Body Language

Mr Ravi Jandhyala surveys academic and association journals to report on advances in research in medical aesthetics and related fields

Efficacy and safety of a novel botulinum toxin type A product for the treatment of moderate to severe glabellar lines: a randomized, double-blind, active-controlled multicenter study.

Won CH, Lee HM, Lee WS, Kang H, Kim BJ, Kim WS, Lee JH, Lee DH, Huh CH. Department of Dermatology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea. Dermatol Surg. 2013 Jan;39(1 Pt 2):171-8.

The aim of this study was to compare the efficacy and safety of NBoNT (Korean BoNT-A) and OBoNT (Onabot) for moderate to severe glabellar wrinkles.

This was a double-blind, randomised, active-controlled, phase III study. A total of 314 patients were randomised at a 1:1 ratio to receive 20U of toxin. The primary end point was the responder rate according to the investigator live assessment, at maximum frown at week four. Secondary end points were responder rates with frowning and at rest at weeks eight, 12 and 16, with photographic assessment by a panel of blinded raters four weeks after injection. Subjective satisfaction scores were also evaluated.

Four weeks after treatment, responder rates for maximum frown were 93.7% in the NBoNT group and 94.5% in the OBoNT group. For secondary end points, there was no significant difference between the two groups for any variable at any time point. Non-inferiority of NBoNT was confirmed. There were no serious adverse effects reported with either toxin.

The study authors concluded that NBoNT is equally as effective as OBoNT for the treatment of glabellar frown lines and that both toxins were well tolerated.

This study was carried out using the Korean BoNT-A, marketed as Neuronox, Botulift, Siax and Meditoxin. This product is currently not approved in the EU but has been approved for therapeutic indications in 22 countries, mostly in Asia, since 2006. It has been approved by the Korean FDA for treatment of glabellar frown lines.

Unlike incobotulinumtoxin A—a pure neurotoxin, free of complexing proteins and which can reasonably be described as ‘novel’—the structure of this BoNT-A appears identical to onabotulinumtoxin A in the authors description: “Both are composed of 100U of botulinum toxin, 0.5 mg of human serum albumin and 0.9mg of sodium chloride, which allows physicians to use both products in a similar manner.”

It would be difficult to see any real differentiators between this BoNT-A and Onabot. The study has proven non-inferiority in the treatment of glabellar frown lines, but the product appears to be a copy of one of the older BoNT-A’s. It would be interesting to see how this paper can support an inevitable application in the EU for glabellar wrinkles. If performance of the product convinces the EU to grant it a licence, the next important consideration would be its cost-effectiveness in relation to the other, currently marketed, BoNT-A’s. I am sure the aesthetics community will be monitoring its progress through the local regulatory process.

Comparative study of the diffusion of five botulinum toxins type-A in five dosages of use: are there differences amongst the commercially-available products?

Costa A, Pegas Pereira ES, de Oliveira Pereira M, Calixto dos Santos FB, Favaro R, Stocco PL, Fávaro de Arruda LH. Pontifitial Catholic University of Campinas, Campinas/SP, Brazil. Dermatol Online J. 2012 Nov 15;18(11):2.

This study evaluated and compared the largest diameter of diffusion halos of five different doses of five commercially available BoNT-As—twenty-five adult female volunteers were involved. Products with 100 units (UI) and the product with 500 UI were reconstituted in a ratio of 1:2.5. The BoNT-A products were applied in five concentrations (1 U/2.5 U, 2 U/5 U, 3 U/7.5 U, 4 U/10 U and 5 U/12.5 U) and, after 30 days, a starch-iodine test was conducted to obtain the largest diameter of each halo.

For all BoNT-As, the study found that the higher the number of units used, the larger the diameter of the diffusion halo. Statistically significant differences (p<0.05), were observed between: the North American and Chinese BoNT-As for the three lowest doses; between the Korean and German BoNT-As for all doses; between the French and Chinese BoNT-As for the four highest doses; between the French and German BoNT-As for all doses; between the Chinese and German BoNT-As for the four highest doses; and between the North American and German BoNT-As for all doses (p<0.01).

Confusingly, the authors chose to refer to the products not by their product name, but by the country in which their manufacturer resides. This may be because the Korean and Chinese toxins have yet to be granted FDA approval and are still referred to by the generic name of “Clostridium Botulinum neurotoxin type A”. This use of the parent country of manufacturer’s origin appears to be the only way of differentiating each of the five from each other.

The observations are interesting and directly contradict previous findings where Abobot was found to move further than Onabot. This study found no difference between the diffusion halos. However, as before, little or no plausible explanation is given in the paper to account for the findings. The authors infer that spread may cause off-target muscles to be affected and raise the possibility of adverse events as a result.

The use of the upper back as a test area may confound those wishing to extrapolate the finding to the forehead or the face. The thickness of skin in the upper back allowed the authors to standardise an injection depth of 3mm—simply not possible in the face.
The use of anhidrotic halos for spread of each toxin cannot be used as surrogate marker for muscle activity. However, It would be interesting to compare these two markers of spread in a future study.

A consistent finding was that the halos increased with increasing dose for each of the products. This is a more straightforward finding to explain using simple diffusion down a concentration gradient and greater volume of product resulting in a wider halo to reach equilibrium. Interestingly, the German BoNT-A appeared consistently to be the product that migrated the least, having the smaller diffusion halos. Again, no explanation has been offered for this finding.

Overall, an interesting paper which has yielded some new data on the newer toxins whilst challenging a previously held idea on migration of the French toxin. It would be good to see this comparison in the forehead at single doses Also, if this paper is to be of value to aesthetic practitioners, off-target adverse events need to be collected in parallel with the other toxins when used for the aesthetics indication. It can be argued this is only endpoint of relevance to those at the cold face.

OnabotulinumtoxinA: a meta-analysis of duration of effect in the treatment of glabellar lines.

Glogau R, Kane M, Beddingfield F, Somogyi C, Lei X, Caulkins C, Gallagher C. Department of Dermatology, University of California at San Francisco, CA, USA. Dermatol Surg. 2012 Nov;38(11):1794-803.

In this paper, phase III clinical trials with similar designs were identified and their data pooled to ascertain duration of clinical effect of onabotulinumtoxinA in glabellar muscles. Duration was calculated using the Kaplan-Meier method for investigator-rated Facial Wrinkle scale (FWS) scores and subject global assessment (SGA) of glabellar lines. Responders were determined according to FWS score at maximum contraction and at repose 30 days after injection.

Data from four trials with 621 onabotulinumtoxinA-treated (20 U) subjects were analysed, 523 of which (84.2%) were identified as day-30 responders on the FWS at maximum contraction. Pooled median duration of effect for day-30 responders was 120 days for FWS at maximum contraction and 131 days for FWS at repose. Higher day 30 SGA scores were correlated with a greater duration of effect on dynamic, but not static lines.

Treatment of glabellar lines with 20 U of onabotulinumtoxinA resulted in sustained clinical benefit for four months in more than 50% of responders—subject satisfaction increased with duration of effect.

This publication focuses on the duration of action of Onabot in the treatment of glabellar frown lines. The official data sheet on Onabot states: “Improvement of severity of glabellar lines generally occurs within one week after treatment. The effect was demonstrated for up to four months after injection.” Initial reading of this data sheet implies that the effect of Onabot in the average patient treated for moderate to severe glabellar frown lines will last only four months, and frown lines would return to baseline beyond this point.

Interestingly the pooled analysis published in this study shows that half the subjects continue to have a benefit from their treatment at four months. It might be interesting to see how statistical modeling might show a comparison between the different products in this respect.

Improving Consent Procedures and Evaluation of Treatment Success in Cosmetic Use of IncobotulinumtoxinA: An Assessment of the Treat-to-Goal Approach.
Jandhyala R. The Jandhyala Institute, Banbury, Oxon, UK. J Drugs Dermatol. 2013 Jan 1;12(1):72-8.

Despite an increasing number of patients undergoing aesthetic BoNT-A procedures, a standardised, objective means of setting treatment goals and measuring the success of treatment is lacking. Treat-To-Goal (TTG) is a new approach to consent that uses the Merz Aesthetics Scale to set objectively defined start points and treatment goals, to better inform the consent process and provide a means of measuring the success of treatment.

The aim of this study was to evaluate the TTG approach versus standard consent procedures in terms of patient understanding of the risks and benefits of treatment. It was undertaken in two phases among consecutive patients presenting for BoNT-A treatment. Phase one consisted of a crossover comparison of patient satisfaction with standard consent versus the TTG approach (n=20).

Patient understanding of the likely outcomes and risks associated with treatment following consent and their overall preference were assessed using 10-point visual analogue scales (VAS). Phase two assigned patients to receive no treatment (n=10) or treatment with BoNT-A (n=54) following consent with the TTG approach. Patients were followed up 28 days later to assess whether the goals defined during consent had been met.

The TTG approach significantly improved patient understanding of outcomes of BoNT-A treatment compared with standard consent (P=.004 when standard consent assessed first and P=.002 when TTG assessed first).

All patients assessed preferred the TTG approach (median VAS score in favour of TTG: 7.0, P<.0001). Target improvements were successfully met or exceeded in at least one treatment area (forehead, glabellar lines or crow’s feet) in all patients treated with BoNT-A. In contrast, none of the untreated patients met their target improvements unless the target was defined as “no change”.

The TTG approach represents an improvement over standard consent in terms of the information provided to patients. Further investigation of this concept is warranted.

Essentially, this approach asks the practitioner to explore how well mutually agreed goals to the treatment can be achieved. This recognises that, as medical professionals, we aspire not only achieving any improvement but one that we intended to achieve.
It should therefore be possible to define this at the consent stage itself using the validated Merz Aesthetics Scale. This also gives the client absolute clarity on what they can expect from the treatment.

Informed consent is crucial ahead of any procedure. My TTG approach shows that using the scales at this stage provides the client with more information and consequently means they are more informed as to what can be achieved compared to a simple standard consent. The paper also offers a good guide as to number of grade improvement that can be achieved in the different areas of the face with Incobot.

Mr Ravi Jandhyala is a member of the Royal College of Surgeons and a founding member of UK Botulinum Toxin Group for Aesthetics. He is also on the Body Language editorial panel