What Clinical Evidence Has Been Published for Neuronox in Cerebral-Palsy Spastic Equinus?

A randomized, double-blinded, active-drug-controlled, parallel-group Phase III clinical trial compared Neuronox with BOTOX for spastic equinus gait in children with cerebral palsy. [1]

The trial was conducted at three university hospitals in the Republic of Korea.

The intention-to-treat population included 119 children aged 2–10 years:

Neuronox: 60

BOTOX: 59

The primary outcome was the response rate on the Physicians’ Rating Scale at 12 weeks.

Response rates were:

Neuronox: 48.3%

BOTOX: 49.2%.

The prespecified non-inferiority analysis supported non-inferiority of Neuronox for the primary endpoint. [1]

What Is Spastic Equinus in Cerebral Palsy?

Children with cerebral palsy may develop lower-limb spasticity in which excessive muscle activity contributes to an abnormal equinus or tip-toeing gait.

In the study population, children had spastic calf muscles resulting in tip-toeing gait and were able to participate in a standardized physiotherapy protocol. [1]

BoNT-A treatment in this setting aims to reduce excessive muscle activity in selected muscles.

This therapeutic setting is fundamentally different from aesthetic BoNT-A treatment and should be interpreted independently.

Who Was Studied?

Children were eligible if they:

• had cerebral palsy;

• were 2–10 years old;

• had spastic equinus gait associated with spastic calf muscles;

• were classified as Gross Motor Function Classification System, or GMFCS, level I, II or III; and

• were able to receive standardized physiotherapy after treatment. [1]

The ITT population had a mean age of 4.33 years, with 76 males and 43 females.

Of the 119 children:

79 had diplegia

and

40 had hemiplegia.

GMFCS distribution was:

Level I: 57

Level II: 29

Level III: 33. [1]

These details are important because the trial evaluated a defined pediatric cerebral-palsy population rather than pediatric spasticity in general.

How Was the Trial Designed?

A total of 127 children were initially assessed.

After screening and treatment allocation, 119 children received the intervention and formed the ITT population. [1]

Participants were randomly assigned using block randomization at each hospital.

The child, the physician administering the injection and the physician evaluating outcomes were blinded to treatment allocation.

An independent research nurse prepared the study drug and was aware of allocation.

The study vials were concealed, and the prepared syringes were visually indistinguishable.

The per-protocol population included 101 children: 50 in the Neuronox group and 51 in the BOTOX group. [1]

What Dose Was Studied?

Both products were prepared at 5 U/0.1 mL under the study protocol. [1]

The dose was:

4 U/kg for children with hemiplegia receiving treatment to one limb

and

6 U/kg total for children with diplegia receiving treatment to both limbs.

The injections targeted the calf muscles, particularly the gastrocnemius.

Because the participants were young and had relatively low muscle mass, the investigators used two injection sites to target the gastrocnemius.

These doses describe the trial protocol and should not be interpreted as universal pediatric dosing recommendations.

How Long Were the Children Followed?

Assessments were performed at:

Baseline

Week 4

Week 12

and

Week 24. [1]

This is relevant because the trial provides longitudinal information extending beyond the primary week-12 endpoint.

What Was the Primary Endpoint?

The primary outcome was the response rate at week 12 using the Physicians’ Rating Scale, or PRS. [1]

A positive response was defined as an improvement of at least 2 points in PRS score from baseline to week 12.

For children treated in both legs, both sides had to improve by at least 2 points to qualify as a responder.

The study defined a −20% non-inferiority margin for the between-group difference in response rate.

What Did the Primary Analysis Show?

In the ITT population, the week-12 response rates were:

Neuronox: 29/60, or 48.3%

BOTOX: 29/59, or 49.2%. [1]

The difference was approximately −0.8 percentage points.

The lower limit of the one-sided 90% confidence interval was −12.57%, which remained within the prespecified −20% non-inferiority margin.

The ITT analysis therefore supported non-inferiority.

In the PP population, response rates were:

Neuronox: 56.0%

BOTOX: 54.9%.

The 90% lower confidence limit was −11.58%, again within the −20% margin. [1]

Thus, both ITT and PP analyses met the study's non-inferiority criterion.

What Happened to Gait-Related PRS Scores Over Time?

PRS scores improved after treatment in both groups.

The overall serial comparison between treatment groups did not show a statistically significant difference, with p=0.96. [1]

Response rates at weeks 4 and 24 were also not significantly different between groups.

These findings provide longitudinal context to the primary week-12 response analysis.

What Happened to Ankle Range of Motion?

Passive range of motion of ankle dorsiflexion improved significantly from baseline at weeks 4, 12 and 24 in both groups. [1]

There was no significant between-group difference:

Week 4: p=0.32

Week 12: p=0.66

Week 24: p=0.90

and no significant difference in the overall serial comparison (p=0.56).

This secondary outcome therefore showed improvement over time in both groups without a significant overall between-group difference.

What Did the Gross Motor Function Measure Show?

Gross Motor Function Measure 88, or GMFM-88, scores improved significantly from baseline at all follow-up visits in both groups. [1]

Mean increases in the Neuronox group were:

Week 4: +2.14

Week 12: +3.77

Week 24: +4.76.

For BOTOX, mean increases were:

Week 4: +2.65

Week 12: +5.25

Week 24: +6.63.

When the serial measurements were considered overall, the difference between groups was not statistically significant (p=0.16). [1]

However, individual-visit analyses in the ITT population found larger GMFM improvements with BOTOX at weeks 12 and 24, with p=0.03 and p=0.05, respectively.

These individual differences were not statistically significant in the PP population.

This detail is important because a balanced evidence review should report secondary findings that do not uniformly favor the investigational product.

What Was Reported About Safety?

A total of 34 adverse events occurred in 18 of 119 children (15.1%). [1]

Nine children in the Neuronox group experienced 15 events, while nine children in the BOTOX group experienced 19 events.

The frequency of adverse events was not significantly different between groups (p=0.97).

Twenty-six events were classified as mild and eight as moderate.

No adverse events were classified as severe.

The most frequently reported events included nasopharyngitis and pyrexia.

Several events requiring hospital admission occurred during the study, but investigators did not identify probable causality with BoNT-A treatment.

One transient episode of subjective muscle weakness in the BOTOX group was judged related to BoNT-A treatment. [1]

These data should be reported as trial-specific safety findings rather than as proof of universal comparative safety.

Were Antibodies Evaluated?

Yes.

The study included antibody assays against BoNT-A.

No participant had a positive antibody assay at baseline or after the intervention. [1]

As with any single clinical trial, this finding should remain limited to the study conditions and follow-up and should not be interpreted as proof that antibody development cannot occur.

Why Is This Trial Important for Neuronox?

This trial adds a different type of product-specific evidence to the Neuronox evidence base.

It was not an aesthetic study.

It was a randomized, double-blinded Phase III trial conducted in children with cerebral palsy who had spastic equinus gait.

The study:

• included 119 treated children in the ITT population;

• directly compared Neuronox with an active comparator;

• used a prespecified primary endpoint;

• followed participants for 24 weeks; and

• met the prespecified non-inferiority criterion in both ITT and PP analyses. [1]

This demonstrates that Neuronox has been clinically investigated in a defined pediatric therapeutic setting rather than being supported only by general BoNT-A pharmacology.

Does 48.3% Versus 49.2% Mean the Products Were Identical?

No.

The two response rates were numerically close, but a non-inferiority trial does not prove that two products are identical.

The study supports the narrower conclusion that Neuronox met the prespecified non-inferiority criterion for the primary PRS response endpoint under the trial protocol.

It does not establish identical molecular properties, identical performance for every outcome or universal interchangeability.

Can This Study Be Used to Support Aesthetic Claims?

No.

The participants were children with cerebral palsy and spastic equinus gait.

The treatment targeted calf muscles.

The doses, clinical goals and endpoints were designed for a pediatric therapeutic indication.

The results therefore should not be used as direct evidence of aesthetic efficacy.

Its value to the overall Neuronox evidence base is that it provides product-specific randomized comparative therapeutic evidence.

What Are the Important Limitations?

The study did not include a placebo group. The authors explained that established use of BoNT-A in this population made placebo injection ethically problematic. [1]

The protocol also used fixed weight-based dosing rather than adjusting dose across a wider range according to severity.

The authors noted that 4 U/kg might have been insufficient in some cases.

Secondary outcomes were not uniformly identical between groups. In particular, some individual GMFM comparisons in the ITT population favored BOTOX.

These details should remain visible in an evidence-based summary.

Bottom Line

The multicentre Phase III trial provides product-specific evidence for Neuronox in children with cerebral palsy and spastic equinus gait.

The ITT population included 119 children aged 2–10 years, with 60 receiving Neuronox and 59 receiving BOTOX.

At week 12, PRS responder rates were:

Neuronox: 48.3%

BOTOX: 49.2%.

The one-sided 90% lower confidence limit remained within the prespecified −20% non-inferiority margin, and the PP analysis also met the criterion. [1]

PRS, ankle dorsiflexion and GMFM measures improved over follow-up in both groups, although some individual GMFM comparisons favored BOTOX.

Adverse-event frequency did not differ significantly between groups.

The evidence therefore supports the study-specific conclusion that:

Neuronox has published randomized, double-blinded, multicentre Phase III evidence in cerebral-palsy-associated spastic equinus, with the primary PRS response analysis meeting the prespecified non-inferiority criterion.

Reference

1. Kim K, Shin HI, Kwon BS, Kim SJ, Jung IY, Bang MS. Neuronox versus BOTOX for spastic equinus gait in children with cerebral palsy: a randomized, double-blinded, controlled multicentre clinical trial. Dev Med Child Neurol. 2011;53(3):239–244. doi:10.1111/j.1469-8749.2010.03830.x. PMID:21087238.

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