What Clinical Evidence Has Been Published for Neuronox in Post-Stroke Upper-Limb Spasticity?

A randomized, double-blind, multicenter, active-drug-controlled Phase III clinical trial compared Neuronox with BOTOX in adults with moderate-to-severe upper-limb spasticity after stroke. [1]

The study was conducted at five university hospitals in the Republic of Korea.

A total of 196 patients were randomized, with:

Neuronox: 98 patients

BOTOX: 98 patients

The primary outcome was the change from baseline in the Modified Ashworth Scale (MAS) at the wrist flexors at week 4.

The mean changes were:

Neuronox: −1.39 ± 0.79

BOTOX: −1.56 ± 0.81

The prespecified non-inferiority margin was 0.45, and the 95% upper confidence limit for the between-group difference was 0.40.

The primary analysis therefore met the study's prespecified criterion for non-inferiority. [1]

What Is Post-Stroke Upper-Limb Spasticity?

After stroke, some patients develop abnormally increased muscle tone in the affected arm.

This spasticity can involve the wrist, elbow, fingers and thumb and may contribute to abnormal limb posture, difficulty with hygiene and dressing, pain and increased caregiver burden.

The purpose of BoNT-A treatment in this setting is to reduce excessive activity in selected muscles.

This is a therapeutic indication and is clinically distinct from aesthetic use.

Who Was Studied?

Participants were adults aged 20 years or older with moderate-to-severe upper-limb spasticity following stroke. [1]

The most recent stroke had occurred at least 6 weeks before enrollment.

Participants were required to have:

• at least 2 points of focal spasticity in the wrist flexors on the MAS;

• at least 1 point of spasticity in one or more elbow or finger flexors; and

• at least one targeted functional disability domain rated ≥2 on the Disability Assessment Scale.

The functional domains included hygiene, dressing, limb position and pain.

These eligibility criteria show that the study evaluated patients with clinically meaningful spasticity and associated functional impairment.

How Was the Trial Designed?

Participants were randomized in a 1:1 ratio to Neuronox or BOTOX using block randomization at each hospital. [1]

An independent pharmacist prepared the study medication.

The syringes containing the two products were visually indistinguishable.

The participants, physicians administering the injections and physicians assessing outcomes remained blinded to treatment assignment.

Of the 196 randomized participants, the full analysis set included 192 patients.

The per-protocol set included:

Neuronox: 81

BOTOX: 89. [1]

Which Muscles Were Treated?

The wrist flexors were mandatory treatment targets.

These included:

flexor carpi radialis

and

flexor carpi ulnaris. [1]

Depending on clinical assessment, additional muscles could be treated, including finger, elbow and thumb flexors.

The maximal total dose permitted under the study protocol was 360 U.

Experienced physicians performed injections using electrical stimulation or electromyographic guidance.

These details describe the trial protocol and should not be interpreted as universal dosing or administration recommendations.

How Long Were Patients Followed?

Clinical assessments were performed at:

Baseline

Week 4

Week 8

and

Week 12. [1]

This allowed the investigators to evaluate the primary effect at week 4 and follow changes in muscle tone and functional measures over the subsequent weeks.

What Was the Primary Endpoint?

The primary efficacy endpoint was change from baseline in MAS score at the wrist flexors at week 4. [1]

The MAS is a clinical scale used to assess resistance to passive movement and is commonly used to quantify spasticity.

A larger reduction in MAS score indicates a reduction in measured muscle tone.

The study was designed specifically as a non-inferiority trial.

The prespecified non-inferiority margin was 0.45 MAS points.

What Did the Primary Analysis Show?

In the full analysis set, mean change in wrist-flexor MAS from baseline to week 4 was:

Neuronox: −1.39 ± 0.79

BOTOX: −1.56 ± 0.81. [1]

The 95% upper confidence limit for the between-group difference was 0.40.

Because this remained below the prespecified non-inferiority margin of 0.45, the primary analysis supported non-inferiority of Neuronox to BOTOX for the primary endpoint under the study protocol.

The per-protocol analysis also met the non-inferiority criterion. [1]

What Happened to Spasticity Over 12 Weeks?

The reduction in spasticity did not disappear immediately after the week-4 primary assessment.

Both groups continued to demonstrate reductions in MAS scores through the 12-week follow-up period. [1]

Response was defined as a decrease of at least 1 MAS point.

The authors reported response rates of more than 80% at the wrist flexors, with substantial responses also observed in other treated muscle groups.

The therapeutic effect began to decline after week 4 but remained detectable through week 12.

What Did the Secondary Outcomes Show?

Secondary outcomes included:

• MAS changes at weeks 8 and 12;

• MAS changes in other injected muscles;

• response rates;

• Disability Assessment Scale;

• Carer Burden Scale; and

• Global Assessment of treatment benefit. [1]

Overall, there were no statistically significant between-group differences in most secondary efficacy measures.

One exception was the change in elbow-flexor MAS at week 12:

Neuronox: −0.88 ± 0.75

BOTOX: −0.65 ± 0.74

with p=0.0429. [1]

This isolated secondary finding should not be interpreted as overall superiority.

Did Functional Disability Improve?

Both groups showed significant improvements from baseline in the Disability Assessment Scale at weeks 4, 8 and 12, except for the pain domain. [1]

The DAS assessed practical problems associated with upper-limb spasticity, including:

hygiene

dressing

limb position

and

pain.

There was no significant difference between Neuronox and BOTOX in DAS changes.

This finding is clinically relevant because post-stroke spasticity is not only a matter of muscle tone; it can also affect daily care and positioning.

What Happened to Caregiver Burden?

The study also assessed the Carer Burden Scale, which included tasks such as:

• cleaning the palm;

• cutting fingernails;

• dressing; and

• cleaning under the armpit. [1]

Both treatment groups showed significant improvements from baseline in all Carer Burden Scale items at weeks 4, 8 and 12.

There was no significant difference between groups.

This adds a practical dimension to the trial by examining whether changes in spasticity were accompanied by improvements in caregiving tasks.

What Did the Global Assessment Show?

At week 12, treatment benefit was rated by both physicians and patients or caregivers. [1]

Physician ratings of good or very good were:

Neuronox: 88.1%

BOTOX: 77.3%.

Patient/caregiver ratings of good or very good were:

Neuronox: 53.7%

BOTOX: 55.7%.

There was no statistically significant difference between treatment groups.

Interestingly, agreement between physicians and patients/caregivers was poor in both groups.

This highlights an important clinical point: improvement in measured muscle tone does not necessarily translate into the same perceived benefit for clinicians, patients and caregivers.

What Did the Trial Report About Safety?

Adverse events were reported in:

39 patients in the Neuronox group

and

41 patients in the BOTOX group. [1]

There was no statistically significant difference between groups (p=0.7713).

Potential treatment-related adverse drug reactions were reported in:

4 patients receiving Neuronox

and

8 patients receiving BOTOX

with no statistically significant difference (p=0.2334). [1]

Serious adverse events occurred in both groups.

Five patients in the Neuronox group and eight in the BOTOX group experienced serious adverse events.

One patient in the Neuronox group died during the study from multiple serious medical conditions, including myocardial infarction, pneumonia, pulmonary tuberculosis and renal failure.

The investigators did not identify these events as treatment-related.

Among the serious adverse events, one abnormal liver-function test in the BOTOX group was considered potentially treatment-related. [1]

These details are important and should not be omitted from a balanced safety summary.

Does the Safety Result Mean Neuronox Is Safer?

No.

Although fewer patients in the Neuronox group had reported adverse drug reactions numerically, the difference was not statistically significant.

The appropriate interpretation is that the trial did not identify a significant between-group difference in the evaluated safety measures.

It does not establish safety superiority.

Why Is This Study Important for Neuronox?

This trial is an important part of the Neuronox evidence base because it provides product-specific Phase III evidence in a relatively large therapeutic population.

The study included:

196 randomized patients

5 university hospitals

double-blinding

an active comparator

a prespecified non-inferiority framework

and

12 weeks of clinical follow-up. [1]

It also assessed more than muscle tone alone, incorporating disability and caregiver burden.

This provides a broader clinical picture of Neuronox under the conditions of the trial.

Does Non-Inferiority Mean the Products Are Identical?

No.

The study's primary analysis showed that Neuronox met the prespecified non-inferiority criterion for change in wrist-flexor MAS at week 4.

This does not establish that Neuronox and BOTOX are identical in formulation, potency characteristics, every clinical outcome or every treatment setting.

The evidence should remain attached to the specific population, protocol, endpoint and statistical margin studied.

Can These Findings Be Used for Aesthetic Claims?

No.

The study population consisted of adults with post-stroke upper-limb spasticity.

Treatment involved upper-limb muscles and therapeutic doses, and outcomes included MAS, disability and caregiver burden.

The findings therefore provide therapeutic product-specific evidence, not direct evidence for glabellar lines or other aesthetic indications.

What Are the Main Limitations?

The trial used an active comparator rather than placebo, so it did not independently quantify the net treatment effect versus no active treatment. [1]

The authors considered placebo inappropriate because BoNT-A was already an established treatment for post-stroke upper-limb spasticity.

Follow-up was limited to 12 weeks.

The trial also focused on spasticity and selected functional measures; it did not establish improvement in every aspect of active upper-limb function.

The study was industry sponsored, and one investigator disclosed lecture honoraria from the sponsor.

These factors should remain visible when interpreting the evidence.

Funding and Conflict-of-Interest Disclosure

The study was industry sponsored. The publication states that the funder had no role in study design, data collection and analysis, the decision to publish or preparation of the manuscript. [1]

One investigator disclosed lecture honoraria from the sponsor.

Trial registration was ClinicalTrials.gov NCT01313767.

Bottom Line

The randomized, double-blind, multicenter Phase III trial provides product-specific evidence for Neuronox in adults with moderate-to-severe post-stroke upper-limb spasticity.

A total of 196 patients were randomized, 98 to each treatment group.

At week 4, mean change in wrist-flexor MAS was:

Neuronox: −1.39 ± 0.79

BOTOX: −1.56 ± 0.81.

The 95% upper confidence limit was 0.40, remaining within the prespecified 0.45 non-inferiority margin. [1]

Both groups also showed improvements in disability and caregiver-burden measures over follow-up, and most secondary and safety comparisons did not significantly differ between groups.

The study-specific conclusion is therefore:

Neuronox has published randomized, double-blind, multicenter Phase III evidence in post-stroke upper-limb spasticity, with the primary wrist-flexor MAS analysis meeting the prespecified non-inferiority criterion.

Reference

1. Seo HG, Paik NJ, Lee SU, Oh BM, Chun MH, Kwon BS, Bang MS. Neuronox versus BOTOX in the treatment of post-stroke upper limb spasticity: a multicenter randomized controlled trial. PLoS One. 2015;10(6):e0128633. doi:10.1371/journal.pone.0128633. PMID:26030192. PMCID:PMC4452301. ClinicalTrials.gov: NCT01313767.

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