Movement Disorders Vol. 20, No. 8, 2005, pp. 937–944 © 2005 Movement Disorder Society Retrospective Evaluation of the Dose of Dysport and BOTOX in the Management of Cervical Dystonia and Blepharospasm: The REAL DOSE Study Albert Marchetti, MD,1 Raf Magar,1* Leslie Findley, MD,2 Jan P. Larsen, MD,3 Zvezdan Pirtosek, MD,4 Evzen Råuzˇizˇka, MD,5 Robert Jech, MD,5 Jaroslaw Sławek, MD,6 and Fayyaz Ahmed, MD7 1Thomson Health Economics Research, Secaucus, New Jersey, USA 2Essex Neuroscience Unit, Romford, United Kingdom 3Central Hospital of Rogaland, Stavanger, Norway 4University Clinical Centre, Ljubljana, Slovenia 5Charles University, Prague, Czech Republic 6St. Adalbert Hospital, Gdansk, Poland 7Hull Royal Infirmary, Hull, United Kingdom Abstract: The purpose of this study is to evaluate the real- ranged from a low of 2:1 to a high of 11:1. Thirty-one percent world dose utilization of Dysport and BOTOX for cervical of patients fell into the Dysport-to-BOTOX ratio grouping of dystonia and blepharospasm. Six investigational sites (five 5:1 to less than 6:1; 30% of patients had a mean ratio of countries) were identified. Investigators abstracted utilization Dysport to BOTOX of 4:1 to less than 5:1; and only 21% of all data for patients who received Dysport before switching to patients evaluated fell into the Dysport-to-BOTOX ratio group- BOTOX or BOTOX before switching to Dysport. Patients were ing of 3:1 to less than 4:1. Results are consistent with United identified during scheduled clinic visits and selected if they met Kingdom labeling for botulinum toxins stating that units of study criteria, which included treatment for at least 2 consec- different serotype A toxins are not interchangeable and simple utive years (at least 1 year with Dysport or BOTOX, then dose-conversion factors are not applicable. © 2005 Movement switched and maintained on BOTOX or Dysport for at least Disorder Society another year). A total of 114 patients were included in the Key words: cervical dystonia; blepharospasm; botulinum assessment. Ratios of mean dose for Dysport to BOTOX toxin type A; dose ratio; adverse events Botulinum neurotoxin, produced by Clostridium bot- proteins help maintain the structure of the neurotoxin, ulinum, is a complex of proteins containing the neuro- which is similar for all serotypes; however, the overall toxin and one or more nontoxic proteins. The botulinum size of the protein complex depends on the nontoxic neurotoxin, which consists of a heavy chain of 100 kDa proteins present. Activation of the neurotoxin occurs and a light chain of 50 kDa linked by a single disulfide upon proteolytic cleavage into the heavy and light bond, is synthesized as a relatively inactive single-chain chains. polypeptide with a molecular mass of approximately 150 There are seven botulinum toxin serotypes (A, B, C, kDa but is the active part of the complex. The nontoxic D, E, F, and G), all of which inhibit acetylcholine re- lease, although their intracellular target proteins, the characteristics of their actions, and their potencies vary *Correspondence to: Raf Magar, 150 Meadowlands Parkway, Se- substantially. Botulinum neurotoxin type A has been the caucus, NJ, USA 07094. E-mail: [email protected] most widely studied serotype for therapeutic purposes. Received 24 February 2004; Revised 25 August 2004; Accepted 22 Two botulinum toxin type A serotypes are commercially October 2004 Published online 4 April 2005 in Wiley InterScience (www. available in Europe, BOTOX (Allergan, Inc., Irvine, CA) interscience.wiley.com). DOI: 10.1002/mds.20468 and Dysport (Ipsen Limited, Slough, Berkshire, UK), for 937 938 A. MARCHETTI ET AL. patients with movement disorders such as cervical dys- In a prospective, open-label pharmacoeconomic study tonia, blepharospasm, and hemifacial spasm. of 835 patients with dystonia who were treated at four The availability of multiple botulinum toxin products different movement disorder clinics in Germany, Dodel to treat dystonias has led to debate concerning the com- and coworkers found that the percentage response to parative effectiveness and safety as well as the dose- BOTOX was rated significantly higher than that to Dys- equivalency ratio that should be used in clinical practice. port (P Ͻ 0.001).14 The overall adverse event rate was There is growing debate as to whether a true dose- significantly higher after treatment with Dysport than equivalency ratio exists. with BOTOX (P Ͻ 0.001). These results suggest that the The two commercially available botulinum toxin type clinical effects of the two formulations are distinct and A serotypes have distinct numbers of units and amounts argue against applying a simple dose conversion. of botulinum neurotoxin protein. BOTOX contains less Dose ratios of Dysport to BOTOX, predetermined by than 5 ng of botulinum toxin type A in a 900-kDa study design, do not necessarily reflect real-world con- complex, whereas Dysport contains 12.5 ng of botulinum ditions and actual clinical utilization. Moreover, most of toxin type A in a 900-kDa preparation. This difference is the research evaluated therapeutic effectiveness and due to the different production methods of the two prod- treatment response on the basis of a single delivered ucts. Because they are typical biologics, their properties dose, which does not reflect actual clinical practice in in many respects (pharmacodynamics/ pharmacokinet- which multiple treatments are often administered. Un- ics) may be the reason for any differences observed. questionably, additional research is needed. Therefore, the protein load of Dysport is greater (12.5 To enhance understanding of current botulinum toxin ng), which may impact the risk of antibody formation use in real-world clinical practice settings and to contrib- compared to a less than 5-ng protein load for BOTOX. ute evidence to the debate surrounding product equiva- The BOTOX formulation contains sodium chloride, lence, a multinational observational study (Retrospective whereas Dysport contains lactose. The products also Evaluation of the Dose of Dysport and BOTOX in the contain different amounts of serum albumin. Each prod- Clinical Management of Cervical Dystonia and Blepha- uct’s distinct formulation results in a unique interaction rospasm [REAL DOSE]) was conducted in Europe, spe- with biologic systems after injection. The system is ex- cifically to evaluate long-term continuous drug utiliza- posed to different ingredients and different numbers of tion in terms of the actual per-patient, per-visit delivered molecules that likely influence local osmotic gradients doses of the available type A toxins, Dysport and BO- and diffusion. Mclellan and colleagues concluded that TOX, for the treatment of patients with cervical dystonia different preparations, because of their unique formula- and/or blepharospasm. The REAL DOSE Study was a tion and stability, are differentially affected by some of multicenter, retrospective, observational review of ran- these factors and that these differences might well con- domly selected medical records of patients in actual 1 tribute to the differences observed in their clinical use. clinical practices who had received Dysport and BOTOX It is clear from the literature and from clinical expe- consistent with a double-arm crossover design. rience that neither the formulations nor the units used to quantify the toxin activity of the two products are equiv- MATERIALS AND METHODS alent. The potential effects of such differences have not been adequately studied. Consequently, several attempts A prestudy assessment was undertaken by question- have been made to evaluate currently available formula- naire at eight potential investigational sites in Europe: (1) tions. Elston and Russell,2 followed by Foran and asso- to estimate the size of the population of patients who ciates3 and Aoki,4,5 demonstrated differences in the po- received Dysport and BOTOX for cervical dystonia tency and biologic activity of botulinum toxin serotypes, and/or blepharospasm in compliance with the study de- but the paucity of clinical data and ongoing unfounded sign, (2) to determine the accessibility of charts as well claims related to benefits and limitations of currently as the quality of medical records, and (3) to gauge marketed brands have led to confusion. In addition, at- interest and ability to contribute de-identified data to the tempts to relate product potency to a single arbitrary study. Six centers in five countries (United Kingdom, dose-conversion factor or ratio add to the confusion. Czech Republic, Norway, Poland, and Slovenia) passed Single-treatment cycle studies have shown equivalence site-screening criteria and were eligible for participation; in therapeutic effect or duration at a dose ratio ranging two centers failed site screening because they could not from 3:1 (Dysport-to-BOTOX units) to as high as 6:1 but provide information on the patient population of interest suggest differences in the incidence of adverse or cited constraints that would compromise the timely events.6–13 submission of data. Movement Disorders, Vol. 20, No. 8, 2005 DYSPORT AND BOTOX DOSING IN MOVEMENT DISORDERS 939 Investigators from eligible centers participated in a TABLE 1. Inclusion/exclusion criteria prestudy orientation session in which study objectives, Inclusion criteria methods, data elements, and endpoints were discussed The following requirements must all be met for entry into the and the protocol and case report form (CRF) was re- study: 1. Patient has a confirmed diagnosis of idiopathic cervical