INTRODUCTION
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.
MATERIALS & METHODS
- 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.
RESULTS
- 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.
DISCUSSION
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.
JEE YOUNG LEE
January 30, 2025