (2.70)
       Non-hereditary ataxia 34 (45.33) 29 (39.19)
        ILOCA 34 (45.33) 29 (39.19)
      Disease duration (yr) 2.33 (0.07–16.47) 3.23 (0.00–22.50) 0.4165
      K-MMSE scores 28.03±1.69 27.93±2.07 0.7894
      Outcome measures Taltirelin group (n=75) Control group (n=74) p value
      Primary efficacy outcome measure
       Changes in K-SARA scores at 24 weeks from baseline -0.51±2.79 0.36±2.62 0.0321*
      Secondary efficacy outcome measures
       Changes in K-SARA scores at 12 weeks from baseline -0.47±3.05 0.05±2.66 0.1151
       Changes in CGI-S scores at 24 weeks from baseline 0.08±0.56 0.03±0.47 0.4925
       Changes in CGI-I scores at 24 weeks from 4 weeks 0.15±0.65 0.31±0.57 0.1170
       Changes in CGI-E scores at 24 weeks from 4 weeks -0.08±0.65 -0.16±0.57 0.3440
       Changes in K-SCOPA-AUT scores at 24 weeks from baseline -2.27±6.09 -0.45±5.34 0.2349
       Changes in EQ-5D-5L scores at 24 weeks from baseline
        EQ-5D-5L descriptive system 0.00±0.16 -0.02±0.13 0.3159
        EQ VAS 1.92±21.72 -3.88±18.32 0.1539
       Changes in Tinetti balance and gait scores at 24 weeks from baseline 0.03±4.02 -0.34±3.25 0.5874
       Spatio-temporal parameters of gait
       Spatial parameters
        Changes in step length at 24 weeks from baseline (cm)
         Left -1.25±8.93 -0.95±7.22 >0.9999
         Right -1.52±8.09 -1.00±6.00 0.9320
        Changes in CoV of step length at 24 weeks from baseline (%)
         Left 0.51±7.43 3.44±13.29 0.2066
         Right 1.86±14.76 -3.07±11.17 0.5682
        Changes in stride length at 24 weeks from baseline (cm)
         Left -2.96±17.19 -1.65±12.23 0.9008
         Right -2.89±15.96 -2.37±12.11 0.8286
        Changes in CoV of stride length at 24 weeks from baseline (%)
         Left 3.51±16.33 -0.68±5.78 0.6273
         Right 1.29±9.67 -0.19±5.30 0.4704
        Changes in base of support at 24 weeks from baseline (cm)
         Left 0.34±4.41 0.29±3.87 0.8388
         Right 0.41±4.40 0.43±3.65 0.9895
        Changes in CoV of base of support at 24 weeks from baseline (%)
         Left -4.72±15.87 -2.12±12.16 0.9112
         Right -3.44±13.87 -2.50±10.98 0.7930
       Temporal parameters
        Changes in walking velocity at 24 weeks from baseline (cm/s) -1.14±14.74 -3.15±13.28 0.5651
        Changes in cadence at 24 weeks from baseline (step/min) 1.49±11.81 -4.41±16.06 0.2761
        Changes in proportion in gait cycle of swing time at 24 weeks from baseline (%GC)
         Left -1.37±7.11 -1.48±7.34 0.2077
         Right -0.62±6.27 -1.42±5.07 0.3792
        Changes in proportion in gait cycle of stance time at 24 weeks from baseline (%GC)
         Left 1.36±7.10 3.00±6.20 0.1023
         Right -0.06±7.48 1.41±5.05 0.2997
        Changes in proportion in gait cycle of single support time at 24 weeks from baseline (%GC)
         Left -0.89±6.53 -1.41±5.03 0.4584
         Right -1.36±7.16 -1.69±7.43 0.1380
        Changes in proportion in gait cycle of double support time at 24 weeks from baseline (%GC)
         Left -0.36±10.25 5.77±14.20 0.1346
         Right 0.69±7.91 4.02±8.93 0.1850
      SOC/PT Safety set taltirelin group (n=77)
      Safety set control group (n=80)
      p value
      n (%) E n (%) E
      AE 0.3828
       Total incidences 22 (28.57) 33 18 (22.50) 22
       Injury, poisoning and procedural complications 7 (9.09) 8 2 (2.50) 3
        Rib fracture 2 (2.60) 3 0 (0.00) 0
        Limb injury 0 (0.00) 0 1 (1.25) 1
        Fall 1 (1.30) 1 0 (0.00) 0
        Ligament sprain 1 (1.30) 1 0 (0.00) 0
        Hand fracture 0 (0.00) 0 1 (1.25) 1
        Procedural pain 1 (1.30) 1 0 (0.00) 0
        Skin laceration 0 (0.00) 0 1 (1.25) 1
        Spinal column injury 1 (1.30) 1 0 (0.00) 0
        Head injury 1 (1.30) 1 0 (0.00) 0
       Psychiatric disorders 2 (2.60) 2 4 (5.00) 4
        Insomnia 2 (2.60) 2 3 (3.75) 3
        Rapid eye movement sleep behaviour disorder 0 (0.00) 0 1 (1.25) 1
       Skin and subcutaneous tissue disorders 2 (2.60) 2 4 (5.00) 4
        Pruritus 1 (1.30) 1 1 (1.25) 1
        Keloid scar 0 (0.00) 0 1 (1.25) 1
        Rash 0 (0.00) 0 1 (1.25) 1
        Urticaria 0 (0.00) 0 1 (1.25) 1
        Psoriasis 1 (1.30) 1 0 (0.00) 0
       Gastrointestinal disorders 4 (5.19) 4 2 (2.50) 2
        Abdominal pain upper 1 (1.30) 1 1 (1.25) 1
        Gastric ulcer 1 (1.30) 1 0 (0.00) 0
        Nausea 1 (1.30) 1 0 (0.00) 0
        Dyspepsia 1 (1.30) 1 0 (0.00) 0
        Dry mouth 0 (0.00) 0 1 (1.25) 1
       Nervous system disorders 5 (6.49) 5 1 (1.25) 1
        Dizziness 3 (3.90) 3 0 (0.00) 0
        Somnolence 1 (1.30) 1 0 (0.00) 0
        Seizure 1 (1.30) 1 0 (0.00) 0
        Headache 0 (0.00) 0 1 (1.25) 1
       Investigations 2 (2.60) 2 2 (2.50) 2
        Blood creatine phosphokinase increased 0 (0.00) 0 2 (2.50) 2
        Thyroxine free increased 1 (1.30) 1 0 (0.00) 0
        Liver function test abnormal 1 (1.30) 1 0 (0.00) 0
       Musculoskeletal and connective tissue disorders 2 (2.60) 2 1 (1.25) 1
        Back pain 0 (0.00) 0 1 (1.25) 1
        Muscular weakness 1 (1.30) 1 0 (0.00) 0
        Arthralgia 1 (1.30) 1 0 (0.00) 0
       Infections and infestations 2 (2.60) 2 0 (0.00) 0
        Nasopharyngitis 1 (1.30) 1 0 (0.00) 0
        Otitis externa 1 (1.30) 1 0 (0.00) 0
       Metabolism and nutrition disorders 1 (1.30) 1 1 (1.25) 1
        Decreased appetite 0 (0.00) 0 1 (1.25) 1
        Hyperlipidaemia 1 (1.30) 1 0 (0.00) 0
       General disorders and administration site conditions 1 (1.30) 1 1 (1.25) 1
        Gait disturbance 1 (1.30) 1 0 (0.00) 0
        Feeling hot 0 (0.00) 0 1 (1.25) 1
       Reproductive system and breast disorders 1 (1.30) 1 0 (0.00) 0
        Menstruation irregular 1 (1.30) 1 0 (0.00) 0
       Renal and urinary disorders 1 (1.30) 1 0 (0.00) 0
        Haematuria 1 (1.30) 1 0 (0.00) 0
       Hepatobiliary disorders 0 (0.00) 0 1 (1.25) 1
        Hepatotoxicity 0 (0.00) 0 1 (1.25) 1
       Congenital, familial and genetic disorders 1 (1.30) 1 0 (0.00) 0
        Congenital cystic kidney disease 1 (1.30) 1 0 (0.00) 0
       Ear and labyrinth disorders 1 (1.30) 1 0 (0.00) 0
        Vertigo 1 (1.30) 1 0 (0.00) 0
       Vascular disorders 0 (0.00) 0 1 (1.25) 1
        Hypertension 0 (0.00) 0 1 (1.25) 1
       Surgical and medical procedures 0 (0.00) 0 1 (1.25) 1
        Removal of internal fixation 0 (0.00) 0 1 (1.25) 1
      Table 1. Baseline characteristics of the patients

      Values are presented as mean±standard deviation, number (%), or median with the range unless otherwise indicated.

      p value<0.05.

      SCA, spinocerebellar ataxia; ILOCA, idiopathic late onset cerebellar ataxia; K-MMSE, Korean Mini-Mental State Examination.

      Table 2. Efficacy outcome measures of taltirelin

      Values are presented as mean±standard deviation.

      p value<0.05.

      K-SARA, Korean version of Scale for the Assessment and Rating of Ataxia; CGI-S, Clinical Global Impression Scale-Severity; CGI-I, Clinical Global Impression Scale-Improvement; CGI-E, Clinical Global Impression Scale-Efficacy Index; K-SCOPA-AUT, Korean version of Scales of Outcome in Parkinson’s Disease Autonomic; EQ-5D-5L, five-level version of the EuroQol five-dimensional questionnaire; EQ, European quality; VAS, visual analogue scale; CoV, coefficient of variation; GC, gait cycle.

      Table 3. Safety outcomes-adverse events

      SOC, system organ class; PT, preferred term; E, number of events; AE, adverse event.


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