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. 2021 Oct 29;9(1):20–30. doi: 10.1002/mdc3.13357

The Efficacy and Safety of Pridopidine on Treatment of Patients with Huntington's Disease: A Systematic Review and Meta‐Analysis

Moamen Mostafa Asla 1, Asmaa Ahmed Nawar 1, Alaa Abdelsalam 1, Esraa Elsayed 1, Marwa Abdelazim Rizk 1, Mohamed Alaa Hussein 1, Walaa A Kamel 2,3,✉
PMCID: PMC8721839  PMID: 35005061

ABSTRACT

Background

Pridopidine is a novel drug that helps stabilize psychomotor function in patients with Huntington's disease (HD) by activating the cortical glutamate pathway. It promises to achieve the unmet needs of current therapies of HD without worsening other symptoms.

Objective

To review the literature discussing the efficacy of pridopidine in alleviating motor symptoms and its safety in patients with HD.

Methods

We searched Scopus, Web of Science, the Cochrane Library, Wiley, and PubMed for randomized controlled trials (RCTs) of pridopidine on HD. Data from eligible studies were extracted and pooled as mean differences for efficacy and risk ratios (RRs) for safety using RevMan software version 5.3.

Results

A total of 4 relevant RCTs with 1130 patients were selected (816 in the pridopidine group and 314 in the placebo group). The pooled effect size favored pridopidine over placebo insignificantly in the Unified Huntington's Disease Rating Scale Total Motor Score (mean difference [MD], −0.93; 95% confidence interval [CI], −2.01 to 0.14; P = 0.09), whereas the effect size of 3 studies significantly favored pridopidine over placebo in the Unified Huntington's Disease Rating Scale Modified Motor Score (MD, −0.81; 95% CI, −1.48 to −0.13; P = 0.02). Pridopidine generally was well tolerated. None of the adverse effects were considerably higher in the case of pridopidine compared with placebo in overall adverse events (RR, 1.03; 95% CI, 0.94–1.13; P = 0.49) and serious adverse events (RR, 1.62; 95% CI, 0.88–2.99; P = 0.12).

Conclusion

The effects of pridopidine on motor functions (especially voluntary movements) in patients with HD are encouraging and provide a good safety profile that motivates further clinical trials on patients to confirm its effectiveness and safety.

Keywords: Pridopidine, Huntington’s disease, HD, safety, efficacy, meta‐analysis

Huntington's disease (HD) is an autosomal dominant neurodegenerative condition. 1 Its progression depends on multiple factors, including genetic, demographic, and environmental factors. 2 , 3 HD often affects individuals at the age of 40, but juvenile‐onset HD may occur at a pediatric age with a worsening progression and a shorter survival duration. 4 , 5 The prevalence of HD has increased in Australia, Western Europe, and North America during the past 50 years; it affects 5.96 to 13.7 patients per 100,000 population. 1 , 6 HD manifestations comprise a triad of motor, behavioral, and cognitive impairment. Patients experience various symptoms such as chorea, dystonia, tremors, and memory and thinking deterioration, leading to disability and a poor quality of life. 5 , 7 A mutant huntingtin (mHtt) protein causes HD, which results from an expanded CAG trinucleotide (a segment consists of a series of 3 DNA building blocks [cytosine, adenine, and guanine] that is a highly sensitive and a specific marker for inheritance of the HD disease mutation) repeats in the huntingtin gene in more than 36 repeats. 8 The mHtt protein undergoes several pathological processes such as protein–protein interactions, misfolding, aggregation, and protein dysfunction. These processes lead to dysfunction and degeneration of brain areas, including the striatum (caudate nucleus and putamen). 9 , 10 As a result of the degeneration of the striatal neuron that normally modulates motor activity, dopamine‐level changes lead to impaired movement. 11 Motor impairment is the primary determinant of HD‐induced disability. Motor dysfunction varies in different cases and exacerbates over time. It includes involuntary movements (chorea and dystonia) and disturbance of voluntary movement (irregularity, impersistence, loss of sequencing, apraxia, and bradykinesia). 11 , 12

The current treatment of HD is nonspecific and aims primarily to ameliorate the symptoms of the disease without slowing the disease progression. Tetrabenazine (TBZ) and its deuterated form deutetrabenazine are the first‐line treatments for controlling choreatic movements in patients with HD. 13 , 14 , 15 Unfortunately, there are some concerns about its safety and tolerability in patients with HD. 14 According to the “International Guidelines for the Treatment of Huntington's Disease,” TBZ may induce or increase patients' rigidity and akathisia and negatively impact their memory. 15 Therefore, finding other effective and safe treatment modalities is crucial. Pridopidine is a novel drug that promises to achieve the unmet needs of current therapies because it stabilizes the psychomotor functions of patients with HD without worsening other symptoms. 11

Pridopidine, formerly known as ACR16 (4‐[3‐(methylsulfonyl) phenyl]‐1‐propylpiperidine), is a new drug from the “dopidines” class that was believed to act as a dopaminergic stabilizer. 10 , 16 It was originally reported that dopidines antagonize the action of dopamine at the postsynaptic receptors, which can normalize the dysregulated dopamine level in HD without affecting normal dopamine functions. 17 According to recent studies, the affinity of sigma‐1 receptors for pridopidine is much higher than dopaminergic receptors. 18 They allow synthesis of nerve cells and decrease oxidative stress, and their impairment contributes to neurodegenerative disease pathogenesis. 19 , 20 , 21 , 22 Pridopidine can act on sigma‐1 receptors that can reduce abnormal protein aggregates with a resultant neuroprotective potential. 19 , 23

In humans, 4 randomized controlled clinical trials have studied the effect of pridopidine on different outcomes in patients with HD. 24 , 25 , 26 , 27 With no published systematic review of these trials, we were encouraged to undertake this systematic review and meta‐analysis to search for evidence from published randomized controlled trials about its efficacy and safety.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement guidelines 28 and performed all steps according to the Cochrane Handbook of Systematic Reviews of Interventions. 29 This systematic review's protocol was registered in International Prospective Register of Systematic Reviews (PROSPERO, CRD42021227513).

Eligibility Criteria

Articles were included according to the population, intervention, control, and outcomes strategy. 29 Inclusion criteria for study selection were the following: (1) population: patients with HD; (2) intervention: oral pridopidine in different doses; (3) control: placebo; (4) outcomes: articles reporting efficacy or safety as endpoints; and (5) study design: randomized controlled trials. We excluded (1) nonrandomized trials, (2) animal trials, and (3) articles without relevant population, intervention, or outcomes.

Literature Search Strategy

A literature search in the Cochrane Library, Scopus, Web of Science, Wiley, and PubMed was performed using the following search terms: (Huntington OR Huntingtin OR HD OR chorea) AND (Pridopidine OR huntexil OR ACR16 OR ASP2314 OR FR‐310826 OR propylpiperidine OR C15H23NO2S). The search was conducted on December 26, 2020, and resulted in 681 citations.

Study Selection and Data Extraction

After title and abstract screening, 2 independent authors performed article selection and data extraction. Any disagreement was resolved with a senior reviewer. Data were extracted using a formatted excel sheet, including baseline characteristics of participants, study design, sample size, eligibility criteria, intervention, follow‐up duration, and outcome measures.

Quality Assessment

A total of 2 reviewers used Cochrane's risk of bias tool (reported in the Cochrane Handbook of Systematic Reviews of Interventions 29 using the quality assessment table in part 2 [chapter 8.5]) to assess the bias in each study. That includes several domains of bias categorized as selection bias, performance bias, attrition bias, detection bias, reporting bias, and other biases to appraise any type of bias not included in previous items. The authors' judgment on each domain was categorized as high, unclear, or low risk of bias. If there was a disagreement between the 2 authors, it was resolved by a third reviewer.

Measures of Effect

The Unified Huntington's Disease Rating Scale (UHDRS) 30 is a clinical scale that examines the following 4 aspects of clinical performance and ability in patients with HD: motor function, cognition, behavior, and functional abilities. UHDRS Total Motor Score (UHDRS‐TMS), which evaluates motor disability, and its Modified Motor Score (UHDRS‐mMS), which focuses on voluntary motor performance, are our efficacy outcomes of interest. 31 We evaluated safety outcomes through the incidence of several adverse events (AEs), overall AEs, serious AEs, and withdrawal AEs.

Data Synthesis

We analyzed continuous data of efficacy outcomes using mean difference (MD) and standard error (SE) and dichotomous safety data using risk ratio (RR). The analysis was conducted using Review Manager Software (version 5.3, Nordic Cochrane Centre). Statistical heterogeneity between studies was measured by chi‐square test 32 and the I‐squared test for heterogeneity. We considered the data as statistically significant with a P value <0.05 and heterogeneous with a P value <0.05. All outcomes were under a fixed‐effect model using the inverse variance method. If the I‐squared test was higher than 60%, a random‐effect model was used. For less than 10 pooled studies, publication bias is not reliable, according to Egger and colleagues. 33 Therefore, in the present study, we could not assess the existence of publication bias by Egger's test for funnel plot asymmetry.

Subgroup Analysis

Subgroup analysis was performed based on the duration and the most tolerable doses (90 mg and 45 mg per day) of pridopidine shown in the included trials to determine their effects on each outcome.

Sensitivity Analysis

We ran a sensitivity analysis to ensure that the results of our analysis were not affected by any of the individual studies.

Results

A total of 681 references were found during our search. Only 15 articles were eligible for full‐text screening after the title and abstract screenings. Finally, the quantitative analysis included 4 randomized controlled trials with a total of 1130 patients with HD (816 in the pridopidine group and 314 in the placebo group; see PRISMA flowchart; Fig. 1). A summary of the design and main findings of the included studies and the baseline characteristics of their participants is shown in Table 1. Table S1 of the Supplementary Material contains the reasons for study exclusion. A summary of each study's estimated risk of bias is shown in Figure 2. According to Cochrane's risk of bias tool, the included studies' quality ranged from good to fair quality. All included studies described their random sequence generation and allocation concealment methods. In terms of performance and attrition bias, all of the studies had a low risk of bias. A total of 3 studies were at low risk of detection bias. 24 , 25 , 27 Only the study by the Huntington Study Group HART Investigators 25 was at a high risk of reporting bias. The authors' judgments with reasons are illustrated for each study in Table S1.

FIG. 1.

FIG. 1

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Flow diagram of article selection process based on Preferred Reporting Items for Systematic Reviews and Meta‐Analyses.

TABLE 1.

A summary of the design and main findings of the included trials with the baseline characteristic of their participants

Study Identification Dose Age (yr) Sex HD Duration (yr) UHDRS‐TMS UHDRS‐mMS Design Follow‐Up Duration Intervention Sample Size Outcomes
Per day Mean ± SD Male/Female Mean ± SD Mean ± SD Mean ± SD
Lundin et al, 201026 50 mg 50.2 ± 7 20/8 7.7 ± 4 36.2 ± 18.6 16.3 ± 7.9 Randomized, double‐blind, placebo‐controlled 4 weeks Pridopidine 50 mg per day vs. placebo 58 patients with HD Pridopidine shows promise as a treatment for some of the symptoms of HD. There was a notable improvement in voluntary motor symptoms.
Placebo 56 ± 10 19/11 6.8 ± 5 37.7 ± 21 15.8 ± 9.4
De Yebenes et al, 201124 45 mg 51 ± 10.7 66/82 4.5 ± 3.6 41.14 ± 15.83 18.38 ± 6.76 Phase 3, randomized, double‐blind, placebo‐controlled trial 26 weeks Pridopidine 45 or 90 mg per day vs. placebo 437 patients with HD Pridopidine up to 90 mg per day was well tolerated in patients with Huntington's disease. It had a potential effect on the motor phenotype of HD.
90 mg 51.8 ± 11.1 81/64 5.1 ± 3.6 41.81 ± 14.87 18.57 ± 6.9
Placebo 49.1 ± 9.6 68/76 4.8 ± 3.3 42.78 ± 17.28 19.43 ± 8.28
Huntington Study Group HART Investigators, 201325 20 mg 54.3 ± 11 23/33 4.6 ± 3.5 38.7 ± 14 17.3 ± 6.5 Randomized double‐blinded placebo‐controlled trial 12 weeks Pridopidine 20, 45, or 90 mg per day vs. placebo 227 patients with HD Pridopidine was generally well tolerated. The overall results suggest that pridopidine may improve motor function in HD.
45 mg 50.5 ± 10.5 28/27 4.4 ± 3.6 34 ± 13.3 14.2 ± 5
90 mg 50.9 ± 9.7 30/28 4.1 ± 2.8 38.3 ± 14.1 16.2 ± 6.4
Placebo 50.4 ± 10.5 25/33 4 ± 3.6 39.9 ± 15 17.2 ± 6.5
Reilmann et al, 201927 90 mg 51.9 ± 11.8 41/40 N/A 40.5 ± 13.28 N/A Phase 2, randomized, double‐blind, placebo‐controlled trial 52 weeks Pridopidine 90, 135, 180 or 225 mg per day vs. placebo 408 patients with HD Pridopidine did not improve the UHDRS‐TMS at week 26 compared with placebo. There was no new safety or tolerability concerns emerged in this study.
135 mg 51 ± 11.8 41/41 N/A 42.9 ± 14.17 N/A
180 mg 51.3 ± 12.7 38/43 N/A 43 ± 15.02 N/A
225 mg 47.5 ± 11.4 43/39 N/A 42.7 ± 12.25 N/A
Placebo 50.3 ± 11.3 42/40 N/A 42.9 ± 13.96 N/A
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Abbreviations: HD, Huntington's disease; UHDRS, Unified Huntington's Disease Rating Scale; TMS, Total Motor Score; mMS, Modified Motor Score; N/A, not available.

FIG. 2.

FIG. 2

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A summary of risk of bias assessment.

Efficacy analysis from baseline to endpoint

Unified Huntington's Disease Rating Scale Total Motor Score

The overall effect estimates insignificantly favored the pridopidine group over the placebo group (MD, −0.93; 95% confidence interval [CI], −2.01 to 0.14; P = 0.09). Pooled studies were homogenous (P = 0.14, I2 = 46%; Fig. 3A). There was no significant difference between pridopidine and placebo at 45 mg (MD, −1.11; 95% CI, −2.56 to 0.33; P = 0.13) and placebo at 90 mg (MD, −1.54; 95% CI, −4.49 to 1.11; P = 0.26). Pooled studies for the 45‐mg subgroup were homogenous (P = 0.91, I2 = 0%; Fig. 4). Pooled studies for the 90‐mg subgroup were heterogeneous (P = 0.03, I2 = 72%). After excluding Reilmann et al, 27 the detected heterogeneity was best resolved (P = 0.92, I2 = 0%); as a result, the overall effect estimates changed significantly (MD, −2.90; 95% CI, −4.49 to −1.30; P = 0.0004; Fig. S2).

FIG. 3.

FIG. 3

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Forest plots of mean difference comparing pridopidine to control arm in (A) Unified Huntington's Disease Rating Scale Total Motor Score and (B) Unified Huntington's Disease Rating Scale Modified Motor Score. CI, confidence interval; SE, standard error; IV, Inverse variance.

FIG. 4.

FIG. 4

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A forest plot of the safety analysis of pridopidine comparing to control arm. CI, confidence interval; M‐H, Mantel‐Haenszel.

Unified Huntington's Disease Rating Scale Modified Motor Score

The overall effect estimates of 3 studies 24 , 25 , 26 favored the pridopidine group over the placebo group (MD, −0.81; 95% CI, −1.48 to −0.13; P = 0.02). Pooled studies were homogenous (P = 0.80, I2 = 0%; Fig. 3B). The difference between pridopidine and placebo was statistically significant at 45 mg (MD, −1.05; 95% CI, −1.79 to −0.31; P = 0.005) and at 90 mg (MD, −1.75; 95% CI, −3.11 to −0.39; P = 0.01). Pooled studies for these subgroups were homogenous (P < 0.1, I2 = 0%; Fig. S3).

Safety Analysis

The frequency of overall AEs (RR, 1.03; 95% CI, 0.94–1.13; P = 0.49), serious AEs (RR, 1.62; 95% CI, 0.88–2.99; P = 0.12), AEs that led to withdrawal (RR, 1.26; 95% CI, 0.75–2.11; P = 0.38), nausea (RR, 0.92; 95% CI, 0.54–1.57; P = 0.77), depression (RR, 0.64; 95% CI, 0.35–1.16; P = 0.14), falls (RR, 1.03; 95% CI, 0.73–1.46; P = 0.87), fatigue (RR, 0.72; 95% CI, 0.44–1.19; P = 0.20), and diarrhea (RR, 0.62; 95% CI, 0.80–2.21; P = 0.27) did not show a statistically significant change toward the pridopidine group over placebo. Pooled studies were homogenous (chi‐square P < 0.1; Fig. 4).

Subgroup Analysis

Subgroup analysis according to dose showed that the effect estimate was likely superior at 90 mg than 45 mg of pridopidine in most efficacy and safety outcomes. According to the duration, after 4 weeks of follow‐up, the overall effect estimates significantly favored the pridopidine group over the placebo group in UHDRS‐mMS (MD, −0.49; 95% CI, −0.91 to −0.07; P = 0.02), whereas the pridopidine group was insignificantly superior in UHDTS‐TMS. After 12 and 26 months of follow‐up, there was insignificant superiority of the pridopidine group over the placebo group in the efficacy outcomes (Table S3 and Figs. [Link], [Link]).

Sensitivity Analysis

After performing a sensitivity analysis, we found that the overall effect estimates significantly favored the pridopidine group over the placebo group in UHDRS‐TMS with the Reilmann et al 27 exclusion (MD, −1.70; 95% CI, −2.96 to −0.45; P = 0.008). Sensitivity analysis for other outcomes is shown in the Table S4.

Discussion

Patients with HD suffer from motor and mental disabilities that affect life expectancy and quality of life negatively. 34 In addition, the available drugs are not very effective, and they are associated with many adverse effects, 14 which prompts the study of new medications on this disease. The UHDRS, which has a high level of reliability in motor scores, was relied on in all of the included studies to assess the efficacy. 30 The current study provides Class I evidence that pridopidine is effective and safe in short‐term management.

Our analysis of 1130 patients with HD showed that pridopidine was well tolerated in patients with HD. There was no significant increase in any of the AEs in pridopidine compared with placebo. The rate of overall AEs, serious AEs, AEs that led to withdrawal, and most other AEs decreased in the group of pridopidine more than in the placebo, except for some adverse effects such as depression, nausea, diarrhea, and fatigue, which increased in the group of pridopidine over placebo. These findings are very similar to the results of Squitieri et al. 35 Subgroup analysis showed that pridopidine at 90 mg was superior to pridopidine at 45 mg in motor functions. The superiority between them was mutual in safety endpoints. Although included trials showed pridopidine was well tolerated, 3 people died in the Mermai HD study: 1 in the placebo group (suicide), 1 in the pridopidine 45 mg per day group (urosepsis), and 1 in the pridopidine 90 mg per day group (subarachnoid hemorrhage). The study drug was found to be unlikely to be the cause of death in the pridopidine groups. 24 A total of 2 deaths occurred during the study by Reilmann et al: 1 in the pridopidine 225 mg per day group (aspiration pneumonia), which was thought to be related to the study drug, and another in the 180 mg per day group (lethal fall), which was determined to be unrelated to the study drug. 27 In terms of efficacy, pridopidine had a clear effect on voluntary movement symptoms. The results indicated that the difference in the mMS significantly preferred the pridopidine over the placebo groups in the total as well as in subgroups of 90 mg and 45 mg. On the other hand, there was an insignificant superiority of the pridopidine over the placebo in the TMS. Results significantly favored the pridopidine group only in the 90‐mg subgroup. Because eye movement and involuntary motor performance are poorly associated with the other UHDRS motor scores, the UHDRS motor assessment items relating to voluntary motor functions (ie, the mMS) have a higher degree of internal consistency. 36 In the short‐term management, the pridopidine group showed superiority in the efficacy measurements. After 4 weeks of follow‐up, there was a statistically significant difference between pridopidine and placebo in mMS. This may indicate the effectiveness of the treatment in a short time during a long period of follow‐up. That needs further clinical trials to fully ensure its effectiveness in the short term and ensure that the effectiveness does not decrease with longer use.

Based on the results of the primary studies that we analyzed, our findings were rational and predictable. In our included clinical trials, Lundin et al conducted the first study of pridopidine on patients with HD in 2010. They found that it might improve disturbed voluntary movement associated with functional disability in HD. 26 In 2011, the Mermai HD study by De Yebenes et al showed the potential ability of pridopidine to improve a wide range of motor deficits, making it an excellent complement to other therapies. Because of the relatively large number of participants (437 patients), the findings of this study were reliable. 24 Another trial by Huntington Study Group HART Investigators concluded that the primary outcome measures showed no significant treatment‐related improvement. 25 Finally, Reilmann et al showed that motor impairment assessed by UHDRS‐TMS did not improve compared with placebo at 26 weeks. 27 This study did not assess the voluntary movement of the participants separately using UHDRS‐mMS but only assessed the motor function using UHDRS‐TMS. All the included trials indicated that pridopidine was generally well tolerated and safe for the enrolled patients. In Reilmann et al, the change in UHDRS‐TMS was largely in favor of the placebo group (large placebo effect). The placebo group's mean TMS decreased by about 5 points between baseline and 26 weeks, which differed from previous studies' findings. 27 That might be because of the different enrollment ratio between studies as the enrolled patients were assigned to active treatment versus placebo groups in a high ratio (4:1) in the Reilmann et al study. Furthermore, the observed improvement in motor functions in previous studies might have increased participant and investigator expectations. 37 We believe that the long follow‐up period in this study brought about physiological changes to the participants, which may have led to pairing the placebo treatment with a real treatment until it produced the desired effect. We also believe that heterogeneity in the Reilmann et al study may also be justified by the variable ethnic origins of patient groups in the study as it was carried out across 12 countries in at least 3 continents. In some studies, the efficacy of pridopidine on eye, dystonia, cognitive, behavioral, and functional outcomes was difficult to assess because they required a longer observation period according to the Huntington Study Group HART Investigators. 25 In 2019, a systematic review was conducted by Feustel et al to assess the benefits and risks of unapproved disease‐modifying treatments for neurodegenerative diseases. 38 It indicated that there was no beneficial effect of the disease‐modifying treatments for neurodegenerative diseases. This review did not give enough attention to HD, not even the pridopidine. In addition, it included only 3 studies 24 , 25 , 26 in the efficacy analysis.

Quality of Evidence

This systematic review and meta‐analysis provide a Class I level of evidence because all of the included studies were randomized, blinded, controlled trials with a representative population and appropriate statistics with a similar baseline patient characteristic.

Strengths and Limitations

Our findings were considered credible because they were based on low‐to‐moderate risk of bias clinical trials. This study is the first meta‐analysis to focus on the effect of pridopidine on patients with HD, including important motor functions. The reported heterogeneity was minor or nonexistent in some outcomes, giving strength to the results. The efficacy and safety of the available doses (45 mg, 90 mg) by subgroup analysis give more power to our study. However, this meta‐analysis had some limitations. The small number of studies affects the susceptibility of our results, considering the acceptable total numbers (1160) of enrolled patients. The duration of follow‐up differed between the included trials. Other functions such as cognition and behavior were difficult to assess because of the lack of reported data in the included studies.

Conclusion

In general, pridopidine is well tolerated and positively affects motor functions, especially voluntary movements. Its effectiveness is more evident at the dose of 90 mg per day. All of that provides motivation for further clinical trials on patients to further validate and rigorously support the drug's efficacy and safety. We also recommended extending its efficacy assessment to include other outcomes such as behavioral and cognitive functions.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

M.M.A.: 2B, 3A

A.A.N.: 1A, 3A

A.A.: 2A, 3A

E.E.: 1C, 2A

M.A.R.: 1C, 2C

M.A.H.: 1C, 3B

W.A.K.: 1B, 2C, 3B

Disclosures

Ethical Compliance Statement: This study did not require approval from the institutional review board or informed patient consent. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.

Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report.

Supporting information

Figure S1. Risk of bias graph

Click here for additional data file. (24.1KB, docx)

Figure S2. A forest plot of subgroup analysis comparing pridopidine to control arm in terms of Unified Huntington's Disease Rating Scale Total Motor Score at 90 and 45 mg/day

Click here for additional data file. (31.4KB, docx)

Figure S3. A forest plot of sub‐group analysis comparing pridopidine to control arm in terms of Unified Huntington's Disease Rating Scale Modified Motor Score at 90 and 45 mg/day

Click here for additional data file. (108.4KB, docx)

Figure S4. A forest plot of sub‐group analysis comparing pridopidine to control arm in terms of Unified Huntington's Disease Rating Scale Total Motor Score after 4, 12, and 26 weeks of follow‐up

Click here for additional data file. (135.5KB, docx)

Figure S5. A forest plot of sub‐group analysis comparing pridopidine to control arm in terms of Unified Huntington's Disease Rating Scale Modified Motor Score after 4 and 12 weeks of follow‐up

Click here for additional data file. (105.5KB, docx)

Table S1. Shows reasons for study exclusion during screening for our meta‐analysis

Click here for additional data file. (23.2KB, docx)

Table S2. Shows the results of risk of bias assessment of included studies

Click here for additional data file. (19.7KB, docx)

Table S3. Subgroup analysis comparing pridopidine to control arm in safety outcomes at 90 and 45 mg/day

Click here for additional data file. (21.4KB, docx)

Table S4. Shows the results of the sensitivity analysis

Click here for additional data file. (21.3KB, docx)

Acknowledgment

We thank Dr. Ibrahim A. Abdelhaleem for facilitating data collection.

Relevant disclosures and conflicts of interest are listed at the end of this article.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Figure S1. Risk of bias graph

Click here for additional data file. (24.1KB, docx)

Figure S2. A forest plot of subgroup analysis comparing pridopidine to control arm in terms of Unified Huntington's Disease Rating Scale Total Motor Score at 90 and 45 mg/day

Click here for additional data file. (31.4KB, docx)

Figure S3. A forest plot of sub‐group analysis comparing pridopidine to control arm in terms of Unified Huntington's Disease Rating Scale Modified Motor Score at 90 and 45 mg/day

Click here for additional data file. (108.4KB, docx)

Figure S4. A forest plot of sub‐group analysis comparing pridopidine to control arm in terms of Unified Huntington's Disease Rating Scale Total Motor Score after 4, 12, and 26 weeks of follow‐up

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Figure S5. A forest plot of sub‐group analysis comparing pridopidine to control arm in terms of Unified Huntington's Disease Rating Scale Modified Motor Score after 4 and 12 weeks of follow‐up

Click here for additional data file. (105.5KB, docx)

Table S1. Shows reasons for study exclusion during screening for our meta‐analysis

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Table S2. Shows the results of risk of bias assessment of included studies

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Table S3. Subgroup analysis comparing pridopidine to control arm in safety outcomes at 90 and 45 mg/day

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Table S4. Shows the results of the sensitivity analysis

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